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More In-Hospital Deaths in MI Patients With Diabetes
CHICAGO – Acute myocardial infarction patients who have diabetes are less likely to present with an ST-elevation MI, yet they run a significantly increased risk for in-hospital death, compared with nondiabetic MI patients.
Moreover, MI patients with diabetes are more likely to experience in-hospital stroke, recurrent MI, and heart failure or pulmonary edema, according to Dr. Quang T. Bui of Harbor-UCLA Medical Center, Los Angeles.
Dr. Bui presented an analysis of 232,927 patients presenting with acute MI to 823 hospitals participating in the National Registry of Myocardial Infarction (NRMI) 4-5. A history of diabetes was noted in 31%.
The in-hospital mortality rate was 10.1% in diabetic patients and 8.3% in nondiabetic patients. In-hospital strokes occurred in 1.4% of diabetics compared with 1.0% of nondiabetic patients. The in-hospital rate of recurrent MI was 1.5% in the diabetic patients and 1.3% in those without diabetes.
Diabetes patients hospitalized for MI had an 18% greater risk of in-hospital mortality than did nondiabetic patients. They also had a 30% greater risk of in-hospital stroke, a 14% increased risk of in-hospital recurrent MI, and a 57% greater risk of developing in-hospital heart failure or pulmonary edema.
An ST-elevation MI occurred in 31% of diabetic patients and 40% of nondiabetic patients. Anterior/septal MI occurred in 14.7% of diabetic MI patients and 18.9% of those without diabetes. However, 11.5% of MI patients with diabetes were Killup class III/IV, compared with 6.5% of those without diabetes.
A history of previous MI was present in 31% of diabetic patients compared with 22% of those without diabetes. The diabetic group also had significantly higher rates of background hypercholesterolemia, hypertension, renal dysfunction, previous revascularization, and prior stroke.
Preadmission use of cardiovascular risk-reducing medications was more common among the diabetic MI patients. Yet the use of these agents was actually low given that diabetes is a well-recognized risk factor for cardiovascular disease, Dr. Bui observed. Less than half of diabetic MI patients were on an ACE inhibitor or an angiotensin receptor blocker prior to their hospitalization for an MI. About 30% were taking a beta-blocker. A similar proportion of patients used a statin or other lipid-lowering agent.
Health care planners will be particularly interested in the NRMI 4-5 finding that the mean hospital length of stay was 6.5 days in acute MI patients with diabetes, compared with 5.2 days in those without a history of diabetes, Dr. Bui noted. Diabetes patients with a history of MI were hospitalized for about 20 hours longer than were nondiabetic patients with a prior MI. And diabetes patients without a prior MI were hospitalized for 14 hours longer than were nondiabetic patients with a history of MI, Dr. Bui said.
The NRMI project is funded by Genentech. Dr. Bui reported having no financial conflicts.
CHICAGO – Acute myocardial infarction patients who have diabetes are less likely to present with an ST-elevation MI, yet they run a significantly increased risk for in-hospital death, compared with nondiabetic MI patients.
Moreover, MI patients with diabetes are more likely to experience in-hospital stroke, recurrent MI, and heart failure or pulmonary edema, according to Dr. Quang T. Bui of Harbor-UCLA Medical Center, Los Angeles.
Dr. Bui presented an analysis of 232,927 patients presenting with acute MI to 823 hospitals participating in the National Registry of Myocardial Infarction (NRMI) 4-5. A history of diabetes was noted in 31%.
The in-hospital mortality rate was 10.1% in diabetic patients and 8.3% in nondiabetic patients. In-hospital strokes occurred in 1.4% of diabetics compared with 1.0% of nondiabetic patients. The in-hospital rate of recurrent MI was 1.5% in the diabetic patients and 1.3% in those without diabetes.
Diabetes patients hospitalized for MI had an 18% greater risk of in-hospital mortality than did nondiabetic patients. They also had a 30% greater risk of in-hospital stroke, a 14% increased risk of in-hospital recurrent MI, and a 57% greater risk of developing in-hospital heart failure or pulmonary edema.
An ST-elevation MI occurred in 31% of diabetic patients and 40% of nondiabetic patients. Anterior/septal MI occurred in 14.7% of diabetic MI patients and 18.9% of those without diabetes. However, 11.5% of MI patients with diabetes were Killup class III/IV, compared with 6.5% of those without diabetes.
A history of previous MI was present in 31% of diabetic patients compared with 22% of those without diabetes. The diabetic group also had significantly higher rates of background hypercholesterolemia, hypertension, renal dysfunction, previous revascularization, and prior stroke.
Preadmission use of cardiovascular risk-reducing medications was more common among the diabetic MI patients. Yet the use of these agents was actually low given that diabetes is a well-recognized risk factor for cardiovascular disease, Dr. Bui observed. Less than half of diabetic MI patients were on an ACE inhibitor or an angiotensin receptor blocker prior to their hospitalization for an MI. About 30% were taking a beta-blocker. A similar proportion of patients used a statin or other lipid-lowering agent.
Health care planners will be particularly interested in the NRMI 4-5 finding that the mean hospital length of stay was 6.5 days in acute MI patients with diabetes, compared with 5.2 days in those without a history of diabetes, Dr. Bui noted. Diabetes patients with a history of MI were hospitalized for about 20 hours longer than were nondiabetic patients with a prior MI. And diabetes patients without a prior MI were hospitalized for 14 hours longer than were nondiabetic patients with a history of MI, Dr. Bui said.
The NRMI project is funded by Genentech. Dr. Bui reported having no financial conflicts.
CHICAGO – Acute myocardial infarction patients who have diabetes are less likely to present with an ST-elevation MI, yet they run a significantly increased risk for in-hospital death, compared with nondiabetic MI patients.
Moreover, MI patients with diabetes are more likely to experience in-hospital stroke, recurrent MI, and heart failure or pulmonary edema, according to Dr. Quang T. Bui of Harbor-UCLA Medical Center, Los Angeles.
Dr. Bui presented an analysis of 232,927 patients presenting with acute MI to 823 hospitals participating in the National Registry of Myocardial Infarction (NRMI) 4-5. A history of diabetes was noted in 31%.
The in-hospital mortality rate was 10.1% in diabetic patients and 8.3% in nondiabetic patients. In-hospital strokes occurred in 1.4% of diabetics compared with 1.0% of nondiabetic patients. The in-hospital rate of recurrent MI was 1.5% in the diabetic patients and 1.3% in those without diabetes.
Diabetes patients hospitalized for MI had an 18% greater risk of in-hospital mortality than did nondiabetic patients. They also had a 30% greater risk of in-hospital stroke, a 14% increased risk of in-hospital recurrent MI, and a 57% greater risk of developing in-hospital heart failure or pulmonary edema.
An ST-elevation MI occurred in 31% of diabetic patients and 40% of nondiabetic patients. Anterior/septal MI occurred in 14.7% of diabetic MI patients and 18.9% of those without diabetes. However, 11.5% of MI patients with diabetes were Killup class III/IV, compared with 6.5% of those without diabetes.
A history of previous MI was present in 31% of diabetic patients compared with 22% of those without diabetes. The diabetic group also had significantly higher rates of background hypercholesterolemia, hypertension, renal dysfunction, previous revascularization, and prior stroke.
Preadmission use of cardiovascular risk-reducing medications was more common among the diabetic MI patients. Yet the use of these agents was actually low given that diabetes is a well-recognized risk factor for cardiovascular disease, Dr. Bui observed. Less than half of diabetic MI patients were on an ACE inhibitor or an angiotensin receptor blocker prior to their hospitalization for an MI. About 30% were taking a beta-blocker. A similar proportion of patients used a statin or other lipid-lowering agent.
Health care planners will be particularly interested in the NRMI 4-5 finding that the mean hospital length of stay was 6.5 days in acute MI patients with diabetes, compared with 5.2 days in those without a history of diabetes, Dr. Bui noted. Diabetes patients with a history of MI were hospitalized for about 20 hours longer than were nondiabetic patients with a prior MI. And diabetes patients without a prior MI were hospitalized for 14 hours longer than were nondiabetic patients with a history of MI, Dr. Bui said.
