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Readmissions rise with endovascular lower limb procedures
CHICAGO – Endovascular lower-extremity procedures were not associated with lower 30-day readmission rates compared with open surgery in a retrospective review of 7,089 patients.
All-cause, 30-day readmissions were actually higher with an endovascular approach at 12.3% vs. 9.6% for open procedures (Relative risk, 1.28; P = .0003).
Among all patients, an index diagnosis of gangrene was most predictive of readmission (RR, 1.89; P less than .0001), Dr. Todd R. Vogel said at the annual meeting of the Midwestern Vascular Surgical Society.
The data were compiled from 7,089 patients in the Cerner Health Facts database who were admitted for peripheral artery disease and elective lower extremity procedures (3,615 open; 3,474 endo) between September 2008 and March 2014. Their average age was 67.7 years, 44.7% were aged 70 years or older, 60% were men, and 21% were African American.
Older patients and men were significantly more likely to receive endovascular procedures (P less than .0001), said Dr. Vogel, chief of vascular surgery, University of Missouri Health System in Columbia.
Overall, 767 patients (11%) were readmitted (344 open; 423 endo), with gangrene accounting for 21.7% of readmissions.
Other index diagnoses associated with higher 30-day readmissions for all lower extremity procedures were fluid and electrolyte disorders, chronic anemia, lower extremity infection, heart failure, chronic kidney disease, and chronic pulmonary disease.
When stratified by procedure type, the reasons for readmission were very different within the same population of patients based on procedure type, Dr. Vogel said.
Patients who underwent an open procedure were more likely to be readmitted if they had heart failure (RR, 1.78; P less than .0001) or posthemorrhagic anemia (RR, 1.54: P = .006).
Infections – be they lower extremity infection, other infection, postoperative infection, or sepsis – were not predictive of readmission when documented at the index admission for the open cohort.
In contrast, chronic conditions were the major predictors of readmission for patients undergoing endovascular procedures, he said. They included chronic anemia (RR, 1.58; P less than .0001), chronic airway obstruction (RR, 1.36; P = .0095), chronic heart disease (RR, 1.33; P = .0019), chronic kidney disease (RR, 1.37; P = .0013), diabetes (RR, 1.34; P = .0012), and hypertension (RR, 1.27; P = .023).
Fluid and electrolyte disorders (RR, 1.65, P less than .0001) and lower extremity infections (RR, 1.57, P = .0016) were also significant predictors of readmission in the endovascular group.
To ensure there were no disparities between index and readmission diagnoses, a final analysis was performed by procedure type in the 767 readmissions. It confirmed that for the endovascular procedures, chronic problems are bringing patients back to the hospital and not necessarily complications from the procedure, whereas infections, device complications, and hemorrhage are the reasons open surgery patients return, Dr. Vogel said.
“The question is are chronic conditions associated with readmissions the fault of the intervention? As physicians can we hope to curb this in patients who have chronic problems and are then readmitted?” he said.
Some audience members argued that no matter if the patient had a chronic condition or not preoperatively, the responsibility rests with the surgeon because he or she opted to put the patient through an elective endovascular procedure and now they’re returning with chronic heart failure, for example.
Dr. Vogel said this was the first pass at the data and trying to understand what drives readmissions and that it’s possible an endovascular procedure could exacerbate a chronic condition, but that surgeons should take steps to mitigate readmission risk in those with known chronic conditions.
Other attendees questioned how many of the readmissions were planned, hinting that the readmissions may not be directly related to the endovascular technique.
Dr. Vogel said it was difficult using only the ICD-9 codes in the database to determine exactly how many readmissions were planned, but noted that further analyses are intended.
“Reasons for readmission can be exacerbation of chronic patient issues, as seen in the endovascular group, or may be secondary to later complications of the procedure such as wound infections and device complications, as seen after open bypass procedures,” he said in an interview. “Identifying patients with increased risk for readmission after vascular procedures may lead to more effective and higher quality care during the index hospitalization. Our future studies will focus on a more detailed, granular evaluation of these high-risk diagnoses groups through use of the electronic medical record.”
Dr. Vogel reported having no financial disclosures.
On Twitter @pwendl
CHICAGO – Endovascular lower-extremity procedures were not associated with lower 30-day readmission rates compared with open surgery in a retrospective review of 7,089 patients.
All-cause, 30-day readmissions were actually higher with an endovascular approach at 12.3% vs. 9.6% for open procedures (Relative risk, 1.28; P = .0003).
Among all patients, an index diagnosis of gangrene was most predictive of readmission (RR, 1.89; P less than .0001), Dr. Todd R. Vogel said at the annual meeting of the Midwestern Vascular Surgical Society.
The data were compiled from 7,089 patients in the Cerner Health Facts database who were admitted for peripheral artery disease and elective lower extremity procedures (3,615 open; 3,474 endo) between September 2008 and March 2014. Their average age was 67.7 years, 44.7% were aged 70 years or older, 60% were men, and 21% were African American.
Older patients and men were significantly more likely to receive endovascular procedures (P less than .0001), said Dr. Vogel, chief of vascular surgery, University of Missouri Health System in Columbia.
Overall, 767 patients (11%) were readmitted (344 open; 423 endo), with gangrene accounting for 21.7% of readmissions.
Other index diagnoses associated with higher 30-day readmissions for all lower extremity procedures were fluid and electrolyte disorders, chronic anemia, lower extremity infection, heart failure, chronic kidney disease, and chronic pulmonary disease.
When stratified by procedure type, the reasons for readmission were very different within the same population of patients based on procedure type, Dr. Vogel said.
Patients who underwent an open procedure were more likely to be readmitted if they had heart failure (RR, 1.78; P less than .0001) or posthemorrhagic anemia (RR, 1.54: P = .006).
Infections – be they lower extremity infection, other infection, postoperative infection, or sepsis – were not predictive of readmission when documented at the index admission for the open cohort.
In contrast, chronic conditions were the major predictors of readmission for patients undergoing endovascular procedures, he said. They included chronic anemia (RR, 1.58; P less than .0001), chronic airway obstruction (RR, 1.36; P = .0095), chronic heart disease (RR, 1.33; P = .0019), chronic kidney disease (RR, 1.37; P = .0013), diabetes (RR, 1.34; P = .0012), and hypertension (RR, 1.27; P = .023).
Fluid and electrolyte disorders (RR, 1.65, P less than .0001) and lower extremity infections (RR, 1.57, P = .0016) were also significant predictors of readmission in the endovascular group.
To ensure there were no disparities between index and readmission diagnoses, a final analysis was performed by procedure type in the 767 readmissions. It confirmed that for the endovascular procedures, chronic problems are bringing patients back to the hospital and not necessarily complications from the procedure, whereas infections, device complications, and hemorrhage are the reasons open surgery patients return, Dr. Vogel said.
“The question is are chronic conditions associated with readmissions the fault of the intervention? As physicians can we hope to curb this in patients who have chronic problems and are then readmitted?” he said.
Some audience members argued that no matter if the patient had a chronic condition or not preoperatively, the responsibility rests with the surgeon because he or she opted to put the patient through an elective endovascular procedure and now they’re returning with chronic heart failure, for example.
Dr. Vogel said this was the first pass at the data and trying to understand what drives readmissions and that it’s possible an endovascular procedure could exacerbate a chronic condition, but that surgeons should take steps to mitigate readmission risk in those with known chronic conditions.
Other attendees questioned how many of the readmissions were planned, hinting that the readmissions may not be directly related to the endovascular technique.
Dr. Vogel said it was difficult using only the ICD-9 codes in the database to determine exactly how many readmissions were planned, but noted that further analyses are intended.
“Reasons for readmission can be exacerbation of chronic patient issues, as seen in the endovascular group, or may be secondary to later complications of the procedure such as wound infections and device complications, as seen after open bypass procedures,” he said in an interview. “Identifying patients with increased risk for readmission after vascular procedures may lead to more effective and higher quality care during the index hospitalization. Our future studies will focus on a more detailed, granular evaluation of these high-risk diagnoses groups through use of the electronic medical record.”
Dr. Vogel reported having no financial disclosures.
On Twitter @pwendl
CHICAGO – Endovascular lower-extremity procedures were not associated with lower 30-day readmission rates compared with open surgery in a retrospective review of 7,089 patients.
All-cause, 30-day readmissions were actually higher with an endovascular approach at 12.3% vs. 9.6% for open procedures (Relative risk, 1.28; P = .0003).
Among all patients, an index diagnosis of gangrene was most predictive of readmission (RR, 1.89; P less than .0001), Dr. Todd R. Vogel said at the annual meeting of the Midwestern Vascular Surgical Society.
The data were compiled from 7,089 patients in the Cerner Health Facts database who were admitted for peripheral artery disease and elective lower extremity procedures (3,615 open; 3,474 endo) between September 2008 and March 2014. Their average age was 67.7 years, 44.7% were aged 70 years or older, 60% were men, and 21% were African American.
Older patients and men were significantly more likely to receive endovascular procedures (P less than .0001), said Dr. Vogel, chief of vascular surgery, University of Missouri Health System in Columbia.
Overall, 767 patients (11%) were readmitted (344 open; 423 endo), with gangrene accounting for 21.7% of readmissions.
Other index diagnoses associated with higher 30-day readmissions for all lower extremity procedures were fluid and electrolyte disorders, chronic anemia, lower extremity infection, heart failure, chronic kidney disease, and chronic pulmonary disease.
When stratified by procedure type, the reasons for readmission were very different within the same population of patients based on procedure type, Dr. Vogel said.
Patients who underwent an open procedure were more likely to be readmitted if they had heart failure (RR, 1.78; P less than .0001) or posthemorrhagic anemia (RR, 1.54: P = .006).
Infections – be they lower extremity infection, other infection, postoperative infection, or sepsis – were not predictive of readmission when documented at the index admission for the open cohort.
In contrast, chronic conditions were the major predictors of readmission for patients undergoing endovascular procedures, he said. They included chronic anemia (RR, 1.58; P less than .0001), chronic airway obstruction (RR, 1.36; P = .0095), chronic heart disease (RR, 1.33; P = .0019), chronic kidney disease (RR, 1.37; P = .0013), diabetes (RR, 1.34; P = .0012), and hypertension (RR, 1.27; P = .023).
Fluid and electrolyte disorders (RR, 1.65, P less than .0001) and lower extremity infections (RR, 1.57, P = .0016) were also significant predictors of readmission in the endovascular group.
To ensure there were no disparities between index and readmission diagnoses, a final analysis was performed by procedure type in the 767 readmissions. It confirmed that for the endovascular procedures, chronic problems are bringing patients back to the hospital and not necessarily complications from the procedure, whereas infections, device complications, and hemorrhage are the reasons open surgery patients return, Dr. Vogel said.
“The question is are chronic conditions associated with readmissions the fault of the intervention? As physicians can we hope to curb this in patients who have chronic problems and are then readmitted?” he said.
Some audience members argued that no matter if the patient had a chronic condition or not preoperatively, the responsibility rests with the surgeon because he or she opted to put the patient through an elective endovascular procedure and now they’re returning with chronic heart failure, for example.
Dr. Vogel said this was the first pass at the data and trying to understand what drives readmissions and that it’s possible an endovascular procedure could exacerbate a chronic condition, but that surgeons should take steps to mitigate readmission risk in those with known chronic conditions.
Other attendees questioned how many of the readmissions were planned, hinting that the readmissions may not be directly related to the endovascular technique.
Dr. Vogel said it was difficult using only the ICD-9 codes in the database to determine exactly how many readmissions were planned, but noted that further analyses are intended.
“Reasons for readmission can be exacerbation of chronic patient issues, as seen in the endovascular group, or may be secondary to later complications of the procedure such as wound infections and device complications, as seen after open bypass procedures,” he said in an interview. “Identifying patients with increased risk for readmission after vascular procedures may lead to more effective and higher quality care during the index hospitalization. Our future studies will focus on a more detailed, granular evaluation of these high-risk diagnoses groups through use of the electronic medical record.”
Dr. Vogel reported having no financial disclosures.
On Twitter @pwendl
AT MIDWESTERN VASCULAR 2015
Key clinical point: Endovascular procedures were not superior to open surgery in reducing 30-day readmissions in patients undergoing lower extremity procedures.
Major finding: All-cause 30-day readmissions were 12.3% for endovascular and 9.6% for open (P = .0003).
Data source: Retrospective study in 7,089 patients undergoing elective lower extremity procedures.
Disclosures: The research was supported by an award from the Agency for Healthcare Research and Quality. Dr. Vogel reported having no conflicts of interest.
MM drugs granted priority review
multiple myeloma
The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).
The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.
The designation shortens the review period from 10 months to 6 months.
Carfilzomib
Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.
Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.
The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.
Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.
Ixazomib
Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.
The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.
In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.
Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:
- TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
- TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
- TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.
Daratumumab
Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.
Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.
The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.
Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.
Daratumumab is under development by Janssen Research & Development, LLC.
Elotuzumab
Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.
The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.
The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.
The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.
Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.
Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities. 
multiple myeloma
The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).
The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.
The designation shortens the review period from 10 months to 6 months.
Carfilzomib
Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.
Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.
The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.
Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.
Ixazomib
Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.
The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.
In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.
Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:
- TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
- TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
- TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.
Daratumumab
Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.
Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.
The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.
Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.
Daratumumab is under development by Janssen Research & Development, LLC.
Elotuzumab
Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.
The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.
The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.
The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.
Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.
Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.
multiple myeloma
The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).
The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.
The designation shortens the review period from 10 months to 6 months.
Carfilzomib
Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.
Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.
The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.
Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.
Ixazomib
Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.
The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.
In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.
Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:
- TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
- TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
- TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.
Daratumumab
Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.
Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.
The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.
Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.
Daratumumab is under development by Janssen Research & Development, LLC.
Elotuzumab
Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.
The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.
The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.
The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.
Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.
Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.
Aspirin, hydrochlorothiazide okay in gout
It’s okay in most cases for gout patients to be on thiazide diuretics or low-dose aspirin, so long as hypouricemic therapy is adjusted as needed, according to rheumatologist and Cleveland Clinic professor Dr. Brian F. Mandell.
Coronary artery disease is common in gout, so patients benefit from inexpensive, well-tolerated, and effective treatments like thiazides for hypertension and 81 mg aspirin daily for cardioprotection, Dr. Mandell said at the annual Perspectives in Rheumatic Diseases conference held by Global Academy for Medical Education.
The concern, however, is that both can elevate serum uric acid. Observational and survey data suggest that the drugs may be associated with an increase in attacks, so some shy away from them in gout.
To make sense of the issue, the first thing to remember is that the drugs cause only “minimal elevations in serum uric acid. Serum urate can still be lowered to less than 6 mg/dL with appropriate therapy without stopping them,” Dr. Mandell said.
Low-dose aspirin raises serum urate by about 0.3 mg/dL. At 12.5 or 25 mg once a day – common hypertension doses – hydrochlorothiazide increases serum urate by 0.8 mg/dL or less in patients with normal renal function (Arthritis Rheum. 2012 Jan;64[1]:121-9).
“In patients with chronic gout treated with a xanthine oxidase inhibitor (allopurinol or febuxostat) to lower the serum urate” to recommended target levels below 6.0 mg/dL, “the small elevation in serum urate is unlikely to negate the clinical efficacy of these drugs when dosing is optimized,” Dr. Mandell wrote in an article that expands upon his presentation points (Cleve Clin J Med. 2014 Feb;81[2]:83-6).
Based on those considerations, “my practice in most patients is to use a thiazide if it helps to control the blood pressure and to adjust the dose of the hypouricemic therapy as needed to reduce the serum urate to the desired level. ... Continuing thiazide therapy and, if necessary, adjusting hypouricemic therapy will not worsen the control of the serum urate level or gouty arthritis, and in most patients will not complicate the management of gout.” In general, “when I add a thiazide to a patient’s regimen, I do not usually need to increase the dose of allopurinol significantly to keep the serum urate level below the desired target,” he said.
The approach is similar with low-dose aspirin. Because of its negligible effect on serum uric acid levels, it does not need to be stopped in hyperuricemia or gout. “Since patients with gout have a higher risk of having cardiovascular disease, metabolic syndrome, and chronic kidney disease, many will benefit from low-dose aspirin therapy,” he said.
Occasionally, it makes sense to switch from a thiazide to another hypertensive, such as losartan, in chronic, hypertensive gout patients with serum urate levels marginally above the precipitation threshold of 6.7 mg/dL. “Losartan is a weak uricosuric and can lower the serum urate level slightly, possibly making the addition of another hypouricemic agent unnecessary, while still controlling the blood pressure with a single pill,” Dr. Mandell said.
The decision “must be individualized, taking into consideration the efficacy and cost of the alternative antihypertensive drug, as well as the potential but as yet unproven cardiovascular and renal benefits of lowering the serum urate with a more potent hypouricemic to a degree not likely to be attained with losartan alone,” he said.
Dr. Mandell has been a consultant for Savient/Crealta, AstraZeneca, Regeneron, and Novartis. Global Academy for Medical Education and this news organization are owned by the same parent company.
It’s okay in most cases for gout patients to be on thiazide diuretics or low-dose aspirin, so long as hypouricemic therapy is adjusted as needed, according to rheumatologist and Cleveland Clinic professor Dr. Brian F. Mandell.
Coronary artery disease is common in gout, so patients benefit from inexpensive, well-tolerated, and effective treatments like thiazides for hypertension and 81 mg aspirin daily for cardioprotection, Dr. Mandell said at the annual Perspectives in Rheumatic Diseases conference held by Global Academy for Medical Education.
The concern, however, is that both can elevate serum uric acid. Observational and survey data suggest that the drugs may be associated with an increase in attacks, so some shy away from them in gout.
To make sense of the issue, the first thing to remember is that the drugs cause only “minimal elevations in serum uric acid. Serum urate can still be lowered to less than 6 mg/dL with appropriate therapy without stopping them,” Dr. Mandell said.
Low-dose aspirin raises serum urate by about 0.3 mg/dL. At 12.5 or 25 mg once a day – common hypertension doses – hydrochlorothiazide increases serum urate by 0.8 mg/dL or less in patients with normal renal function (Arthritis Rheum. 2012 Jan;64[1]:121-9).
“In patients with chronic gout treated with a xanthine oxidase inhibitor (allopurinol or febuxostat) to lower the serum urate” to recommended target levels below 6.0 mg/dL, “the small elevation in serum urate is unlikely to negate the clinical efficacy of these drugs when dosing is optimized,” Dr. Mandell wrote in an article that expands upon his presentation points (Cleve Clin J Med. 2014 Feb;81[2]:83-6).
Based on those considerations, “my practice in most patients is to use a thiazide if it helps to control the blood pressure and to adjust the dose of the hypouricemic therapy as needed to reduce the serum urate to the desired level. ... Continuing thiazide therapy and, if necessary, adjusting hypouricemic therapy will not worsen the control of the serum urate level or gouty arthritis, and in most patients will not complicate the management of gout.” In general, “when I add a thiazide to a patient’s regimen, I do not usually need to increase the dose of allopurinol significantly to keep the serum urate level below the desired target,” he said.
The approach is similar with low-dose aspirin. Because of its negligible effect on serum uric acid levels, it does not need to be stopped in hyperuricemia or gout. “Since patients with gout have a higher risk of having cardiovascular disease, metabolic syndrome, and chronic kidney disease, many will benefit from low-dose aspirin therapy,” he said.
Occasionally, it makes sense to switch from a thiazide to another hypertensive, such as losartan, in chronic, hypertensive gout patients with serum urate levels marginally above the precipitation threshold of 6.7 mg/dL. “Losartan is a weak uricosuric and can lower the serum urate level slightly, possibly making the addition of another hypouricemic agent unnecessary, while still controlling the blood pressure with a single pill,” Dr. Mandell said.
The decision “must be individualized, taking into consideration the efficacy and cost of the alternative antihypertensive drug, as well as the potential but as yet unproven cardiovascular and renal benefits of lowering the serum urate with a more potent hypouricemic to a degree not likely to be attained with losartan alone,” he said.
Dr. Mandell has been a consultant for Savient/Crealta, AstraZeneca, Regeneron, and Novartis. Global Academy for Medical Education and this news organization are owned by the same parent company.
It’s okay in most cases for gout patients to be on thiazide diuretics or low-dose aspirin, so long as hypouricemic therapy is adjusted as needed, according to rheumatologist and Cleveland Clinic professor Dr. Brian F. Mandell.
Coronary artery disease is common in gout, so patients benefit from inexpensive, well-tolerated, and effective treatments like thiazides for hypertension and 81 mg aspirin daily for cardioprotection, Dr. Mandell said at the annual Perspectives in Rheumatic Diseases conference held by Global Academy for Medical Education.
The concern, however, is that both can elevate serum uric acid. Observational and survey data suggest that the drugs may be associated with an increase in attacks, so some shy away from them in gout.
To make sense of the issue, the first thing to remember is that the drugs cause only “minimal elevations in serum uric acid. Serum urate can still be lowered to less than 6 mg/dL with appropriate therapy without stopping them,” Dr. Mandell said.
Low-dose aspirin raises serum urate by about 0.3 mg/dL. At 12.5 or 25 mg once a day – common hypertension doses – hydrochlorothiazide increases serum urate by 0.8 mg/dL or less in patients with normal renal function (Arthritis Rheum. 2012 Jan;64[1]:121-9).
“In patients with chronic gout treated with a xanthine oxidase inhibitor (allopurinol or febuxostat) to lower the serum urate” to recommended target levels below 6.0 mg/dL, “the small elevation in serum urate is unlikely to negate the clinical efficacy of these drugs when dosing is optimized,” Dr. Mandell wrote in an article that expands upon his presentation points (Cleve Clin J Med. 2014 Feb;81[2]:83-6).
Based on those considerations, “my practice in most patients is to use a thiazide if it helps to control the blood pressure and to adjust the dose of the hypouricemic therapy as needed to reduce the serum urate to the desired level. ... Continuing thiazide therapy and, if necessary, adjusting hypouricemic therapy will not worsen the control of the serum urate level or gouty arthritis, and in most patients will not complicate the management of gout.” In general, “when I add a thiazide to a patient’s regimen, I do not usually need to increase the dose of allopurinol significantly to keep the serum urate level below the desired target,” he said.