The NRMI project is funded by Genentech. Dr. Bui reported having no financial conflicts.
FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY
Major Finding: Patients with diabetes who are hospitalized for acute MI are at an adjusted 18% increased risk for in-hospital mortality, compared with nondiabetic MI patients.
Data Source: Data are from the National Registry of Myocardial Infarction (NRMI) 4-5, which in this analysis included nearly 250,000 patients presenting with acute MI to 823 hospitals.
Disclosures: The NRMI project is funded by Genentech. Dr. Bui reported having no financial conflicts.
Benzodiazepines Improve Dyspnea in Palliative Care Patients
DENVER – Low-dose adjunctive benzodiazepines are effective in combination with opioids for dyspnea in palliative care patients who don’t respond to opioids alone, according to Dr. Patama Gomutbutra.
When opioids alone aren’t bringing significant improvement, adding a benzodiazepine is worthwhile, she said. The question of whether benzodiazepines alone are effective in the management of dyspnea must await answers from randomized clinical trials.
Dr. Gomutbutra conducted a retrospective chart review of 303 inpatients with dyspnea evaluated by members of the University of California, San Francisco, palliative care program. These were seriously ill patients: Twenty-three percent had primary lung cancer, 32% had cancer outside the lung, 12% had heart failure, and 7% had chronic obstructive pulmonary disease. Of these patients, 47% died in the hospital and 25% were discharged to hospice.
At baseline, physicians rated dyspnea as severe in 19% of patients, moderate in 28%, and mild in 53%. At baseline, 49% of patients were already on opioids at a median dose of 52 mg/day; 87% of these patients remained on opioids at 24 hours, with a bump up in dose to a median of 60 mg/day. Of the patients not initially taking an opioid, 41% were placed on the medication at a median dose of 22 mg/day.
"Our results should not dissuade people from using opioids as the first-line treatment."
At baseline, 17% of patients were on a benzodiazepine at a median dose of 1 mg/day of oral lorazepam or its equivalent. At 24 hours, 24% of patients were on a benzodiazepine, again at a median daily dose of 1 mg.
At follow-up 24 hours after adjustment of dosages or addition of an opioid or a benzodiazepine, the population with severe dyspnea had fallen from 19% to 4%. Dyspnea was rated moderate in 18% and mild in 44%, and was absent in 34%.
Overall, 57% of patients had a clinically meaningful improvement in dyspnea of one severity grade or more, 37% remained the same, and the rest became worse, according to Dr. Gomutbutra of Chiang Mai (Thailand) University.
Taking an opioid and a benzodiazepine at follow-up was independently associated with a 2.1-fold increased likelihood of significant improvement in dyspnea. Having moderate or severe dyspnea at baseline was associated with 4.1- and 4.5-fold increased likelihoods of improvement, respectively.
Surprisingly, being on an opioid at baseline wasn’t associated with significant improvement at follow-up, even though opioids are guideline-recommended therapy for dyspnea.
Dr. Gomutbutra cautioned against overinterpretation of this finding, given that her study was retrospective and thus vulnerable to confounding. For example, she noted, the respiratory rate typically slows near death, so affected patients may not have received continued or increased doses of opioids.
"Our results should not dissuade people from using opioids as the first-line treatment," Dr. Gomutbutra emphasized.
Dr. Gomutbutra carried out this study after observing big differences in how dyspnea is managed in palliative care settings in the United States, compared with Thailand. While the median daily dose of opioids at baseline in the San Francisco study was 52 mg/day, a typical dose in Thailand would be 6 mg/day. And benzodiazepines are far more widely used in treating dyspnea there, she added.
She reported having no financial conflicts.
DENVER – Low-dose adjunctive benzodiazepines are effective in combination with opioids for dyspnea in palliative care patients who don’t respond to opioids alone, according to Dr. Patama Gomutbutra.
When opioids alone aren’t bringing significant improvement, adding a benzodiazepine is worthwhile, she said. The question of whether benzodiazepines alone are effective in the management of dyspnea must await answers from randomized clinical trials.
Dr. Gomutbutra conducted a retrospective chart review of 303 inpatients with dyspnea evaluated by members of the University of California, San Francisco, palliative care program. These were seriously ill patients: Twenty-three percent had primary lung cancer, 32% had cancer outside the lung, 12% had heart failure, and 7% had chronic obstructive pulmonary disease. Of these patients, 47% died in the hospital and 25% were discharged to hospice.
At baseline, physicians rated dyspnea as severe in 19% of patients, moderate in 28%, and mild in 53%. At baseline, 49% of patients were already on opioids at a median dose of 52 mg/day; 87% of these patients remained on opioids at 24 hours, with a bump up in dose to a median of 60 mg/day. Of the patients not initially taking an opioid, 41% were placed on the medication at a median dose of 22 mg/day.
"Our results should not dissuade people from using opioids as the first-line treatment."
At baseline, 17% of patients were on a benzodiazepine at a median dose of 1 mg/day of oral lorazepam or its equivalent. At 24 hours, 24% of patients were on a benzodiazepine, again at a median daily dose of 1 mg.
At follow-up 24 hours after adjustment of dosages or addition of an opioid or a benzodiazepine, the population with severe dyspnea had fallen from 19% to 4%. Dyspnea was rated moderate in 18% and mild in 44%, and was absent in 34%.
Overall, 57% of patients had a clinically meaningful improvement in dyspnea of one severity grade or more, 37% remained the same, and the rest became worse, according to Dr. Gomutbutra of Chiang Mai (Thailand) University.
Taking an opioid and a benzodiazepine at follow-up was independently associated with a 2.1-fold increased likelihood of significant improvement in dyspnea. Having moderate or severe dyspnea at baseline was associated with 4.1- and 4.5-fold increased likelihoods of improvement, respectively.
Surprisingly, being on an opioid at baseline wasn’t associated with significant improvement at follow-up, even though opioids are guideline-recommended therapy for dyspnea.
Dr. Gomutbutra cautioned against overinterpretation of this finding, given that her study was retrospective and thus vulnerable to confounding. For example, she noted, the respiratory rate typically slows near death, so affected patients may not have received continued or increased doses of opioids.
"Our results should not dissuade people from using opioids as the first-line treatment," Dr. Gomutbutra emphasized.
Dr. Gomutbutra carried out this study after observing big differences in how dyspnea is managed in palliative care settings in the United States, compared with Thailand. While the median daily dose of opioids at baseline in the San Francisco study was 52 mg/day, a typical dose in Thailand would be 6 mg/day. And benzodiazepines are far more widely used in treating dyspnea there, she added.
She reported having no financial conflicts.
DENVER – Low-dose adjunctive benzodiazepines are effective in combination with opioids for dyspnea in palliative care patients who don’t respond to opioids alone, according to Dr. Patama Gomutbutra.
When opioids alone aren’t bringing significant improvement, adding a benzodiazepine is worthwhile, she said. The question of whether benzodiazepines alone are effective in the management of dyspnea must await answers from randomized clinical trials.
Dr. Gomutbutra conducted a retrospective chart review of 303 inpatients with dyspnea evaluated by members of the University of California, San Francisco, palliative care program. These were seriously ill patients: Twenty-three percent had primary lung cancer, 32% had cancer outside the lung, 12% had heart failure, and 7% had chronic obstructive pulmonary disease. Of these patients, 47% died in the hospital and 25% were discharged to hospice.
At baseline, physicians rated dyspnea as severe in 19% of patients, moderate in 28%, and mild in 53%. At baseline, 49% of patients were already on opioids at a median dose of 52 mg/day; 87% of these patients remained on opioids at 24 hours, with a bump up in dose to a median of 60 mg/day. Of the patients not initially taking an opioid, 41% were placed on the medication at a median dose of 22 mg/day.
"Our results should not dissuade people from using opioids as the first-line treatment."
At baseline, 17% of patients were on a benzodiazepine at a median dose of 1 mg/day of oral lorazepam or its equivalent. At 24 hours, 24% of patients were on a benzodiazepine, again at a median daily dose of 1 mg.
At follow-up 24 hours after adjustment of dosages or addition of an opioid or a benzodiazepine, the population with severe dyspnea had fallen from 19% to 4%. Dyspnea was rated moderate in 18% and mild in 44%, and was absent in 34%.
Overall, 57% of patients had a clinically meaningful improvement in dyspnea of one severity grade or more, 37% remained the same, and the rest became worse, according to Dr. Gomutbutra of Chiang Mai (Thailand) University.
Taking an opioid and a benzodiazepine at follow-up was independently associated with a 2.1-fold increased likelihood of significant improvement in dyspnea. Having moderate or severe dyspnea at baseline was associated with 4.1- and 4.5-fold increased likelihoods of improvement, respectively.
Surprisingly, being on an opioid at baseline wasn’t associated with significant improvement at follow-up, even though opioids are guideline-recommended therapy for dyspnea.
Dr. Gomutbutra cautioned against overinterpretation of this finding, given that her study was retrospective and thus vulnerable to confounding. For example, she noted, the respiratory rate typically slows near death, so affected patients may not have received continued or increased doses of opioids.
"Our results should not dissuade people from using opioids as the first-line treatment," Dr. Gomutbutra emphasized.
Dr. Gomutbutra carried out this study after observing big differences in how dyspnea is managed in palliative care settings in the United States, compared with Thailand. While the median daily dose of opioids at baseline in the San Francisco study was 52 mg/day, a typical dose in Thailand would be 6 mg/day. And benzodiazepines are far more widely used in treating dyspnea there, she added.
She reported having no financial conflicts.
FROM THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF HOSPICE AND PALLIATIVE CARE MEDICINE
Major Finding: At follow-up 24 hours after adjustment of dosages or addition of an opioid or a benzodiazepine, the population with severe dyspnea had fallen from 19% to 4%. Dyspnea was rated moderate in 18% and mild in 44%, and was absent in 34%.
Data Source: Data were taken from a retrospective chart review of 303 inpatients with dyspnea evaluated by members of the University of California, San Francisco, palliative care program.
Disclosures: Dr. Gomutbutra reported having no financial conflicts.
Diabetes Managed More Tightly in Demented Patients
DENVER – It would seem logical to loosen the reins and manage diabetes less intensively in patients with comorbid dementia. That’s what American Geriatrics Society guidelines recommend. After all, the cognitive impairment in such patients renders them less able to manage a complicated medical regimen, and less communicative in describing complications when they arise.
But is less-stringent metabolic control in diabetic patients with comorbid dementia actually what happens in clinical practice? Mostly not, according to Dr. Paul Tatum of the University of Missouri, Columbia.
He pointed to a massive cross-sectional study involving 497,900 veterans aged 65 and older with type 2 diabetes. The combined prevalence of dementia and cognitive impairment was 13.1% in those aged 65-74, climbing to 24.2% among those aged 75 and older.
The veterans with dementia/cognitive impairment had more intensive diabetes management than did patients with neither condition. Their mean HbA1c value was lower. More of them were on insulin (30%, compared with 24% in elderly patients without dementia or cognitive impairment). And among all subjects on insulin, 26.5% of those with dementia and 19.5% with cognitive impairment experienced hypoglycemic episodes during the 2-year study period, significantly higher rates than the 14.4% among insulin-using diabetic patients without either condition.
The unadjusted odds ratio for hypoglycemia was 2.4 in veterans with dementia and 1.7 for those with cognitive impairment. After adjustment for other comorbid conditions, demographics, nursing home stays, and other potential confounders, the adjusted odds ratios for hypoglycemia were attenuated but still significant, at 1.58 for dementia and 1.13 for cognitive impairment (J. Am. Geriatr. Soc. 2011;59:2263-72).
"We can help change that paradigm," Dr. Tatum urged at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.
The American Geriatrics Society guideline on diabetes can be an ally in this regard. It states that "for frail older adults, persons with life expectancy of less than 5 years, and other in whom the risks of intensive glycemic control appear to outweigh the benefits, a less stringent target such as 8% is appropriate" (J. Am. Geriatr. Soc. 2003;51[5 suppl. guidelines]:S265-80).
The average life expectancy from the initial diagnosis of Alzheimer’s dementia is 4.5 years (Ann. Intern. Med. 2004;140:501-9).
The American Geriatrics Society guideline also emphasizes the importance of screening for cognitive impairment in older patients with diabetes. This point was driven home in a large, longitudinal cohort study conducted at Kaiser Permanente in Northern California.
The investigators followed 16,667 patients with type 2 diabetes, no cognitive impairment at baseline, and a mean age of 65 years. Subjects who experienced one or more acute hypoglycemic episodes severe enough to require hospitalization during 1980-2002 turned out to have an increased risk of being diagnosed with dementia in 2003-2007.
The risk was graded. Patients with a single episode of severe hypoglycemia had a fully adjusted 1.26-fold greater likelihood of later being diagnosed with dementia, compared with patients who had no episodes. Those with two episodes had a 1.8-fold increased risk, and three or more episodes placed an individual at a 1.94-fold increased risk. A similar relationship held true for emergency department visits for hypoglycemia and subsequent dementia risk. These findings were independent of HbA1c level, diabetes comorbidities, and diabetes medications (JAMA 2009;301:1565-72).
It’s unclear whether hypoglycemia increases the risk of dementia in older type 2 diabetes patients because severe hypoglycemia can cause lasting neurologic insult, or whether severe hypoglycemia is an early marker for cognitive decline.
For busy clinicians who say they simply can’t fit in cognitive assessments in older patients, diabetic or otherwise, Dr. Tatum recommended the Mini-Cog as a 3-minute test that approximates the Mini-Mental State Exam, which takes at least twice as long. The Mini-Cog involves a three-item recall test for memory, along with a simply scored clock-drawing test.
"It’s at least a start for that busy physician who says, ‘I just don’t have time,’ " according to Dr. Tatum.
The Mini-Mental State Exam is not a great instrument for assessing executive function, which often deteriorates well before memory. He recommended the Montreal Cognitive Assessment as a useful tool for a more detailed evaluation of executive function as part of cognitive testing.
Dr. Tatum said that the American Geriatrics Society recommendations regarding diabetes and dementia are consistent with the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines on dementia, which he finds quite helpful. Among the best practices highlighted in the NICE guidelines: "Adopt a palliative care approach from diagnosis until death to support the quality of life of people with dementia and to enable them to die with dignity and in the place of their choosing."
Dr. Tatum reported having no relevant financial conflicts.
Ideally targeted glucose values for specific patient populations – such as those hospitalized with acute illness, or frail older adults – remains a series of moving targets.
 |
|
Guidelines are offered for both populations and are not dissimilar. In 2011, the American College of Physicians put forth recommendations for glycemic control in hospitalized patients (Ann. Intern. Med. 2011;154:260-7). For non-ICU patients, intensive insulin therapy should not be given to control glucose strictly, nor should it be administered with the intent of normalizing glucose values. The American Geriatrics Society loosens the HbA1c goal for the elderly to 8% (J. Am. Geriatr. Soc. 2003;51[5 suppl. guidelines]:S265-280). When these AGS guidelines are followed, the early part of the implementation process is accompanied by a rise in severe hypoglycemic episodes requiring emergency department visits (J. Am. Geriatr. Soc. 2011;59:666-72).
The association between hypoglycemia and cognition prompts hospitalists to be more wary of the ACP guidelines, and to implement thoughtful discharge plans around glycemic control for their elderly patients. It appears that an attempt at tighter control of glucose values may lead to less-desirable outcomes in the form of diminished cognition and greater resource utilization. This association may also cause us to reevaluate an even more liberal view on elderly HbA1c goals.
Dr. Stephen J. Bekanich is the medical director of palliative care services at the University of Miami.
Ideally targeted glucose values for specific patient populations – such as those hospitalized with acute illness, or frail older adults – remains a series of moving targets.
|
|
Guidelines are offered for both populations and are not dissimilar. In 2011, the American College of Physicians put forth recommendations for glycemic control in hospitalized patients (Ann. Intern. Med. 2011;154:260-7). For non-ICU patients, intensive insulin therapy should not be given to control glucose strictly, nor should it be administered with the intent of normalizing glucose values. The American Geriatrics Society loosens the HbA1c goal for the elderly to 8% (J. Am. Geriatr. Soc. 2003;51[5 suppl. guidelines]:S265-280). When these AGS guidelines are followed, the early part of the implementation process is accompanied by a rise in severe hypoglycemic episodes requiring emergency department visits (J. Am. Geriatr. Soc. 2011;59:666-72).