The approach is similar with low-dose aspirin. Because of its negligible effect on serum uric acid levels, it does not need to be stopped in hyperuricemia or gout. “Since patients with gout have a higher risk of having cardiovascular disease, metabolic syndrome, and chronic kidney disease, many will benefit from low-dose aspirin therapy,” he said.
Occasionally, it makes sense to switch from a thiazide to another hypertensive, such as losartan, in chronic, hypertensive gout patients with serum urate levels marginally above the precipitation threshold of 6.7 mg/dL. “Losartan is a weak uricosuric and can lower the serum urate level slightly, possibly making the addition of another hypouricemic agent unnecessary, while still controlling the blood pressure with a single pill,” Dr. Mandell said.
The decision “must be individualized, taking into consideration the efficacy and cost of the alternative antihypertensive drug, as well as the potential but as yet unproven cardiovascular and renal benefits of lowering the serum urate with a more potent hypouricemic to a degree not likely to be attained with losartan alone,” he said.
Dr. Mandell has been a consultant for Savient/Crealta, AstraZeneca, Regeneron, and Novartis. Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM THE ANNUAL PERSPECTIVES IN RHEUMATIC DISEASES
Traffic-related pollution linked to AML, not ALL, in kids
A French study has revealed an increased incidence of acute myeloid leukemia (AML) among children living close to heavily used roads.
The incidence of AML was 30% higher among children who lived within 150 m of heavily used roads and where the combined length of road sections
within this radius exceeded 260 m.
The researchers believe the association between AML and road proximity may be driven by traffic-related benzene exposure.
Previous research has shown an increased risk of leukemia among adults with a history of occupational exposure to benzene.
The current study did not suggest an increased risk of acute lymphoblastic leukemia (ALL) among children living closed to heavily used roads.
Jacqueline Clavel, MD, PhD, of INSERM in Paris, France, and her colleagues reported these findings in the American Journal of Epidemiology.
The team analyzed 2760 cases of leukemia diagnosed in children younger than 15 years of age in metropolitan France between 2002 and 2007, including 418 cases of AML and 2275 cases of ALL.
The researchers compared these cases to a contemporary sample of 30,000 control children representative of the metropolitan population.
The data showed that neither distance from the nearest major road(s) nor the length of major roads within 150 m of a child’s residence was associated with ALL.
However, there was an association for AML. For children whose home was less than 150 m from the nearest major road(s), the odds ratio (OR) was 1.2.
When the total length of major road(s) within 150 m from the child’s residence was 257-308 m (second tertile) or 309 m or greater (third tertile), the OR was 1.3. When the total length of major roads was 1-256 m (first tertile), the OR was 0.90.
The researchers noted that traffic-related nitrogen dioxide concentration was not associated with ALL or AML. But their data indicated that benzene concentration was associated with AML.
To assess this potential association, the team studied the Île-de-France region of Paris, the most urbanized region, for which the mean annual concentration of benzene, mainly from road traffic, was estimated in the vicinity of each residence.
The median estimated benzene concentration for controls living in the Île-de-France region was 1.3 μg/m3 (range, 0.3 to 8.5 μg/m3). And the length of major roads within 150 m of a child’s residence was positively and significantly correlated with log benzene concentration (r=0.3, P<0.001).
So it followed that exposure to an estimated benzene concentration greater than the median was associated with AML (OR=1.6).
The researchers also used a composite variable based on the estimated benzene concentration and the length of major roads around a child’s residence.
The association with AML was largest among children with at least 309 m of major roads within 150 m of their residence and estimated benzene concentrations of 1.3 μg/m3 or greater (OR=2.2).
The researchers said these results support a role for traffic-related benzene exposure in the etiology of childhood AML.
A French study has revealed an increased incidence of acute myeloid leukemia (AML) among children living close to heavily used roads.
The incidence of AML was 30% higher among children who lived within 150 m of heavily used roads and where the combined length of road sections
within this radius exceeded 260 m.
The researchers believe the association between AML and road proximity may be driven by traffic-related benzene exposure.
Previous research has shown an increased risk of leukemia among adults with a history of occupational exposure to benzene.
The current study did not suggest an increased risk of acute lymphoblastic leukemia (ALL) among children living closed to heavily used roads.
Jacqueline Clavel, MD, PhD, of INSERM in Paris, France, and her colleagues reported these findings in the American Journal of Epidemiology.
The team analyzed 2760 cases of leukemia diagnosed in children younger than 15 years of age in metropolitan France between 2002 and 2007, including 418 cases of AML and 2275 cases of ALL.
The researchers compared these cases to a contemporary sample of 30,000 control children representative of the metropolitan population.
The data showed that neither distance from the nearest major road(s) nor the length of major roads within 150 m of a child’s residence was associated with ALL.
However, there was an association for AML. For children whose home was less than 150 m from the nearest major road(s), the odds ratio (OR) was 1.2.
When the total length of major road(s) within 150 m from the child’s residence was 257-308 m (second tertile) or 309 m or greater (third tertile), the OR was 1.3. When the total length of major roads was 1-256 m (first tertile), the OR was 0.90.
The researchers noted that traffic-related nitrogen dioxide concentration was not associated with ALL or AML. But their data indicated that benzene concentration was associated with AML.
To assess this potential association, the team studied the Île-de-France region of Paris, the most urbanized region, for which the mean annual concentration of benzene, mainly from road traffic, was estimated in the vicinity of each residence.
The median estimated benzene concentration for controls living in the Île-de-France region was 1.3 μg/m3 (range, 0.3 to 8.5 μg/m3). And the length of major roads within 150 m of a child’s residence was positively and significantly correlated with log benzene concentration (r=0.3, P<0.001).
So it followed that exposure to an estimated benzene concentration greater than the median was associated with AML (OR=1.6).
The researchers also used a composite variable based on the estimated benzene concentration and the length of major roads around a child’s residence.
The association with AML was largest among children with at least 309 m of major roads within 150 m of their residence and estimated benzene concentrations of 1.3 μg/m3 or greater (OR=2.2).
The researchers said these results support a role for traffic-related benzene exposure in the etiology of childhood AML.
A French study has revealed an increased incidence of acute myeloid leukemia (AML) among children living close to heavily used roads.
The incidence of AML was 30% higher among children who lived within 150 m of heavily used roads and where the combined length of road sections
within this radius exceeded 260 m.
The researchers believe the association between AML and road proximity may be driven by traffic-related benzene exposure.
Previous research has shown an increased risk of leukemia among adults with a history of occupational exposure to benzene.
The current study did not suggest an increased risk of acute lymphoblastic leukemia (ALL) among children living closed to heavily used roads.
Jacqueline Clavel, MD, PhD, of INSERM in Paris, France, and her colleagues reported these findings in the American Journal of Epidemiology.
The team analyzed 2760 cases of leukemia diagnosed in children younger than 15 years of age in metropolitan France between 2002 and 2007, including 418 cases of AML and 2275 cases of ALL.
The researchers compared these cases to a contemporary sample of 30,000 control children representative of the metropolitan population.
The data showed that neither distance from the nearest major road(s) nor the length of major roads within 150 m of a child’s residence was associated with ALL.
However, there was an association for AML. For children whose home was less than 150 m from the nearest major road(s), the odds ratio (OR) was 1.2.
When the total length of major road(s) within 150 m from the child’s residence was 257-308 m (second tertile) or 309 m or greater (third tertile), the OR was 1.3. When the total length of major roads was 1-256 m (first tertile), the OR was 0.90.
The researchers noted that traffic-related nitrogen dioxide concentration was not associated with ALL or AML. But their data indicated that benzene concentration was associated with AML.
To assess this potential association, the team studied the Île-de-France region of Paris, the most urbanized region, for which the mean annual concentration of benzene, mainly from road traffic, was estimated in the vicinity of each residence.
The median estimated benzene concentration for controls living in the Île-de-France region was 1.3 μg/m3 (range, 0.3 to 8.5 μg/m3). And the length of major roads within 150 m of a child’s residence was positively and significantly correlated with log benzene concentration (r=0.3, P<0.001).
So it followed that exposure to an estimated benzene concentration greater than the median was associated with AML (OR=1.6).
The researchers also used a composite variable based on the estimated benzene concentration and the length of major roads around a child’s residence.
The association with AML was largest among children with at least 309 m of major roads within 150 m of their residence and estimated benzene concentrations of 1.3 μg/m3 or greater (OR=2.2).
The researchers said these results support a role for traffic-related benzene exposure in the etiology of childhood AML.
CHADS2 Variant Calculates Stroke Risk in Heart Failure Patients
NEW YORK - A variant of the CHADS2 score that's used to estimate ischemic stroke risk in patients with atrial fibrillation (AF) is also modestly accurate in heart failure patients, even in those without AF, researchers say. The variant, CHA2DS2-VASc, calculates stroke risk based on 10 possible points with higher scores indicating higher risk.
Line Melgaard from Aalborg University in Denmark and colleagues used three Danish nationwide registries to investigate whether the CHA2DS2-VASc score could predict ischemic stroke, thromboembolism, and death in patients with heart failure without AF as effectively as it does in patients with AF.
Patients with heart failure had a high risk of all three outcomes, whether or not AF was present, and the CHA2DS2-VASc score modestly predicted these endpoints at one-year and five-year follow-up (C statistics, 0.67 and 0.69, respectively).
Heart failure patients without AF whose CHA2DS2-VASc score was 4 or higher had increased risks of ischemic stroke, thromboembolism, and death in a manner comparable to patients with AF, according to the August 30 JAMA online report.
The negative predictive value (NPV) was around 90% at one-year follow-up for all three outcomes, although NPVs were strongly attenuated by the five-year follow-up.
"In our study, one of our principal findings was that the absolute risk of ischemic stroke among patients without AF was about 1.5% per year or higher with CHA2DS2-VASc scores of 2 or higher, with associated five-year absolute ischemic stroke risks in excess of 4% or more," the researchers noted. This risk level would be sufficient to prompt initiation of long-term anticoagulation in patients with AF, they say.
"The poor prognosis of atrial fibrillation for ischemic stroke and death in patients with heart failure was evident in our study and expected," Melgaard said. "But the observation that additional risk factors in patients with heart failure are particularly significant among those without atrial fibrillation is an important and (to some extent) unexpected result."
"I hope physicians will recognize that patients with heart failure and sinus rhythm have an increased risk of ischemic stroke, and that some subgroups within this population most likely need thromboprophylaxis," Melgaard concluded. "Especially patients with multiple comorbidities (high CHA2DS2-VASc score) need attention in the clinic."
NEW YORK - A variant of the CHADS2 score that's used to estimate ischemic stroke risk in patients with atrial fibrillation (AF) is also modestly accurate in heart failure patients, even in those without AF, researchers say. The variant, CHA2DS2-VASc, calculates stroke risk based on 10 possible points with higher scores indicating higher risk.