The association between hypoglycemia and cognition prompts hospitalists to be more wary of the ACP guidelines, and to implement thoughtful discharge plans around glycemic control for their elderly patients. It appears that an attempt at tighter control of glucose values may lead to less-desirable outcomes in the form of diminished cognition and greater resource utilization. This association may also cause us to reevaluate an even more liberal view on elderly HbA1c goals.
Dr. Stephen J. Bekanich is the medical director of palliative care services at the University of Miami.
Ideally targeted glucose values for specific patient populations – such as those hospitalized with acute illness, or frail older adults – remains a series of moving targets.
|
|
Guidelines are offered for both populations and are not dissimilar. In 2011, the American College of Physicians put forth recommendations for glycemic control in hospitalized patients (Ann. Intern. Med. 2011;154:260-7). For non-ICU patients, intensive insulin therapy should not be given to control glucose strictly, nor should it be administered with the intent of normalizing glucose values. The American Geriatrics Society loosens the HbA1c goal for the elderly to 8% (J. Am. Geriatr. Soc. 2003;51[5 suppl. guidelines]:S265-280). When these AGS guidelines are followed, the early part of the implementation process is accompanied by a rise in severe hypoglycemic episodes requiring emergency department visits (J. Am. Geriatr. Soc. 2011;59:666-72).
The association between hypoglycemia and cognition prompts hospitalists to be more wary of the ACP guidelines, and to implement thoughtful discharge plans around glycemic control for their elderly patients. It appears that an attempt at tighter control of glucose values may lead to less-desirable outcomes in the form of diminished cognition and greater resource utilization. This association may also cause us to reevaluate an even more liberal view on elderly HbA1c goals.
Dr. Stephen J. Bekanich is the medical director of palliative care services at the University of Miami.
DENVER – It would seem logical to loosen the reins and manage diabetes less intensively in patients with comorbid dementia. That’s what American Geriatrics Society guidelines recommend. After all, the cognitive impairment in such patients renders them less able to manage a complicated medical regimen, and less communicative in describing complications when they arise.
But is less-stringent metabolic control in diabetic patients with comorbid dementia actually what happens in clinical practice? Mostly not, according to Dr. Paul Tatum of the University of Missouri, Columbia.
He pointed to a massive cross-sectional study involving 497,900 veterans aged 65 and older with type 2 diabetes. The combined prevalence of dementia and cognitive impairment was 13.1% in those aged 65-74, climbing to 24.2% among those aged 75 and older.
The veterans with dementia/cognitive impairment had more intensive diabetes management than did patients with neither condition. Their mean HbA1c value was lower. More of them were on insulin (30%, compared with 24% in elderly patients without dementia or cognitive impairment). And among all subjects on insulin, 26.5% of those with dementia and 19.5% with cognitive impairment experienced hypoglycemic episodes during the 2-year study period, significantly higher rates than the 14.4% among insulin-using diabetic patients without either condition.
The unadjusted odds ratio for hypoglycemia was 2.4 in veterans with dementia and 1.7 for those with cognitive impairment. After adjustment for other comorbid conditions, demographics, nursing home stays, and other potential confounders, the adjusted odds ratios for hypoglycemia were attenuated but still significant, at 1.58 for dementia and 1.13 for cognitive impairment (J. Am. Geriatr. Soc. 2011;59:2263-72).
"We can help change that paradigm," Dr. Tatum urged at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.
The American Geriatrics Society guideline on diabetes can be an ally in this regard. It states that "for frail older adults, persons with life expectancy of less than 5 years, and other in whom the risks of intensive glycemic control appear to outweigh the benefits, a less stringent target such as 8% is appropriate" (J. Am. Geriatr. Soc. 2003;51[5 suppl. guidelines]:S265-80).
The average life expectancy from the initial diagnosis of Alzheimer’s dementia is 4.5 years (Ann. Intern. Med. 2004;140:501-9).
The American Geriatrics Society guideline also emphasizes the importance of screening for cognitive impairment in older patients with diabetes. This point was driven home in a large, longitudinal cohort study conducted at Kaiser Permanente in Northern California.
The investigators followed 16,667 patients with type 2 diabetes, no cognitive impairment at baseline, and a mean age of 65 years. Subjects who experienced one or more acute hypoglycemic episodes severe enough to require hospitalization during 1980-2002 turned out to have an increased risk of being diagnosed with dementia in 2003-2007.
The risk was graded. Patients with a single episode of severe hypoglycemia had a fully adjusted 1.26-fold greater likelihood of later being diagnosed with dementia, compared with patients who had no episodes. Those with two episodes had a 1.8-fold increased risk, and three or more episodes placed an individual at a 1.94-fold increased risk. A similar relationship held true for emergency department visits for hypoglycemia and subsequent dementia risk. These findings were independent of HbA1c level, diabetes comorbidities, and diabetes medications (JAMA 2009;301:1565-72).
It’s unclear whether hypoglycemia increases the risk of dementia in older type 2 diabetes patients because severe hypoglycemia can cause lasting neurologic insult, or whether severe hypoglycemia is an early marker for cognitive decline.
For busy clinicians who say they simply can’t fit in cognitive assessments in older patients, diabetic or otherwise, Dr. Tatum recommended the Mini-Cog as a 3-minute test that approximates the Mini-Mental State Exam, which takes at least twice as long. The Mini-Cog involves a three-item recall test for memory, along with a simply scored clock-drawing test.
"It’s at least a start for that busy physician who says, ‘I just don’t have time,’ " according to Dr. Tatum.
The Mini-Mental State Exam is not a great instrument for assessing executive function, which often deteriorates well before memory. He recommended the Montreal Cognitive Assessment as a useful tool for a more detailed evaluation of executive function as part of cognitive testing.
Dr. Tatum said that the American Geriatrics Society recommendations regarding diabetes and dementia are consistent with the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines on dementia, which he finds quite helpful. Among the best practices highlighted in the NICE guidelines: "Adopt a palliative care approach from diagnosis until death to support the quality of life of people with dementia and to enable them to die with dignity and in the place of their choosing."
Dr. Tatum reported having no relevant financial conflicts.
DENVER – It would seem logical to loosen the reins and manage diabetes less intensively in patients with comorbid dementia. That’s what American Geriatrics Society guidelines recommend. After all, the cognitive impairment in such patients renders them less able to manage a complicated medical regimen, and less communicative in describing complications when they arise.
But is less-stringent metabolic control in diabetic patients with comorbid dementia actually what happens in clinical practice? Mostly not, according to Dr. Paul Tatum of the University of Missouri, Columbia.
He pointed to a massive cross-sectional study involving 497,900 veterans aged 65 and older with type 2 diabetes. The combined prevalence of dementia and cognitive impairment was 13.1% in those aged 65-74, climbing to 24.2% among those aged 75 and older.
The veterans with dementia/cognitive impairment had more intensive diabetes management than did patients with neither condition. Their mean HbA1c value was lower. More of them were on insulin (30%, compared with 24% in elderly patients without dementia or cognitive impairment). And among all subjects on insulin, 26.5% of those with dementia and 19.5% with cognitive impairment experienced hypoglycemic episodes during the 2-year study period, significantly higher rates than the 14.4% among insulin-using diabetic patients without either condition.
The unadjusted odds ratio for hypoglycemia was 2.4 in veterans with dementia and 1.7 for those with cognitive impairment. After adjustment for other comorbid conditions, demographics, nursing home stays, and other potential confounders, the adjusted odds ratios for hypoglycemia were attenuated but still significant, at 1.58 for dementia and 1.13 for cognitive impairment (J. Am. Geriatr. Soc. 2011;59:2263-72).
"We can help change that paradigm," Dr. Tatum urged at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.
The American Geriatrics Society guideline on diabetes can be an ally in this regard. It states that "for frail older adults, persons with life expectancy of less than 5 years, and other in whom the risks of intensive glycemic control appear to outweigh the benefits, a less stringent target such as 8% is appropriate" (J. Am. Geriatr. Soc. 2003;51[5 suppl. guidelines]:S265-80).
The average life expectancy from the initial diagnosis of Alzheimer’s dementia is 4.5 years (Ann. Intern. Med. 2004;140:501-9).
The American Geriatrics Society guideline also emphasizes the importance of screening for cognitive impairment in older patients with diabetes. This point was driven home in a large, longitudinal cohort study conducted at Kaiser Permanente in Northern California.
The investigators followed 16,667 patients with type 2 diabetes, no cognitive impairment at baseline, and a mean age of 65 years. Subjects who experienced one or more acute hypoglycemic episodes severe enough to require hospitalization during 1980-2002 turned out to have an increased risk of being diagnosed with dementia in 2003-2007.
The risk was graded. Patients with a single episode of severe hypoglycemia had a fully adjusted 1.26-fold greater likelihood of later being diagnosed with dementia, compared with patients who had no episodes. Those with two episodes had a 1.8-fold increased risk, and three or more episodes placed an individual at a 1.94-fold increased risk. A similar relationship held true for emergency department visits for hypoglycemia and subsequent dementia risk. These findings were independent of HbA1c level, diabetes comorbidities, and diabetes medications (JAMA 2009;301:1565-72).
It’s unclear whether hypoglycemia increases the risk of dementia in older type 2 diabetes patients because severe hypoglycemia can cause lasting neurologic insult, or whether severe hypoglycemia is an early marker for cognitive decline.
For busy clinicians who say they simply can’t fit in cognitive assessments in older patients, diabetic or otherwise, Dr. Tatum recommended the Mini-Cog as a 3-minute test that approximates the Mini-Mental State Exam, which takes at least twice as long. The Mini-Cog involves a three-item recall test for memory, along with a simply scored clock-drawing test.
"It’s at least a start for that busy physician who says, ‘I just don’t have time,’ " according to Dr. Tatum.
The Mini-Mental State Exam is not a great instrument for assessing executive function, which often deteriorates well before memory. He recommended the Montreal Cognitive Assessment as a useful tool for a more detailed evaluation of executive function as part of cognitive testing.
Dr. Tatum said that the American Geriatrics Society recommendations regarding diabetes and dementia are consistent with the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines on dementia, which he finds quite helpful. Among the best practices highlighted in the NICE guidelines: "Adopt a palliative care approach from diagnosis until death to support the quality of life of people with dementia and to enable them to die with dignity and in the place of their choosing."
Dr. Tatum reported having no relevant financial conflicts.
EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF HOSPICE AND PALLIATIVE CARE MEDICINE
Novel Agent Lowered LDL Up to 72%
CHICAGO – An investigational fully human monoclonal antibody slashed low-density lipoprotein cholesterol levels by up to 72% in a phase II clinical trial in dyslipidemic patients not at goal despite already being on a statin.
The study results for the monoclonal antibody known for now as SAR236553/REGN727 caused head-swiveling and double-takes at the annual meeting of the American College of Cardiology.
"We need to understand: This is a ‘wow.’ It could be a game changer in the future," commented scientific session program committee cochair Dr. Rick A. Nishimura, professor of medicine at the Mayo Clinic, Rochester, Minn. He was referring to the randomized, double-blind, placebo-controlled, 12-week phase II study presented by James M. McKenney, Pharm.D. The trial involved 183 patients with an LDL cholesterol level above the target of 100 mg/dL despite an average of 7 years of statin therapy. The participants remained on atorvastatin at 10, 20, or 40 mg/day as background therapy while being randomized to 12 weeks of subcutaneously administered SAR236553/REGN727 at one of five dosing regimens or to placebo.
At the most effective dosing schedule – 150 mg once every 2 weeks – LDL dropped by a mean of 72% at 12 weeks, from a baseline of 124 mg/dL. Within the first 2 weeks the LDL level had already fallen by 60%.
A clear dose-response relationship was evident, with dosing at 50 and 100 mg once every 2 weeks eliciting mean 40% and 64% LDL reductions, respectively, reported Dr. McKenney, chief executive officer at National Clinical Research, Richmond, Va.
"This is monumental clearance of LDL. It’s just unheard of, especially considering the statin these patients were on should already have produced about a 40% decrease in LDL," he said. "If the drug pans out, if it continues to show efficacy and especially if it shows safety, we may be moving into a new era in the treatment of lipid disorders and, more importantly, in the reduction of heart disease in this country."
At the optimal dosing regimen of SAR236553/REGN727, an agent Dr. McKenney referred to as "553" for the sake of brevity, patients also had mean reductions of 27% in lipoprotein(a), 56% in apolipoprotein B, and 63% in non-HDL (non-high-density lipoprotein) cholesterol, along with a nonsignificant trend for lower triglycerides.
The monoclonal antibody is highly specific for proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9). This protein plays a pivotal role in the degradation of LDL receptors, thereby interfering with cholesterol uptake by the liver.
Treatment with 553 was well tolerated; the most common side effect was mild, transient, injection site reactions. Importantly, given that patients were already on statin therapy, there were no increases in hepatic or muscle-related enzymes.
The one significant adverse event was a case of biopsy-confirmed leukocytoclastic vasculitis occurring 9 days after a patient received a first 300-mg injection of 553. The reaction took the form of a rash on the arms, legs, and abdomen, with no other organ involvement. It responded quickly to drug withdrawal and initiation of prednisone. No other cases of leukocytoclastic vasculitis occurred in any other 553-treated patients, including those who participated in three just-published phase I studies (N. Engl. J. Med. 2012;366:1108-18).
No antidrug antibodies were detected shortly after the patient developed leukocytoclastic vasculitis; however, low-level titers were found at week 20. The patient remained negative for antinuclear antibodies through 6 months of follow-up blood tests.
Leukocytoclastic vasculitis is a rare, generally benign disease with an incidence of 40-60 cases per million persons per year. Medications are identified as the cause of about 20% of cases, with antibiotics and NSAIDs being among the most common offenders. Leukocytoclastic vasculitis is listed as a possible adverse event in the product labeling for most monoclonal antibody therapies, Dr. McKenney noted.
Large phase III clinical trials will begin enrollment later this year. They will focus on patients at high cardiovascular risk, including those with familial hypercholesterolemia and/or prior vascular events who aren’t at goal despite statin therapy.
Coinvestigator Dr. Dean J. Kereiakes said in an interview that one of the most intriguing observations in the phase II study was that mean LDL levels were still on their way down when 553 was stopped after 12 weeks.
"We didn’t hit the nadir. The LDL hadn’t plateaued. If we had taken patients out to 18-20 weeks, we might have seen an even greater delta," according to Dr. Kereiakes of Christ Hospital, Cincinnati.
He sees the target population for 553 as being the large number of patients who can’t reach their LDL target despite maximum doses of currently approved medications, as well as those who can’t do so because they can’t tolerate maximum doses of those drugs.
"I’d say probably more than one-third of my patients are on combination therapy for lipid lowering," the cardiologist said.
With 553, it will also become possible to take to its logical conclusion the hypothesis that a lower LDL is better for preventing atherosclerosis.
"The average LDL in a newborn is 35 mg/dL, and they have clean vasculature. There aren’t even the lipid streaks that occur as the first step in the atherosclerotic process," he noted.
In phase III, the monoclonal antibody will be self-administered subcutaneously using a fixed-dose pen, much like the insulin-sensitizing agent exenatide (Byetta or Bydureon).
Discussant Dr. Karol E. Watson said 553 "has a lot of potential and certainly does offer up some hope." But she zeroed in on the fact that as a monoclonal antibody – even a fully human one – it has the potential for autoimmunity.
"That is something that clearly would limit the usefulness of this molecule. I’d want to see more data on that," added Dr. Watson, codirector of the University of California, Los Angeles, program in preventive cardiology.
Her fellow panelist Dr. Christie M. Ballantyne was particularly intrigued by the fact that C-reactive protein levels did not change significantly during the phase II study.