Line Melgaard from Aalborg University in Denmark and colleagues used three Danish nationwide registries to investigate whether the CHA2DS2-VASc score could predict ischemic stroke, thromboembolism, and death in patients with heart failure without AF as effectively as it does in patients with AF.
Patients with heart failure had a high risk of all three outcomes, whether or not AF was present, and the CHA2DS2-VASc score modestly predicted these endpoints at one-year and five-year follow-up (C statistics, 0.67 and 0.69, respectively).
Heart failure patients without AF whose CHA2DS2-VASc score was 4 or higher had increased risks of ischemic stroke, thromboembolism, and death in a manner comparable to patients with AF, according to the August 30 JAMA online report.
The negative predictive value (NPV) was around 90% at one-year follow-up for all three outcomes, although NPVs were strongly attenuated by the five-year follow-up.
"In our study, one of our principal findings was that the absolute risk of ischemic stroke among patients without AF was about 1.5% per year or higher with CHA2DS2-VASc scores of 2 or higher, with associated five-year absolute ischemic stroke risks in excess of 4% or more," the researchers noted. This risk level would be sufficient to prompt initiation of long-term anticoagulation in patients with AF, they say.
"The poor prognosis of atrial fibrillation for ischemic stroke and death in patients with heart failure was evident in our study and expected," Melgaard said. "But the observation that additional risk factors in patients with heart failure are particularly significant among those without atrial fibrillation is an important and (to some extent) unexpected result."
"I hope physicians will recognize that patients with heart failure and sinus rhythm have an increased risk of ischemic stroke, and that some subgroups within this population most likely need thromboprophylaxis," Melgaard concluded. "Especially patients with multiple comorbidities (high CHA2DS2-VASc score) need attention in the clinic."
NEW YORK - A variant of the CHADS2 score that's used to estimate ischemic stroke risk in patients with atrial fibrillation (AF) is also modestly accurate in heart failure patients, even in those without AF, researchers say. The variant, CHA2DS2-VASc, calculates stroke risk based on 10 possible points with higher scores indicating higher risk.
Line Melgaard from Aalborg University in Denmark and colleagues used three Danish nationwide registries to investigate whether the CHA2DS2-VASc score could predict ischemic stroke, thromboembolism, and death in patients with heart failure without AF as effectively as it does in patients with AF.
Patients with heart failure had a high risk of all three outcomes, whether or not AF was present, and the CHA2DS2-VASc score modestly predicted these endpoints at one-year and five-year follow-up (C statistics, 0.67 and 0.69, respectively).
Heart failure patients without AF whose CHA2DS2-VASc score was 4 or higher had increased risks of ischemic stroke, thromboembolism, and death in a manner comparable to patients with AF, according to the August 30 JAMA online report.
The negative predictive value (NPV) was around 90% at one-year follow-up for all three outcomes, although NPVs were strongly attenuated by the five-year follow-up.
"In our study, one of our principal findings was that the absolute risk of ischemic stroke among patients without AF was about 1.5% per year or higher with CHA2DS2-VASc scores of 2 or higher, with associated five-year absolute ischemic stroke risks in excess of 4% or more," the researchers noted. This risk level would be sufficient to prompt initiation of long-term anticoagulation in patients with AF, they say.
"The poor prognosis of atrial fibrillation for ischemic stroke and death in patients with heart failure was evident in our study and expected," Melgaard said. "But the observation that additional risk factors in patients with heart failure are particularly significant among those without atrial fibrillation is an important and (to some extent) unexpected result."
"I hope physicians will recognize that patients with heart failure and sinus rhythm have an increased risk of ischemic stroke, and that some subgroups within this population most likely need thromboprophylaxis," Melgaard concluded. "Especially patients with multiple comorbidities (high CHA2DS2-VASc score) need attention in the clinic."
Low-Dose Screening CT for High-Risk NSCLC/SCLC: The Providence VA’s Experience
Background: There are about 200,000 new cases of lung cancer each year in the U.S. and about 150,000 deaths. Lung cancer is the second most common malignancy but the most common cause of cancer deaths. In 2010, the National Lung Screening Trial described a 20.3% reduction in lung cancer mortality in high-risk patients who were screened by CT scan. In 2012, guidelines were set forth by multiple groups. The National Comprehensive Cancer Network encouraged low-dose CT screening for patients aged 55 to 75 years, ≥ 30 pack-years of smoking, or smoking cessation within 15 years.
Methods: In late 2013, screening was implemented at the Providence VA Medical Center (PVAMC); a rise in the incidence of early stage lung cancer was anticipated. We reviewed the number and stages of cases of non-small cell (NSCLC) and small cell (SCLC) lung cancer in 2012, 2013 (mostly pre-screening), 2014 (screening), and 2015 (4 months of screening).
Results: In 2012 there were 23 cases of NSCLC (5 stage I; 5 stage II; 8 stage III; 2 stage IV; 3 unknown) and 4 cases of SCLC (extensive). In 2013 there were 42 cases of NSCLC (9 stage I; 2 stage II; 10 stage III [1 screened]; 17 stage IV; 4 unknown [1 screened]) and 9 cases of SCLC (1 lim-ited, 8 extensive). In 2014, there were 54 cases of NSCLC (15 stage I [5 screened]; 10 stage II [2 screened]; 11 stage III [3 screened]; 14 stage IV [1 screened]; and 4 unknown) and 5 cases of SCLC (5 extensive). In the first 7 months of 2015, there were 36 cases of NSCLC (13 stage I [10 screened]; 5 stage II [3 screened]; 7 stage III [3 screened]; 8 stage IV [1 screened]; and 3 unknown [1 screened]) and 1 SCLC (extensive) not screened and 1 SCLC (limited) screened.
Discussion: The total number of lung cancer cases has increased with screening (36 in 2012; 51 in 2013; 59 in 2014; 38 in 7 months of 2015). With screening in 2014 there were more cases of late stage disease (NSCLC stage III/IV) than anticipated. In the first 7 months of 2015 72% of screened patients were stage I/II, 22% were stage III/IV, and 6% were unknown. As time progresses and the same patients are screened yearly, the percentage of early stage cases should increase and late stages decrease. It will be worthwhile to reevaluate these data over the next several years.
Background: There are about 200,000 new cases of lung cancer each year in the U.S. and about 150,000 deaths. Lung cancer is the second most common malignancy but the most common cause of cancer deaths. In 2010, the National Lung Screening Trial described a 20.3% reduction in lung cancer mortality in high-risk patients who were screened by CT scan. In 2012, guidelines were set forth by multiple groups. The National Comprehensive Cancer Network encouraged low-dose CT screening for patients aged 55 to 75 years, ≥ 30 pack-years of smoking, or smoking cessation within 15 years.
Methods: In late 2013, screening was implemented at the Providence VA Medical Center (PVAMC); a rise in the incidence of early stage lung cancer was anticipated. We reviewed the number and stages of cases of non-small cell (NSCLC) and small cell (SCLC) lung cancer in 2012, 2013 (mostly pre-screening), 2014 (screening), and 2015 (4 months of screening).
Results: In 2012 there were 23 cases of NSCLC (5 stage I; 5 stage II; 8 stage III; 2 stage IV; 3 unknown) and 4 cases of SCLC (extensive). In 2013 there were 42 cases of NSCLC (9 stage I; 2 stage II; 10 stage III [1 screened]; 17 stage IV; 4 unknown [1 screened]) and 9 cases of SCLC (1 lim-ited, 8 extensive). In 2014, there were 54 cases of NSCLC (15 stage I [5 screened]; 10 stage II [2 screened]; 11 stage III [3 screened]; 14 stage IV [1 screened]; and 4 unknown) and 5 cases of SCLC (5 extensive). In the first 7 months of 2015, there were 36 cases of NSCLC (13 stage I [10 screened]; 5 stage II [3 screened]; 7 stage III [3 screened]; 8 stage IV [1 screened]; and 3 unknown [1 screened]) and 1 SCLC (extensive) not screened and 1 SCLC (limited) screened.
Discussion: The total number of lung cancer cases has increased with screening (36 in 2012; 51 in 2013; 59 in 2014; 38 in 7 months of 2015). With screening in 2014 there were more cases of late stage disease (NSCLC stage III/IV) than anticipated. In the first 7 months of 2015 72% of screened patients were stage I/II, 22% were stage III/IV, and 6% were unknown. As time progresses and the same patients are screened yearly, the percentage of early stage cases should increase and late stages decrease. It will be worthwhile to reevaluate these data over the next several years.
Background: There are about 200,000 new cases of lung cancer each year in the U.S. and about 150,000 deaths. Lung cancer is the second most common malignancy but the most common cause of cancer deaths. In 2010, the National Lung Screening Trial described a 20.3% reduction in lung cancer mortality in high-risk patients who were screened by CT scan. In 2012, guidelines were set forth by multiple groups. The National Comprehensive Cancer Network encouraged low-dose CT screening for patients aged 55 to 75 years, ≥ 30 pack-years of smoking, or smoking cessation within 15 years.
Methods: In late 2013, screening was implemented at the Providence VA Medical Center (PVAMC); a rise in the incidence of early stage lung cancer was anticipated. We reviewed the number and stages of cases of non-small cell (NSCLC) and small cell (SCLC) lung cancer in 2012, 2013 (mostly pre-screening), 2014 (screening), and 2015 (4 months of screening).
Results: In 2012 there were 23 cases of NSCLC (5 stage I; 5 stage II; 8 stage III; 2 stage IV; 3 unknown) and 4 cases of SCLC (extensive). In 2013 there were 42 cases of NSCLC (9 stage I; 2 stage II; 10 stage III [1 screened]; 17 stage IV; 4 unknown [1 screened]) and 9 cases of SCLC (1 lim-ited, 8 extensive). In 2014, there were 54 cases of NSCLC (15 stage I [5 screened]; 10 stage II [2 screened]; 11 stage III [3 screened]; 14 stage IV [1 screened]; and 4 unknown) and 5 cases of SCLC (5 extensive). In the first 7 months of 2015, there were 36 cases of NSCLC (13 stage I [10 screened]; 5 stage II [3 screened]; 7 stage III [3 screened]; 8 stage IV [1 screened]; and 3 unknown [1 screened]) and 1 SCLC (extensive) not screened and 1 SCLC (limited) screened.
Discussion: The total number of lung cancer cases has increased with screening (36 in 2012; 51 in 2013; 59 in 2014; 38 in 7 months of 2015). With screening in 2014 there were more cases of late stage disease (NSCLC stage III/IV) than anticipated. In the first 7 months of 2015 72% of screened patients were stage I/II, 22% were stage III/IV, and 6% were unknown. As time progresses and the same patients are screened yearly, the percentage of early stage cases should increase and late stages decrease. It will be worthwhile to reevaluate these data over the next several years.
Gauging the Use of Single Fraction Radiotherapy for Painful Bone Metastases: The Experience of a Single Veterans Administration Radiation Oncology Center
Background: In addition to patient and/or family convenience, there is mounting category 1 evidence of the effectiveness of single fraction radiotherapy (SFRT) and its utility in the treatment of uncomplicated painful bone metastases. Surveys indicated that physicians in the U.S. still prefer multiple fractions radiotherapy (MFRT) for uncomplicated bone metastases compared with their Canadian or European colleagues. This report used code tracking to determine the scope of use of SFRT for painful malignant bone lesions compared with MFRT.
Methods: We reviewed encounters logged as international classification of disease (ICD) code 198.5 (secondary malignancy of bone and or bone marrow) and current procedural terminology (CPT) codes: 77427 (physician weekly visit for 3 to 5 treatments); and 77431 (physician weekly visit for 1 to 2 treatments) from 2002 to 2008 and 2009 to 2014.
Results: Data limitations/assumptions: The ICD 198.5 diagnosis code was pulled from either the primary or secondary position. By merging CPT/ICD codes to track use patterns, we noted a 43% increase in the use of SFRT for painful bone lesions at James J. Peters VA Medical Center. The CPT code 77431 was used on a yearly average of 2.45% of bone metastases cases from periods 2002 to 2008, and 5.67% (8.50% ex-cluding years 2009/2010) from 2009 to 2014. Of note, from the period years of 2003, 2008, and 2009 to 2010, CPT code 77431 was not used at all.
Conclusions: We saw an increased use of SFRT for bone metastases over the time period covered, and that tracking the encounters by ICD and CPT codes served, in part, as a useful tool in providing a snapshot view (if proper code is used) of SFRT usage. Physician education is a requisite for the proper use of CPT 77431 to capture the true rate of usage of SFRT in clinical practice.
Background: In addition to patient and/or family convenience, there is mounting category 1 evidence of the effectiveness of single fraction radiotherapy (SFRT) and its utility in the treatment of uncomplicated painful bone metastases. Surveys indicated that physicians in the U.S. still prefer multiple fractions radiotherapy (MFRT) for uncomplicated bone metastases compared with their Canadian or European colleagues. This report used code tracking to determine the scope of use of SFRT for painful malignant bone lesions compared with MFRT.
Methods: We reviewed encounters logged as international classification of disease (ICD) code 198.5 (secondary malignancy of bone and or bone marrow) and current procedural terminology (CPT) codes: 77427 (physician weekly visit for 3 to 5 treatments); and 77431 (physician weekly visit for 1 to 2 treatments) from 2002 to 2008 and 2009 to 2014.
Results: Data limitations/assumptions: The ICD 198.5 diagnosis code was pulled from either the primary or secondary position. By merging CPT/ICD codes to track use patterns, we noted a 43% increase in the use of SFRT for painful bone lesions at James J. Peters VA Medical Center. The CPT code 77431 was used on a yearly average of 2.45% of bone metastases cases from periods 2002 to 2008, and 5.67% (8.50% ex-cluding years 2009/2010) from 2009 to 2014. Of note, from the period years of 2003, 2008, and 2009 to 2010, CPT code 77431 was not used at all.
Conclusions: We saw an increased use of SFRT for bone metastases over the time period covered, and that tracking the encounters by ICD and CPT codes served, in part, as a useful tool in providing a snapshot view (if proper code is used) of SFRT usage. Physician education is a requisite for the proper use of CPT 77431 to capture the true rate of usage of SFRT in clinical practice.
Background: In addition to patient and/or family convenience, there is mounting category 1 evidence of the effectiveness of single fraction radiotherapy (SFRT) and its utility in the treatment of uncomplicated painful bone metastases. Surveys indicated that physicians in the U.S. still prefer multiple fractions radiotherapy (MFRT) for uncomplicated bone metastases compared with their Canadian or European colleagues. This report used code tracking to determine the scope of use of SFRT for painful malignant bone lesions compared with MFRT.
Methods: We reviewed encounters logged as international classification of disease (ICD) code 198.5 (secondary malignancy of bone and or bone marrow) and current procedural terminology (CPT) codes: 77427 (physician weekly visit for 3 to 5 treatments); and 77431 (physician weekly visit for 1 to 2 treatments) from 2002 to 2008 and 2009 to 2014.
Results: Data limitations/assumptions: The ICD 198.5 diagnosis code was pulled from either the primary or secondary position. By merging CPT/ICD codes to track use patterns, we noted a 43% increase in the use of SFRT for painful bone lesions at James J. Peters VA Medical Center. The CPT code 77431 was used on a yearly average of 2.45% of bone metastases cases from periods 2002 to 2008, and 5.67% (8.50% ex-cluding years 2009/2010) from 2009 to 2014. Of note, from the period years of 2003, 2008, and 2009 to 2010, CPT code 77431 was not used at all.
Conclusions: We saw an increased use of SFRT for bone metastases over the time period covered, and that tracking the encounters by ICD and CPT codes served, in part, as a useful tool in providing a snapshot view (if proper code is used) of SFRT usage. Physician education is a requisite for the proper use of CPT 77431 to capture the true rate of usage of SFRT in clinical practice.
Trabectedin superior for advanced liposarcoma, leiomyosarcoma
Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.
Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.
In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.
Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).
Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).
Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.
This study confirms what we originally heard a decade ago from European investigators: Trabectedin shows clinical activity against liposarcomas and leiomyosarcomas. But the benefits demonstrated here still seem small, and it is not yet clear whether the data are now sufficient to make trabectedin the standard of care for all patients who have these sarcomas.
The primary end point – improving overall survival to a greater degree than dacarbazine – was not met. However, in the investigators’ defense, this was partly because the dacarbazine group survived much longer than expected. This, in turn, may be because more patients who had disease progression with dacarbazine (56%) than with trabectedin (47%) crossed over to other anticancer drugs, including the receptor tyrosine kinase inhibitor pazopanib, which was approved during the course of this study.
Dr. Gary K. Schwartz is at the Herbert Irving Comprehensive Cancer Center and Columbia University, New York. He reported ties to Novartis, AstraZeneca, and Boehringer Ingelheim. Dr. Schwartz made these remarks in an editorial accompanying Dr. Demetri’s report (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.63.5938]).
This study confirms what we originally heard a decade ago from European investigators: Trabectedin shows clinical activity against liposarcomas and leiomyosarcomas. But the benefits demonstrated here still seem small, and it is not yet clear whether the data are now sufficient to make trabectedin the standard of care for all patients who have these sarcomas.
The primary end point – improving overall survival to a greater degree than dacarbazine – was not met. However, in the investigators’ defense, this was partly because the dacarbazine group survived much longer than expected. This, in turn, may be because more patients who had disease progression with dacarbazine (56%) than with trabectedin (47%) crossed over to other anticancer drugs, including the receptor tyrosine kinase inhibitor pazopanib, which was approved during the course of this study.
Dr. Gary K. Schwartz is at the Herbert Irving Comprehensive Cancer Center and Columbia University, New York. He reported ties to Novartis, AstraZeneca, and Boehringer Ingelheim. Dr. Schwartz made these remarks in an editorial accompanying Dr. Demetri’s report (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.63.5938]).
This study confirms what we originally heard a decade ago from European investigators: Trabectedin shows clinical activity against liposarcomas and leiomyosarcomas. But the benefits demonstrated here still seem small, and it is not yet clear whether the data are now sufficient to make trabectedin the standard of care for all patients who have these sarcomas.
The primary end point – improving overall survival to a greater degree than dacarbazine – was not met. However, in the investigators’ defense, this was partly because the dacarbazine group survived much longer than expected. This, in turn, may be because more patients who had disease progression with dacarbazine (56%) than with trabectedin (47%) crossed over to other anticancer drugs, including the receptor tyrosine kinase inhibitor pazopanib, which was approved during the course of this study.
Dr. Gary K. Schwartz is at the Herbert Irving Comprehensive Cancer Center and Columbia University, New York. He reported ties to Novartis, AstraZeneca, and Boehringer Ingelheim. Dr. Schwartz made these remarks in an editorial accompanying Dr. Demetri’s report (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.63.5938]).
Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.
Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.
In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.
Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).
Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).
Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.
Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.
Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.
In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.
Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).
Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).
Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Trabectedin was superior to standard dacarbazine by most measures in advanced, refractory liposarcoma and leiomyosarcoma, though not for overall survival.
Major finding: Trabectedin reduced the risk of disease progression by 45% (HR, 0.55).
Data source: An international industry-sponsored open-label randomized phase III clinical trial involving 518 patients.
Disclosures: This study was supported by Janssen Pharmaceuticals and the Adelson Medical Research Foundation. Dr. Demetri and his associates reported ties to numerous industry sources.
Smoother orthopedic implants may minimize bacterial adherence
SAN DIEGO – Rough materials used for orthopedic implants, such as cobalt chromium and titanium, increased bacterial adherence, while smoother materials such as stainless steel did not, results from an image analysis demonstrated.
“In light of these results, it is important to question why we utilize the types of materials we use for various orthopedic procedures,” Dioscaris R. Garcia, Ph.D., said in an interview in advance of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. “There was no one-size-fits-all material to minimize adherence per the findings of this study, but the findings may suggest that having a smoother surface may minimize the ability of bacterial pathogens to adhere to the surface.”
He characterized the topic of bacterial adherence to orthopedic implants as “an issue of great interest due to how little is known about the biological implications of the materials utilized. The most researched of these materials is titanium, which is touted for its biocompatibility. This study aims to provide a base and a glimpse into how the most commonly utilized orthopedic-relevant materials interact with some of the most commonly encountered pathogens.”
For the study, Dr. Garcia, a molecular pharmacologist at Rhode Island Hospital in Providence, Dr. Alan H. Daniels, an orthopedic surgeon at the hospital, and their associates used scanning electron microscopy and confocal laser scanning microscopy to evaluate the adherence pattern, density, and propagation of six commonly encountered bacterial pathogens (methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, coagulase-negative Staphylococcus epidermidis, multidrug-resistant Acinetobacter baumannii, Propionibacterium acnes, and vancomycin-resistant Enterococcus faecalis) on five commonly used spinal implant materials (titanium, titanium alloy, stainless steel, cobalt chromium, and polyetherether ketone). The samples were fixed and dehydrated via ethanol dehydration gradient and critical point drying.
The researchers found that some pathogens, such as vancomycin-resistant E. faecalis and multidrug-resistant A. baumannii, were more likely to adhere to more textured materials such as cobalt chromium and titanium, compared with smoother materials such as stainless steel. “Additionally, the findings suggest that the microtopography of these materials may be the driving force behind the adherence of pathogens on the materials themselves,” Dr. Garcia said. Compared with smoother, polished materials, he explained, the rougher materials were more likely to harbor dense proliferation of bacterial pathogens, which could be characterized as biofilms.
“This study has been successful in providing a platform for future studies to build upon and expand to study additional parameters and statistical tools to give further insight into additional driving forces behind adherence and means for improvement of material design,” Dr. Garcia concluded.
Dr. Christopher T. Born, head of the Diane N. Weiss Center for Orthopedic Trauma Research at Rhode Island Hospital, was the study’s principal investigator. The study was supported by Stryker Corp.*
*Correction, 9/19/2015: Dr. Born is a consultant for Stryker. He also has stock ownership in Biointraface, does consulting for the company, and is a member of its board.
SAN DIEGO – Rough materials used for orthopedic implants, such as cobalt chromium and titanium, increased bacterial adherence, while smoother materials such as stainless steel did not, results from an image analysis demonstrated.