A clinical trial with 553 could settle the question of whether the clinical benefits of statin therapy are due solely to LDL lowering, or if the concomitant decrease in CRP is also essential, said Dr. Ballantyne, professor of medicine at Baylor College of Medicine, Houston.
The study was sponsored by Sanofi and Regeneron. Dr. McKenney reported that he has received research grants from both companies to conduct clinical trials of 553. He also serves as a consultant to Sanofi, which is developing 553, and to numerous other pharmaceutical companies with an interest in lipid-altering agents. Dr. Kereiakes reported having no financial conflicts.
CHICAGO – An investigational fully human monoclonal antibody slashed low-density lipoprotein cholesterol levels by up to 72% in a phase II clinical trial in dyslipidemic patients not at goal despite already being on a statin.
The study results for the monoclonal antibody known for now as SAR236553/REGN727 caused head-swiveling and double-takes at the annual meeting of the American College of Cardiology.
"We need to understand: This is a ‘wow.’ It could be a game changer in the future," commented scientific session program committee cochair Dr. Rick A. Nishimura, professor of medicine at the Mayo Clinic, Rochester, Minn. He was referring to the randomized, double-blind, placebo-controlled, 12-week phase II study presented by James M. McKenney, Pharm.D. The trial involved 183 patients with an LDL cholesterol level above the target of 100 mg/dL despite an average of 7 years of statin therapy. The participants remained on atorvastatin at 10, 20, or 40 mg/day as background therapy while being randomized to 12 weeks of subcutaneously administered SAR236553/REGN727 at one of five dosing regimens or to placebo.
At the most effective dosing schedule – 150 mg once every 2 weeks – LDL dropped by a mean of 72% at 12 weeks, from a baseline of 124 mg/dL. Within the first 2 weeks the LDL level had already fallen by 60%.
A clear dose-response relationship was evident, with dosing at 50 and 100 mg once every 2 weeks eliciting mean 40% and 64% LDL reductions, respectively, reported Dr. McKenney, chief executive officer at National Clinical Research, Richmond, Va.
"This is monumental clearance of LDL. It’s just unheard of, especially considering the statin these patients were on should already have produced about a 40% decrease in LDL," he said. "If the drug pans out, if it continues to show efficacy and especially if it shows safety, we may be moving into a new era in the treatment of lipid disorders and, more importantly, in the reduction of heart disease in this country."
At the optimal dosing regimen of SAR236553/REGN727, an agent Dr. McKenney referred to as "553" for the sake of brevity, patients also had mean reductions of 27% in lipoprotein(a), 56% in apolipoprotein B, and 63% in non-HDL (non-high-density lipoprotein) cholesterol, along with a nonsignificant trend for lower triglycerides.
The monoclonal antibody is highly specific for proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9). This protein plays a pivotal role in the degradation of LDL receptors, thereby interfering with cholesterol uptake by the liver.
Treatment with 553 was well tolerated; the most common side effect was mild, transient, injection site reactions. Importantly, given that patients were already on statin therapy, there were no increases in hepatic or muscle-related enzymes.
The one significant adverse event was a case of biopsy-confirmed leukocytoclastic vasculitis occurring 9 days after a patient received a first 300-mg injection of 553. The reaction took the form of a rash on the arms, legs, and abdomen, with no other organ involvement. It responded quickly to drug withdrawal and initiation of prednisone. No other cases of leukocytoclastic vasculitis occurred in any other 553-treated patients, including those who participated in three just-published phase I studies (N. Engl. J. Med. 2012;366:1108-18).
No antidrug antibodies were detected shortly after the patient developed leukocytoclastic vasculitis; however, low-level titers were found at week 20. The patient remained negative for antinuclear antibodies through 6 months of follow-up blood tests.
Leukocytoclastic vasculitis is a rare, generally benign disease with an incidence of 40-60 cases per million persons per year. Medications are identified as the cause of about 20% of cases, with antibiotics and NSAIDs being among the most common offenders. Leukocytoclastic vasculitis is listed as a possible adverse event in the product labeling for most monoclonal antibody therapies, Dr. McKenney noted.
Large phase III clinical trials will begin enrollment later this year. They will focus on patients at high cardiovascular risk, including those with familial hypercholesterolemia and/or prior vascular events who aren’t at goal despite statin therapy.
Coinvestigator Dr. Dean J. Kereiakes said in an interview that one of the most intriguing observations in the phase II study was that mean LDL levels were still on their way down when 553 was stopped after 12 weeks.
"We didn’t hit the nadir. The LDL hadn’t plateaued. If we had taken patients out to 18-20 weeks, we might have seen an even greater delta," according to Dr. Kereiakes of Christ Hospital, Cincinnati.
He sees the target population for 553 as being the large number of patients who can’t reach their LDL target despite maximum doses of currently approved medications, as well as those who can’t do so because they can’t tolerate maximum doses of those drugs.
"I’d say probably more than one-third of my patients are on combination therapy for lipid lowering," the cardiologist said.
With 553, it will also become possible to take to its logical conclusion the hypothesis that a lower LDL is better for preventing atherosclerosis.
"The average LDL in a newborn is 35 mg/dL, and they have clean vasculature. There aren’t even the lipid streaks that occur as the first step in the atherosclerotic process," he noted.
In phase III, the monoclonal antibody will be self-administered subcutaneously using a fixed-dose pen, much like the insulin-sensitizing agent exenatide (Byetta or Bydureon).
Discussant Dr. Karol E. Watson said 553 "has a lot of potential and certainly does offer up some hope." But she zeroed in on the fact that as a monoclonal antibody – even a fully human one – it has the potential for autoimmunity.
"That is something that clearly would limit the usefulness of this molecule. I’d want to see more data on that," added Dr. Watson, codirector of the University of California, Los Angeles, program in preventive cardiology.
Her fellow panelist Dr. Christie M. Ballantyne was particularly intrigued by the fact that C-reactive protein levels did not change significantly during the phase II study.
A clinical trial with 553 could settle the question of whether the clinical benefits of statin therapy are due solely to LDL lowering, or if the concomitant decrease in CRP is also essential, said Dr. Ballantyne, professor of medicine at Baylor College of Medicine, Houston.
The study was sponsored by Sanofi and Regeneron. Dr. McKenney reported that he has received research grants from both companies to conduct clinical trials of 553. He also serves as a consultant to Sanofi, which is developing 553, and to numerous other pharmaceutical companies with an interest in lipid-altering agents. Dr. Kereiakes reported having no financial conflicts.
CHICAGO – An investigational fully human monoclonal antibody slashed low-density lipoprotein cholesterol levels by up to 72% in a phase II clinical trial in dyslipidemic patients not at goal despite already being on a statin.
The study results for the monoclonal antibody known for now as SAR236553/REGN727 caused head-swiveling and double-takes at the annual meeting of the American College of Cardiology.
"We need to understand: This is a ‘wow.’ It could be a game changer in the future," commented scientific session program committee cochair Dr. Rick A. Nishimura, professor of medicine at the Mayo Clinic, Rochester, Minn. He was referring to the randomized, double-blind, placebo-controlled, 12-week phase II study presented by James M. McKenney, Pharm.D. The trial involved 183 patients with an LDL cholesterol level above the target of 100 mg/dL despite an average of 7 years of statin therapy. The participants remained on atorvastatin at 10, 20, or 40 mg/day as background therapy while being randomized to 12 weeks of subcutaneously administered SAR236553/REGN727 at one of five dosing regimens or to placebo.
At the most effective dosing schedule – 150 mg once every 2 weeks – LDL dropped by a mean of 72% at 12 weeks, from a baseline of 124 mg/dL. Within the first 2 weeks the LDL level had already fallen by 60%.
A clear dose-response relationship was evident, with dosing at 50 and 100 mg once every 2 weeks eliciting mean 40% and 64% LDL reductions, respectively, reported Dr. McKenney, chief executive officer at National Clinical Research, Richmond, Va.
"This is monumental clearance of LDL. It’s just unheard of, especially considering the statin these patients were on should already have produced about a 40% decrease in LDL," he said. "If the drug pans out, if it continues to show efficacy and especially if it shows safety, we may be moving into a new era in the treatment of lipid disorders and, more importantly, in the reduction of heart disease in this country."