“In light of these results, it is important to question why we utilize the types of materials we use for various orthopedic procedures,” Dioscaris R. Garcia, Ph.D., said in an interview in advance of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. “There was no one-size-fits-all material to minimize adherence per the findings of this study, but the findings may suggest that having a smoother surface may minimize the ability of bacterial pathogens to adhere to the surface.”
He characterized the topic of bacterial adherence to orthopedic implants as “an issue of great interest due to how little is known about the biological implications of the materials utilized. The most researched of these materials is titanium, which is touted for its biocompatibility. This study aims to provide a base and a glimpse into how the most commonly utilized orthopedic-relevant materials interact with some of the most commonly encountered pathogens.”
For the study, Dr. Garcia, a molecular pharmacologist at Rhode Island Hospital in Providence, Dr. Alan H. Daniels, an orthopedic surgeon at the hospital, and their associates used scanning electron microscopy and confocal laser scanning microscopy to evaluate the adherence pattern, density, and propagation of six commonly encountered bacterial pathogens (methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, coagulase-negative Staphylococcus epidermidis, multidrug-resistant Acinetobacter baumannii, Propionibacterium acnes, and vancomycin-resistant Enterococcus faecalis) on five commonly used spinal implant materials (titanium, titanium alloy, stainless steel, cobalt chromium, and polyetherether ketone). The samples were fixed and dehydrated via ethanol dehydration gradient and critical point drying.
The researchers found that some pathogens, such as vancomycin-resistant E. faecalis and multidrug-resistant A. baumannii, were more likely to adhere to more textured materials such as cobalt chromium and titanium, compared with smoother materials such as stainless steel. “Additionally, the findings suggest that the microtopography of these materials may be the driving force behind the adherence of pathogens on the materials themselves,” Dr. Garcia said. Compared with smoother, polished materials, he explained, the rougher materials were more likely to harbor dense proliferation of bacterial pathogens, which could be characterized as biofilms.
“This study has been successful in providing a platform for future studies to build upon and expand to study additional parameters and statistical tools to give further insight into additional driving forces behind adherence and means for improvement of material design,” Dr. Garcia concluded.
Dr. Christopher T. Born, head of the Diane N. Weiss Center for Orthopedic Trauma Research at Rhode Island Hospital, was the study’s principal investigator. The study was supported by Stryker Corp.*
*Correction, 9/19/2015: Dr. Born is a consultant for Stryker. He also has stock ownership in Biointraface, does consulting for the company, and is a member of its board.
SAN DIEGO – Rough materials used for orthopedic implants, such as cobalt chromium and titanium, increased bacterial adherence, while smoother materials such as stainless steel did not, results from an image analysis demonstrated.
“In light of these results, it is important to question why we utilize the types of materials we use for various orthopedic procedures,” Dioscaris R. Garcia, Ph.D., said in an interview in advance of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. “There was no one-size-fits-all material to minimize adherence per the findings of this study, but the findings may suggest that having a smoother surface may minimize the ability of bacterial pathogens to adhere to the surface.”
He characterized the topic of bacterial adherence to orthopedic implants as “an issue of great interest due to how little is known about the biological implications of the materials utilized. The most researched of these materials is titanium, which is touted for its biocompatibility. This study aims to provide a base and a glimpse into how the most commonly utilized orthopedic-relevant materials interact with some of the most commonly encountered pathogens.”
For the study, Dr. Garcia, a molecular pharmacologist at Rhode Island Hospital in Providence, Dr. Alan H. Daniels, an orthopedic surgeon at the hospital, and their associates used scanning electron microscopy and confocal laser scanning microscopy to evaluate the adherence pattern, density, and propagation of six commonly encountered bacterial pathogens (methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, coagulase-negative Staphylococcus epidermidis, multidrug-resistant Acinetobacter baumannii, Propionibacterium acnes, and vancomycin-resistant Enterococcus faecalis) on five commonly used spinal implant materials (titanium, titanium alloy, stainless steel, cobalt chromium, and polyetherether ketone). The samples were fixed and dehydrated via ethanol dehydration gradient and critical point drying.
The researchers found that some pathogens, such as vancomycin-resistant E. faecalis and multidrug-resistant A. baumannii, were more likely to adhere to more textured materials such as cobalt chromium and titanium, compared with smoother materials such as stainless steel. “Additionally, the findings suggest that the microtopography of these materials may be the driving force behind the adherence of pathogens on the materials themselves,” Dr. Garcia said. Compared with smoother, polished materials, he explained, the rougher materials were more likely to harbor dense proliferation of bacterial pathogens, which could be characterized as biofilms.
“This study has been successful in providing a platform for future studies to build upon and expand to study additional parameters and statistical tools to give further insight into additional driving forces behind adherence and means for improvement of material design,” Dr. Garcia concluded.
Dr. Christopher T. Born, head of the Diane N. Weiss Center for Orthopedic Trauma Research at Rhode Island Hospital, was the study’s principal investigator. The study was supported by Stryker Corp.*
*Correction, 9/19/2015: Dr. Born is a consultant for Stryker. He also has stock ownership in Biointraface, does consulting for the company, and is a member of its board.
AT ICAAC 2015
Key clinical point: Orthopedic implants made from smoother material may minimize bacterial adherence.
Major finding: Some pathogens, such as vancomycin-resistant Enterococcus faecalis and multidrug-resistant Acinetobacter baumannii, were more likely to adhere to more textured materials like cobalt chromium and titanium, compared with smoother materials such as stainless steel.
Data source: A study that used scanning electron microscopy and confocal laser scanning microscopy to evaluate the adherence pattern, density, and propagation of six commonly encountered bacterial pathogens on five commonly used spinal implant materials.
Disclosures: The study was supported by Stryker Corp. Dr. Born is a consultant for Stryker. He also has stock ownership in Biointraface, does consulting for the company, and is a member of its board.*
EASD: SGLT2 inhibitor empagliflozin cuts CV risk in patients with type 2 diabetes
STOCKHOLM – The combined risk for cardiovascular death, nonfatal MI, and nonfatal stroke was reduced by 14% when empagliflozin was added to standard care for type 2 diabetes in patients at high cardiovascular risk, compared with standard care alone, in the EMPA-REG OUTCOME study.
This primary composite endpoint was reached by 10.5% of the 4,687 patients treated with the antidiabetic drug versus 12.1% of the 2,333 patients given a placebo, with a hazard ratio (HR) of 0.86 and 95% confidence interval (CI) of 0.74 to 0.99 (P = .04 for superiority and P less than .001 for noninferiority).
The results of the EMPA-REG OUTCOME study, which were reported for the first time at the annual meeting of the European Association for the Study of Diabetes, were published simultaneously Sept. 17 online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1504720).
Dr. Silvio Inzucchi, professor of medicine at Yale University, New Haven, Conn., and the study investigator who presented the key outcome findings, said during the Q&A session that this was the first presentation of these data and that of course there had to be a little bit of caution before making any firm recommendations.
“It is really important that the diabetes and cardiology communities digest [these data], to try to understand them, and that we also have to be cautious here. This was a group of patients with 10 years’ duration of diabetes, all of whom had cardiovascular disease, so we can not necessarily ‘cut and paste’ these expectations to the entirety of the diabetes population.”
Putting the results into context ahead of their presentation in detail at the meeting, Dr. Naveed Sattar of the University of Glasgow, Scotland, said in an interview that there had been four other cardiovascular outcomes trials in this high-risk population of patients with type 2 diabetes and cardiovascular disease – three with DPP-4 inhibitors, namely the SAVOR-TIMI 53 trial, the EXAMINEtrial, and the recent TECOS. The fourth such trial involved a GLP-1 antagonist (ELIXA). All of these had shown modest or small additional reductions in blood glucose levels with the tested drugs versus standard of care or placebo control but had “shown unequivocally no benefit in [reducing] cardiovascular events.” Cardiovascular effects had simply been neutral or no cause for concern.
So to now have a trial with a drug that is potentially more potent at lowering blood glucose than the others and is showing a cardiovascular benefit is potentially game changing, said Dr. Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Evidence suggests that empagliflozin does more than just lower blood glucose, said Dr. Sattar, who was not involved in the EMPA-REG trial. “Empagliflozin lowers blood pressure, it reduces weight, so is it these added effects that have conferred this benefit or is it something else?” He added: “Most people’s perception is that it is possibly a class effect, but the data need to be seen.”
Dr. Lars Rydén, professor of cardiology at the Karolinska Institute in Stockholm, singled out the EMPA-REG study as one to watch. Speaking in an interview at the annual meeting of the European Society of Cardiology in London, he said that if the cardiovascular risk reduction touted were true it would make empagliflozin “the only modern glucose-lowering drug to have shown such a capacity.”
EMPA-REG OUTCOME was a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin, given at an oral dose of 10 mg/day or 25 mg/day compared to the best usual care in patients with type 2 diabetes who were at increased cardiovascular risk due to the presence of established cardiovascular disease. The study was done at 590 sites in 42 countries across six continents and involved more than 7,000 patients observed over a median of 3.1 years.
Looking at the individual components of the primary composite endpoint, there was no significant difference in terms of the relative risk reduction for MI or stroke. However, the unexpected results were that cardiovascular death, hospitalization for heart failure, and all-cause mortality were all reduced by more than one-third, with respective relative risk reductions of 38% (HR, 0.62; 95% CI, 0.49-0.77; P less than .001), 35% (HR, 0.68; 95% CI, 0.57-0.82; P less than .001), and 32% (HR, 0.65; 95% CI, 0.50-0.85; P = .002).
Even when the results were shown separating out the two doses of empagliflozin, the HR remained highly significant for these and the primary composite endpoint.
The key secondary outcome of the trial was a composite of the primary outcome plus hospitalization for unstable angina. However, no significant difference for superiority was seen between the groups (P = .008, P less than .001 for noninferiority).
“I am here because of the importance of this,” said Dr. Andrew Boulton outgoing president of the EASD and professor of medicine at the University of Manchester, England, who introduced the EASD-sponsored symposium where the results were revealed.
In an interview, Dr. Boulton said it “looks promising.”
The results were presented by the senior authors of the study and independently commented upon afterward by the EASD-invited discussant Dr. Hertzel Gerstein of McMaster University and Hamilton (Ont.) Health Sciences. “Without question, the EMPA-REG investigators have designed a good protocol, and they have answered a very important question,” he said. “This was a well done and very important study,” he noted.
Dr. Gerstein observed that empagliflozin “clearly reduces CV death and heart failure hospitalization,” an effect that starts to appear after just 3 months. This early effect is unlikely to be down to just glucose-lowering, antihypertensive effects of the background medications used, or weight loss because of this speed of onset. It could be due to the diuretic properties of the SLGT2 inhibitor or, maybe more likely, a combination of beneficial effects. “It is probably a class effect,” he said, “but you can never be certain.”
Based on the findings, he suggested that empagliflozin “may become first-line treatment for middle aged people with type 2 diabetes at risk for CV outcomes” and that the trial had “identified a treatment that could save many lives and reduce much suffering.” The results were unexpected and will open up new avenues for research.