At the optimal dosing regimen of SAR236553/REGN727, an agent Dr. McKenney referred to as "553" for the sake of brevity, patients also had mean reductions of 27% in lipoprotein(a), 56% in apolipoprotein B, and 63% in non-HDL (non-high-density lipoprotein) cholesterol, along with a nonsignificant trend for lower triglycerides.
The monoclonal antibody is highly specific for proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9). This protein plays a pivotal role in the degradation of LDL receptors, thereby interfering with cholesterol uptake by the liver.
Treatment with 553 was well tolerated; the most common side effect was mild, transient, injection site reactions. Importantly, given that patients were already on statin therapy, there were no increases in hepatic or muscle-related enzymes.
The one significant adverse event was a case of biopsy-confirmed leukocytoclastic vasculitis occurring 9 days after a patient received a first 300-mg injection of 553. The reaction took the form of a rash on the arms, legs, and abdomen, with no other organ involvement. It responded quickly to drug withdrawal and initiation of prednisone. No other cases of leukocytoclastic vasculitis occurred in any other 553-treated patients, including those who participated in three just-published phase I studies (N. Engl. J. Med. 2012;366:1108-18).
No antidrug antibodies were detected shortly after the patient developed leukocytoclastic vasculitis; however, low-level titers were found at week 20. The patient remained negative for antinuclear antibodies through 6 months of follow-up blood tests.
Leukocytoclastic vasculitis is a rare, generally benign disease with an incidence of 40-60 cases per million persons per year. Medications are identified as the cause of about 20% of cases, with antibiotics and NSAIDs being among the most common offenders. Leukocytoclastic vasculitis is listed as a possible adverse event in the product labeling for most monoclonal antibody therapies, Dr. McKenney noted.
Large phase III clinical trials will begin enrollment later this year. They will focus on patients at high cardiovascular risk, including those with familial hypercholesterolemia and/or prior vascular events who aren’t at goal despite statin therapy.
Coinvestigator Dr. Dean J. Kereiakes said in an interview that one of the most intriguing observations in the phase II study was that mean LDL levels were still on their way down when 553 was stopped after 12 weeks.
"We didn’t hit the nadir. The LDL hadn’t plateaued. If we had taken patients out to 18-20 weeks, we might have seen an even greater delta," according to Dr. Kereiakes of Christ Hospital, Cincinnati.
He sees the target population for 553 as being the large number of patients who can’t reach their LDL target despite maximum doses of currently approved medications, as well as those who can’t do so because they can’t tolerate maximum doses of those drugs.
"I’d say probably more than one-third of my patients are on combination therapy for lipid lowering," the cardiologist said.
With 553, it will also become possible to take to its logical conclusion the hypothesis that a lower LDL is better for preventing atherosclerosis.
"The average LDL in a newborn is 35 mg/dL, and they have clean vasculature. There aren’t even the lipid streaks that occur as the first step in the atherosclerotic process," he noted.
In phase III, the monoclonal antibody will be self-administered subcutaneously using a fixed-dose pen, much like the insulin-sensitizing agent exenatide (Byetta or Bydureon).
Discussant Dr. Karol E. Watson said 553 "has a lot of potential and certainly does offer up some hope." But she zeroed in on the fact that as a monoclonal antibody – even a fully human one – it has the potential for autoimmunity.
"That is something that clearly would limit the usefulness of this molecule. I’d want to see more data on that," added Dr. Watson, codirector of the University of California, Los Angeles, program in preventive cardiology.
Her fellow panelist Dr. Christie M. Ballantyne was particularly intrigued by the fact that C-reactive protein levels did not change significantly during the phase II study.
A clinical trial with 553 could settle the question of whether the clinical benefits of statin therapy are due solely to LDL lowering, or if the concomitant decrease in CRP is also essential, said Dr. Ballantyne, professor of medicine at Baylor College of Medicine, Houston.
The study was sponsored by Sanofi and Regeneron. Dr. McKenney reported that he has received research grants from both companies to conduct clinical trials of 553. He also serves as a consultant to Sanofi, which is developing 553, and to numerous other pharmaceutical companies with an interest in lipid-altering agents. Dr. Kereiakes reported having no financial conflicts.
FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY
Major Finding: At 150 mg SAR236553/REGN727 once every 2 weeks, LDL
dropped by a mean of 72% at 12 weeks, from a baseline of 124 mg/dL.
Within the first 2 weeks the LDL level had already fallen by 60%.
Data Source: The 12weeks phase II study was randomized, double-blind, placebo-controlled and involved 183 patients
with an LDL cholesterol level above the target of 100 mg/dL despite an
average of 7 years of statin therapy.
Disclosures: The study was sponsored by Sanofi and Regeneron. Dr. McKenney reported
that he has received research grants from both companies to conduct
clinical trials of 553. He also serves as a consultant to Sanofi, which
is developing 553, and to numerous other pharmaceutical companies with
an interest in lipid-altering agents. Dr. Kereiakes reported having no
financial conflicts.
Term 'Hemangioma' Used Incorrectly in 71% of Cases
WAIKOLOA, HAWAII – The term "hemangioma" is used erroneously in 70% of cases of vascular anomalies, a study has shown.
"We’re not doing so well. That’s a high rate of misses," Dr. Moise L. Levy said in highlighting the findings.
The study, conducted by investigators at Harvard Medical School, Boston, involved an analysis of all 320 English language articles in PubMed that were published in 2009 with the word "hemangioma" in the title or abstract.
The investigators sought to learn whether the approved binary classification system for vascular anomalies introduced by the International Society for the Study of Vascular Anomalies (ISSVA) 15 years ago was being utilized by physicians and the consequences, in terms of treatment appropriateness, when it wasn’t.
Overall, the term "hemangioma" was used incorrectly in 71% of cases. Improper use of the term diagnostically was associated with a 21% rate of erroneous treatment. In contrast, patients whose lesions were described using ISSVA terminology had a 0% rate of improper treatment.
Physicians in some specialties did better than others. Radiologists used the term inappropriately in 84% of cases. Pediatricians, internists, general surgeons, ob.gyns., and pathologists who authored papers misused the term "hemangioma" in 60%-70% of cases. And, dermatologists, plastic surgeons, pediatric surgeons, and otolaryngologists used the term inappropriately in 32% of cases.
The investigators noted that the 71% incidence of incorrect nomenclature and 21% rate of incorrect treatment probably underestimate the true rates in clinical practice (Plast. Reconstr. Surg. 2011;127:347-51).
Dr. Levy said the study results indicate most physicians still use the antiquated method of classifying vascular anomalies learned during training. They’re using the term "hemangioma" to describe a wide variety of vascular birthmarks with differing etiologies and behavior patterns, ranging from strawberry hemangiomas to port wine stains, capillary hemangiomas, infantile hemangiomas, and lower-segment hemangiomas, he said.
The ISSVA system of classification divides vascular anomalies into two categories: tumors and malformations. Tumors show rapid growth in the neonatal period, followed in most cases by slow involution. These lesions are comprised of biologically active tissues that procreate in culture. Examples include infantile hemangioma, tufted angioma, and pyogenic granuloma.
Malformations are by definition present at birth. Their growth rate is commensurate with that of the child. Examples include capillary, venous, and lymphatic malformations, explained Dr. Levy, a pediatric dermatologist at Dell Children’s Medical Center of Central Texas in Austin.
In the Harvard study, misdiagnosis of malformations occurred significantly more often than for vascular tumors. The high misdiagnosis rates underscore a key point: Nonspecialists should consider referral of any patient with a complicated lesion, or one raising aesthetic concern, or when the diagnosis is unclear, Dr. Levy said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).
"The bottom line is we need to encourage our primary care providers to get cases to us early rather than after a problem is discovered," he said.
Infantile hemangiomas are the most common type of vascular tumors in infancy. They vary tremendously in their threat level. The first weeks to months of life are a critical time in the growth of these lesions. Useful guidance as to when to refer children with infantile hemangiomas and when reassurance can be offered is provided by a multicenter prospective study published by pediatric dermatologists several years ago, Dr. Levy continued.