Dr. Bernard Zinman of Mount Sinai Hospital, Toronto, lead author for the trial, said during the session that the number of patients needed to be treated with empagliflozin for 3 years to prevent one cardiovascular death was 39. By comparison, he said, the numbers needed to treat with simvastatin or ramipril for 5 years were 30 and 59, respectively.
Good safety was observed in the trial, reported Dr. David Fitchett, fellow author. Dr. Fitchett, a cardiologist at St Michael’s Hospital and associate professor at the University of Toronto, noted that overall rates of both any adverse events and serious adverse events were similar between the groups, with the exception of genital infections that were mainly mycoses and mostly in women.
Rates of confirmed hypoglycemic events were similar, he said, and there was no increase in diabetic ketoacidosis or bone fracture, which have been the focus of recent warnings issued by the Food and Drug Administration with regard to SLGT2 inhibitors.
Boehringer Ingelheim and Eli Lilly funded the study. Dr. Sattar disclosed ties with Amgen, Sanofi, and Merck Sharp & Dohme. Dr. Sattar and Dr. Rydén were on the panel of experts invited to talk about the study in a satellite symposium sponsored by Boehringer Ingelheim and Eli Lilly. Dr. Boulton did not report having disclosures. Dr. Gerstein reported ties with Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Abbot, Bayer, Berlin Chemie, Roche, GSK, Amgen, and Kaneq Bioscience. Dr. Zinman disclosed ties with Boehringer Ingelheim. Dr. Fitchett disclosed consulting for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Merck Sharp & Dohme. Dr. Inzucchi disclosed ties with Boehringer Ingelheim, Merck, Janssen, Novo Nordisk, Sanofi/Regeron, Intarcia, Lexicon, Paxel, Takeda, and Eli Lilly. He acknowledged CME-funding to Yale University from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbot, Merck Sharp & Dohme, and Sanofi.
The EMPA-REG OUTCOME study results are spectacular in terms of the hard endpoints that were measured and the explicit reductions seen. It is exciting news because we have had quite a few negative trials with DPP4-inhibtiors where nothing much has happened and we don’t have cardiovascular outcomes. So that’s the upside, and that’s very exciting.
The downside has to be that the population studied included people who were post MI or were at higher cardiovascular risk than the general population with type 2 diabetes. So the study participants were people who are way into their diabetes pathology and are already having cardiovascular events. While it is of course good that these patients greatly benefit, one must not start to generalize and say that this shows that everyone with type 2 diabetes ought to be on an SGLT2 inhibitor.
In the future, I think one has to be very careful about the way that trials are set up and about who has gone into those trials. We still do not know very much about people who are newly onset with type 2 diabetes and if the SGLT2 inhibitors will be useful for them generally, but it is very nice to have positive outcomes in the group of patients studied.
These are big effects, which, as clinicians, we all like to see, and these are unlikely to be by chance because they are so big. The EMPA-REG OUTCOME findings clearly did not occur by chance. This is a really positive and exciting outcome for empagliflozin and it will affect the way people treat their patients. But the warning is that we must not generalize from the specifics of this trial in terms of who the patients treated were: they tended to be male, they were all people who had major events.
These remarks come from an interview with Dr. David Matthews, conducted onsite at EASD 2015 and exclusive to this news organization. Dr. Matthews is professor of diabetes and emeritus founding chairman, Oxford Centre for Diabetes, Endocrinology & Metabolism, Oxford, England. He is the coinvestigator for a Janssen-sponsored canagliflozin trial and has received honoraria and support from Janssen.
The EMPA-REG OUTCOME study results are spectacular in terms of the hard endpoints that were measured and the explicit reductions seen. It is exciting news because we have had quite a few negative trials with DPP4-inhibtiors where nothing much has happened and we don’t have cardiovascular outcomes. So that’s the upside, and that’s very exciting.
The downside has to be that the population studied included people who were post MI or were at higher cardiovascular risk than the general population with type 2 diabetes. So the study participants were people who are way into their diabetes pathology and are already having cardiovascular events. While it is of course good that these patients greatly benefit, one must not start to generalize and say that this shows that everyone with type 2 diabetes ought to be on an SGLT2 inhibitor.
In the future, I think one has to be very careful about the way that trials are set up and about who has gone into those trials. We still do not know very much about people who are newly onset with type 2 diabetes and if the SGLT2 inhibitors will be useful for them generally, but it is very nice to have positive outcomes in the group of patients studied.
These are big effects, which, as clinicians, we all like to see, and these are unlikely to be by chance because they are so big. The EMPA-REG OUTCOME findings clearly did not occur by chance. This is a really positive and exciting outcome for empagliflozin and it will affect the way people treat their patients. But the warning is that we must not generalize from the specifics of this trial in terms of who the patients treated were: they tended to be male, they were all people who had major events.
These remarks come from an interview with Dr. David Matthews, conducted onsite at EASD 2015 and exclusive to this news organization. Dr. Matthews is professor of diabetes and emeritus founding chairman, Oxford Centre for Diabetes, Endocrinology & Metabolism, Oxford, England. He is the coinvestigator for a Janssen-sponsored canagliflozin trial and has received honoraria and support from Janssen.
The EMPA-REG OUTCOME study results are spectacular in terms of the hard endpoints that were measured and the explicit reductions seen. It is exciting news because we have had quite a few negative trials with DPP4-inhibtiors where nothing much has happened and we don’t have cardiovascular outcomes. So that’s the upside, and that’s very exciting.
The downside has to be that the population studied included people who were post MI or were at higher cardiovascular risk than the general population with type 2 diabetes. So the study participants were people who are way into their diabetes pathology and are already having cardiovascular events. While it is of course good that these patients greatly benefit, one must not start to generalize and say that this shows that everyone with type 2 diabetes ought to be on an SGLT2 inhibitor.
In the future, I think one has to be very careful about the way that trials are set up and about who has gone into those trials. We still do not know very much about people who are newly onset with type 2 diabetes and if the SGLT2 inhibitors will be useful for them generally, but it is very nice to have positive outcomes in the group of patients studied.
These are big effects, which, as clinicians, we all like to see, and these are unlikely to be by chance because they are so big. The EMPA-REG OUTCOME findings clearly did not occur by chance. This is a really positive and exciting outcome for empagliflozin and it will affect the way people treat their patients. But the warning is that we must not generalize from the specifics of this trial in terms of who the patients treated were: they tended to be male, they were all people who had major events.
These remarks come from an interview with Dr. David Matthews, conducted onsite at EASD 2015 and exclusive to this news organization. Dr. Matthews is professor of diabetes and emeritus founding chairman, Oxford Centre for Diabetes, Endocrinology & Metabolism, Oxford, England. He is the coinvestigator for a Janssen-sponsored canagliflozin trial and has received honoraria and support from Janssen.
STOCKHOLM – The combined risk for cardiovascular death, nonfatal MI, and nonfatal stroke was reduced by 14% when empagliflozin was added to standard care for type 2 diabetes in patients at high cardiovascular risk, compared with standard care alone, in the EMPA-REG OUTCOME study.
This primary composite endpoint was reached by 10.5% of the 4,687 patients treated with the antidiabetic drug versus 12.1% of the 2,333 patients given a placebo, with a hazard ratio (HR) of 0.86 and 95% confidence interval (CI) of 0.74 to 0.99 (P = .04 for superiority and P less than .001 for noninferiority).
The results of the EMPA-REG OUTCOME study, which were reported for the first time at the annual meeting of the European Association for the Study of Diabetes, were published simultaneously Sept. 17 online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1504720).
Dr. Silvio Inzucchi, professor of medicine at Yale University, New Haven, Conn., and the study investigator who presented the key outcome findings, said during the Q&A session that this was the first presentation of these data and that of course there had to be a little bit of caution before making any firm recommendations.
“It is really important that the diabetes and cardiology communities digest [these data], to try to understand them, and that we also have to be cautious here. This was a group of patients with 10 years’ duration of diabetes, all of whom had cardiovascular disease, so we can not necessarily ‘cut and paste’ these expectations to the entirety of the diabetes population.”
Putting the results into context ahead of their presentation in detail at the meeting, Dr. Naveed Sattar of the University of Glasgow, Scotland, said in an interview that there had been four other cardiovascular outcomes trials in this high-risk population of patients with type 2 diabetes and cardiovascular disease – three with DPP-4 inhibitors, namely the SAVOR-TIMI 53 trial, the EXAMINEtrial, and the recent TECOS. The fourth such trial involved a GLP-1 antagonist (ELIXA). All of these had shown modest or small additional reductions in blood glucose levels with the tested drugs versus standard of care or placebo control but had “shown unequivocally no benefit in [reducing] cardiovascular events.” Cardiovascular effects had simply been neutral or no cause for concern.
So to now have a trial with a drug that is potentially more potent at lowering blood glucose than the others and is showing a cardiovascular benefit is potentially game changing, said Dr. Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Evidence suggests that empagliflozin does more than just lower blood glucose, said Dr. Sattar, who was not involved in the EMPA-REG trial. “Empagliflozin lowers blood pressure, it reduces weight, so is it these added effects that have conferred this benefit or is it something else?” He added: “Most people’s perception is that it is possibly a class effect, but the data need to be seen.”
Dr. Lars Rydén, professor of cardiology at the Karolinska Institute in Stockholm, singled out the EMPA-REG study as one to watch. Speaking in an interview at the annual meeting of the European Society of Cardiology in London, he said that if the cardiovascular risk reduction touted were true it would make empagliflozin “the only modern glucose-lowering drug to have shown such a capacity.”
EMPA-REG OUTCOME was a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin, given at an oral dose of 10 mg/day or 25 mg/day compared to the best usual care in patients with type 2 diabetes who were at increased cardiovascular risk due to the presence of established cardiovascular disease. The study was done at 590 sites in 42 countries across six continents and involved more than 7,000 patients observed over a median of 3.1 years.
Looking at the individual components of the primary composite endpoint, there was no significant difference in terms of the relative risk reduction for MI or stroke. However, the unexpected results were that cardiovascular death, hospitalization for heart failure, and all-cause mortality were all reduced by more than one-third, with respective relative risk reductions of 38% (HR, 0.62; 95% CI, 0.49-0.77; P less than .001), 35% (HR, 0.68; 95% CI, 0.57-0.82; P less than .001), and 32% (HR, 0.65; 95% CI, 0.50-0.85; P = .002).
Even when the results were shown separating out the two doses of empagliflozin, the HR remained highly significant for these and the primary composite endpoint.
The key secondary outcome of the trial was a composite of the primary outcome plus hospitalization for unstable angina. However, no significant difference for superiority was seen between the groups (P = .008, P less than .001 for noninferiority).
“I am here because of the importance of this,” said Dr. Andrew Boulton outgoing president of the EASD and professor of medicine at the University of Manchester, England, who introduced the EASD-sponsored symposium where the results were revealed.
In an interview, Dr. Boulton said it “looks promising.”
The results were presented by the senior authors of the study and independently commented upon afterward by the EASD-invited discussant Dr. Hertzel Gerstein of McMaster University and Hamilton (Ont.) Health Sciences. “Without question, the EMPA-REG investigators have designed a good protocol, and they have answered a very important question,” he said. “This was a well done and very important study,” he noted.
Dr. Gerstein observed that empagliflozin “clearly reduces CV death and heart failure hospitalization,” an effect that starts to appear after just 3 months. This early effect is unlikely to be down to just glucose-lowering, antihypertensive effects of the background medications used, or weight loss because of this speed of onset. It could be due to the diuretic properties of the SLGT2 inhibitor or, maybe more likely, a combination of beneficial effects. “It is probably a class effect,” he said, “but you can never be certain.”
Based on the findings, he suggested that empagliflozin “may become first-line treatment for middle aged people with type 2 diabetes at risk for CV outcomes” and that the trial had “identified a treatment that could save many lives and reduce much suffering.” The results were unexpected and will open up new avenues for research.
Dr. Bernard Zinman of Mount Sinai Hospital, Toronto, lead author for the trial, said during the session that the number of patients needed to be treated with empagliflozin for 3 years to prevent one cardiovascular death was 39. By comparison, he said, the numbers needed to treat with simvastatin or ramipril for 5 years were 30 and 59, respectively.
Good safety was observed in the trial, reported Dr. David Fitchett, fellow author. Dr. Fitchett, a cardiologist at St Michael’s Hospital and associate professor at the University of Toronto, noted that overall rates of both any adverse events and serious adverse events were similar between the groups, with the exception of genital infections that were mainly mycoses and mostly in women.
Rates of confirmed hypoglycemic events were similar, he said, and there was no increase in diabetic ketoacidosis or bone fracture, which have been the focus of recent warnings issued by the Food and Drug Administration with regard to SLGT2 inhibitors.
Boehringer Ingelheim and Eli Lilly funded the study. Dr. Sattar disclosed ties with Amgen, Sanofi, and Merck Sharp & Dohme. Dr. Sattar and Dr. Rydén were on the panel of experts invited to talk about the study in a satellite symposium sponsored by Boehringer Ingelheim and Eli Lilly. Dr. Boulton did not report having disclosures. Dr. Gerstein reported ties with Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Abbot, Bayer, Berlin Chemie, Roche, GSK, Amgen, and Kaneq Bioscience. Dr. Zinman disclosed ties with Boehringer Ingelheim. Dr. Fitchett disclosed consulting for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Merck Sharp & Dohme. Dr. Inzucchi disclosed ties with Boehringer Ingelheim, Merck, Janssen, Novo Nordisk, Sanofi/Regeron, Intarcia, Lexicon, Paxel, Takeda, and Eli Lilly. He acknowledged CME-funding to Yale University from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbot, Merck Sharp & Dohme, and Sanofi.
STOCKHOLM – The combined risk for cardiovascular death, nonfatal MI, and nonfatal stroke was reduced by 14% when empagliflozin was added to standard care for type 2 diabetes in patients at high cardiovascular risk, compared with standard care alone, in the EMPA-REG OUTCOME study.
This primary composite endpoint was reached by 10.5% of the 4,687 patients treated with the antidiabetic drug versus 12.1% of the 2,333 patients given a placebo, with a hazard ratio (HR) of 0.86 and 95% confidence interval (CI) of 0.74 to 0.99 (P = .04 for superiority and P less than .001 for noninferiority).
The results of the EMPA-REG OUTCOME study, which were reported for the first time at the annual meeting of the European Association for the Study of Diabetes, were published simultaneously Sept. 17 online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1504720).
Dr. Silvio Inzucchi, professor of medicine at Yale University, New Haven, Conn., and the study investigator who presented the key outcome findings, said during the Q&A session that this was the first presentation of these data and that of course there had to be a little bit of caution before making any firm recommendations.
“It is really important that the diabetes and cardiology communities digest [these data], to try to understand them, and that we also have to be cautious here. This was a group of patients with 10 years’ duration of diabetes, all of whom had cardiovascular disease, so we can not necessarily ‘cut and paste’ these expectations to the entirety of the diabetes population.”
Putting the results into context ahead of their presentation in detail at the meeting, Dr. Naveed Sattar of the University of Glasgow, Scotland, said in an interview that there had been four other cardiovascular outcomes trials in this high-risk population of patients with type 2 diabetes and cardiovascular disease – three with DPP-4 inhibitors, namely the SAVOR-TIMI 53 trial, the EXAMINEtrial, and the recent TECOS. The fourth such trial involved a GLP-1 antagonist (ELIXA). All of these had shown modest or small additional reductions in blood glucose levels with the tested drugs versus standard of care or placebo control but had “shown unequivocally no benefit in [reducing] cardiovascular events.” Cardiovascular effects had simply been neutral or no cause for concern.
So to now have a trial with a drug that is potentially more potent at lowering blood glucose than the others and is showing a cardiovascular benefit is potentially game changing, said Dr. Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Evidence suggests that empagliflozin does more than just lower blood glucose, said Dr. Sattar, who was not involved in the EMPA-REG trial. “Empagliflozin lowers blood pressure, it reduces weight, so is it these added effects that have conferred this benefit or is it something else?” He added: “Most people’s perception is that it is possibly a class effect, but the data need to be seen.”
Dr. Lars Rydén, professor of cardiology at the Karolinska Institute in Stockholm, singled out the EMPA-REG study as one to watch. Speaking in an interview at the annual meeting of the European Society of Cardiology in London, he said that if the cardiovascular risk reduction touted were true it would make empagliflozin “the only modern glucose-lowering drug to have shown such a capacity.”
EMPA-REG OUTCOME was a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin, given at an oral dose of 10 mg/day or 25 mg/day compared to the best usual care in patients with type 2 diabetes who were at increased cardiovascular risk due to the presence of established cardiovascular disease. The study was done at 590 sites in 42 countries across six continents and involved more than 7,000 patients observed over a median of 3.1 years.
Looking at the individual components of the primary composite endpoint, there was no significant difference in terms of the relative risk reduction for MI or stroke. However, the unexpected results were that cardiovascular death, hospitalization for heart failure, and all-cause mortality were all reduced by more than one-third, with respective relative risk reductions of 38% (HR, 0.62; 95% CI, 0.49-0.77; P less than .001), 35% (HR, 0.68; 95% CI, 0.57-0.82; P less than .001), and 32% (HR, 0.65; 95% CI, 0.50-0.85; P = .002).
Even when the results were shown separating out the two doses of empagliflozin, the HR remained highly significant for these and the primary composite endpoint.
The key secondary outcome of the trial was a composite of the primary outcome plus hospitalization for unstable angina. However, no significant difference for superiority was seen between the groups (P = .008, P less than .001 for noninferiority).
“I am here because of the importance of this,” said Dr. Andrew Boulton outgoing president of the EASD and professor of medicine at the University of Manchester, England, who introduced the EASD-sponsored symposium where the results were revealed.
In an interview, Dr. Boulton said it “looks promising.”
The results were presented by the senior authors of the study and independently commented upon afterward by the EASD-invited discussant Dr. Hertzel Gerstein of McMaster University and Hamilton (Ont.) Health Sciences. “Without question, the EMPA-REG investigators have designed a good protocol, and they have answered a very important question,” he said. “This was a well done and very important study,” he noted.
Dr. Gerstein observed that empagliflozin “clearly reduces CV death and heart failure hospitalization,” an effect that starts to appear after just 3 months. This early effect is unlikely to be down to just glucose-lowering, antihypertensive effects of the background medications used, or weight loss because of this speed of onset. It could be due to the diuretic properties of the SLGT2 inhibitor or, maybe more likely, a combination of beneficial effects. “It is probably a class effect,” he said, “but you can never be certain.”
Based on the findings, he suggested that empagliflozin “may become first-line treatment for middle aged people with type 2 diabetes at risk for CV outcomes” and that the trial had “identified a treatment that could save many lives and reduce much suffering.” The results were unexpected and will open up new avenues for research.
Dr. Bernard Zinman of Mount Sinai Hospital, Toronto, lead author for the trial, said during the session that the number of patients needed to be treated with empagliflozin for 3 years to prevent one cardiovascular death was 39. By comparison, he said, the numbers needed to treat with simvastatin or ramipril for 5 years were 30 and 59, respectively.
Good safety was observed in the trial, reported Dr. David Fitchett, fellow author. Dr. Fitchett, a cardiologist at St Michael’s Hospital and associate professor at the University of Toronto, noted that overall rates of both any adverse events and serious adverse events were similar between the groups, with the exception of genital infections that were mainly mycoses and mostly in women.
Rates of confirmed hypoglycemic events were similar, he said, and there was no increase in diabetic ketoacidosis or bone fracture, which have been the focus of recent warnings issued by the Food and Drug Administration with regard to SLGT2 inhibitors.
Boehringer Ingelheim and Eli Lilly funded the study. Dr. Sattar disclosed ties with Amgen, Sanofi, and Merck Sharp & Dohme. Dr. Sattar and Dr. Rydén were on the panel of experts invited to talk about the study in a satellite symposium sponsored by Boehringer Ingelheim and Eli Lilly. Dr. Boulton did not report having disclosures. Dr. Gerstein reported ties with Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Abbot, Bayer, Berlin Chemie, Roche, GSK, Amgen, and Kaneq Bioscience. Dr. Zinman disclosed ties with Boehringer Ingelheim. Dr. Fitchett disclosed consulting for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Merck Sharp & Dohme. Dr. Inzucchi disclosed ties with Boehringer Ingelheim, Merck, Janssen, Novo Nordisk, Sanofi/Regeron, Intarcia, Lexicon, Paxel, Takeda, and Eli Lilly. He acknowledged CME-funding to Yale University from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbot, Merck Sharp & Dohme, and Sanofi.
AT EASD 2015
Key clinical point: Empagliflozin reduced cardiovascular risk in patients with type 2 diabetes who were at high cardiovascular risk, making it the first antidiabetic drug to have been shown to have such an effect.
Major finding: This primary composite endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke was reached by 10.5% (N = 4,687) of patients treated with empagliflozin versus 12.1% (N = 2,333) of those given placebo.
Data source: EMPA-REG OUTCOME: a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin added to usual care versus usual care alone in more than 7,000 patients with type 2 diabetes at high cardiovascular risk.
Disclosures: Boehringer Ingelheim and Eli Lilly funded the study. Dr. Sattar disclosed ties with Amgen, Sanofi, and Merck Sharp & Dohme. Dr. Sattar and Dr. Rydén were on the panel of experts invited to talk about the study in a satellite symposium sponsored by Boehringer Ingelheim and Eli Lilly. Dr. Boulton did not report having disclosures. Dr. Gerstein reported ties with Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Abbot, Bayer, Berlin Chemie, Roche, GSK, Amgen, and Kaneq Bioscience. Dr. Zinman disclosed ties with Boehringer Ingelheim. Dr. Fitchett disclosed consulting for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Merck Sharp & Dohme. Dr. Inzucchi disclosed ties with Boehringer Ingelheim, Merck, Janssen, Novo Nordisk, Sanofi/Regeron, Intarcia, Lexicon, Paxel, Takeda, and Eli Lilly. He acknowledged CME-funding to Yale University from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbot, Merck Sharp & Dohme, and Sanofi.