The investigators concluded that infantile hemangiomas posing the greatest risk for serious morbidity based upon morphology and/or anatomic site include large, segmented facial lesions because of the possibility of PHACES syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities, and sternal clefting).
Other red flag infantile hemangiomas identified in the study as warranting referral included perioral, periocular, perineal, axillary, or retrobulbar lesions; segmental lesions on the central neck, or what in later life would be called the beard area; and segmental lesions overlying the lumbosacral spine (Pediatrics 2008;122:360-7).
Dr. Levy reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.
WAIKOLOA, HAWAII – The term "hemangioma" is used erroneously in 70% of cases of vascular anomalies, a study has shown.
"We’re not doing so well. That’s a high rate of misses," Dr. Moise L. Levy said in highlighting the findings.
The study, conducted by investigators at Harvard Medical School, Boston, involved an analysis of all 320 English language articles in PubMed that were published in 2009 with the word "hemangioma" in the title or abstract.
The investigators sought to learn whether the approved binary classification system for vascular anomalies introduced by the International Society for the Study of Vascular Anomalies (ISSVA) 15 years ago was being utilized by physicians and the consequences, in terms of treatment appropriateness, when it wasn’t.
Overall, the term "hemangioma" was used incorrectly in 71% of cases. Improper use of the term diagnostically was associated with a 21% rate of erroneous treatment. In contrast, patients whose lesions were described using ISSVA terminology had a 0% rate of improper treatment.
Physicians in some specialties did better than others. Radiologists used the term inappropriately in 84% of cases. Pediatricians, internists, general surgeons, ob.gyns., and pathologists who authored papers misused the term "hemangioma" in 60%-70% of cases. And, dermatologists, plastic surgeons, pediatric surgeons, and otolaryngologists used the term inappropriately in 32% of cases.
The investigators noted that the 71% incidence of incorrect nomenclature and 21% rate of incorrect treatment probably underestimate the true rates in clinical practice (Plast. Reconstr. Surg. 2011;127:347-51).
Dr. Levy said the study results indicate most physicians still use the antiquated method of classifying vascular anomalies learned during training. They’re using the term "hemangioma" to describe a wide variety of vascular birthmarks with differing etiologies and behavior patterns, ranging from strawberry hemangiomas to port wine stains, capillary hemangiomas, infantile hemangiomas, and lower-segment hemangiomas, he said.
The ISSVA system of classification divides vascular anomalies into two categories: tumors and malformations. Tumors show rapid growth in the neonatal period, followed in most cases by slow involution. These lesions are comprised of biologically active tissues that procreate in culture. Examples include infantile hemangioma, tufted angioma, and pyogenic granuloma.
Malformations are by definition present at birth. Their growth rate is commensurate with that of the child. Examples include capillary, venous, and lymphatic malformations, explained Dr. Levy, a pediatric dermatologist at Dell Children’s Medical Center of Central Texas in Austin.
In the Harvard study, misdiagnosis of malformations occurred significantly more often than for vascular tumors. The high misdiagnosis rates underscore a key point: Nonspecialists should consider referral of any patient with a complicated lesion, or one raising aesthetic concern, or when the diagnosis is unclear, Dr. Levy said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).
"The bottom line is we need to encourage our primary care providers to get cases to us early rather than after a problem is discovered," he said.
Infantile hemangiomas are the most common type of vascular tumors in infancy. They vary tremendously in their threat level. The first weeks to months of life are a critical time in the growth of these lesions. Useful guidance as to when to refer children with infantile hemangiomas and when reassurance can be offered is provided by a multicenter prospective study published by pediatric dermatologists several years ago, Dr. Levy continued.
The investigators concluded that infantile hemangiomas posing the greatest risk for serious morbidity based upon morphology and/or anatomic site include large, segmented facial lesions because of the possibility of PHACES syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities, and sternal clefting).
Other red flag infantile hemangiomas identified in the study as warranting referral included perioral, periocular, perineal, axillary, or retrobulbar lesions; segmental lesions on the central neck, or what in later life would be called the beard area; and segmental lesions overlying the lumbosacral spine (Pediatrics 2008;122:360-7).
Dr. Levy reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.
WAIKOLOA, HAWAII – The term "hemangioma" is used erroneously in 70% of cases of vascular anomalies, a study has shown.
"We’re not doing so well. That’s a high rate of misses," Dr. Moise L. Levy said in highlighting the findings.
The study, conducted by investigators at Harvard Medical School, Boston, involved an analysis of all 320 English language articles in PubMed that were published in 2009 with the word "hemangioma" in the title or abstract.
The investigators sought to learn whether the approved binary classification system for vascular anomalies introduced by the International Society for the Study of Vascular Anomalies (ISSVA) 15 years ago was being utilized by physicians and the consequences, in terms of treatment appropriateness, when it wasn’t.
Overall, the term "hemangioma" was used incorrectly in 71% of cases. Improper use of the term diagnostically was associated with a 21% rate of erroneous treatment. In contrast, patients whose lesions were described using ISSVA terminology had a 0% rate of improper treatment.
Physicians in some specialties did better than others. Radiologists used the term inappropriately in 84% of cases. Pediatricians, internists, general surgeons, ob.gyns., and pathologists who authored papers misused the term "hemangioma" in 60%-70% of cases. And, dermatologists, plastic surgeons, pediatric surgeons, and otolaryngologists used the term inappropriately in 32% of cases.
The investigators noted that the 71% incidence of incorrect nomenclature and 21% rate of incorrect treatment probably underestimate the true rates in clinical practice (Plast. Reconstr. Surg. 2011;127:347-51).
Dr. Levy said the study results indicate most physicians still use the antiquated method of classifying vascular anomalies learned during training. They’re using the term "hemangioma" to describe a wide variety of vascular birthmarks with differing etiologies and behavior patterns, ranging from strawberry hemangiomas to port wine stains, capillary hemangiomas, infantile hemangiomas, and lower-segment hemangiomas, he said.
The ISSVA system of classification divides vascular anomalies into two categories: tumors and malformations. Tumors show rapid growth in the neonatal period, followed in most cases by slow involution. These lesions are comprised of biologically active tissues that procreate in culture. Examples include infantile hemangioma, tufted angioma, and pyogenic granuloma.
Malformations are by definition present at birth. Their growth rate is commensurate with that of the child. Examples include capillary, venous, and lymphatic malformations, explained Dr. Levy, a pediatric dermatologist at Dell Children’s Medical Center of Central Texas in Austin.
In the Harvard study, misdiagnosis of malformations occurred significantly more often than for vascular tumors. The high misdiagnosis rates underscore a key point: Nonspecialists should consider referral of any patient with a complicated lesion, or one raising aesthetic concern, or when the diagnosis is unclear, Dr. Levy said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).
"The bottom line is we need to encourage our primary care providers to get cases to us early rather than after a problem is discovered," he said.
Infantile hemangiomas are the most common type of vascular tumors in infancy. They vary tremendously in their threat level. The first weeks to months of life are a critical time in the growth of these lesions. Useful guidance as to when to refer children with infantile hemangiomas and when reassurance can be offered is provided by a multicenter prospective study published by pediatric dermatologists several years ago, Dr. Levy continued.
The investigators concluded that infantile hemangiomas posing the greatest risk for serious morbidity based upon morphology and/or anatomic site include large, segmented facial lesions because of the possibility of PHACES syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities, and sternal clefting).
Other red flag infantile hemangiomas identified in the study as warranting referral included perioral, periocular, perineal, axillary, or retrobulbar lesions; segmental lesions on the central neck, or what in later life would be called the beard area; and segmental lesions overlying the lumbosacral spine (Pediatrics 2008;122:360-7).
Dr. Levy reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.
EXPERT ANALYSIS FROM THE SDEF HAWAII DERMATOLOGY SEMINAR
Bariatric Surgery Bests Medication In Obese Diabetics
CHICAGO – Bariatric surgery crushed intensive medical therapy for the management of hyperglycemia in a randomized trial involving obese patients with poorly controlled type 2 diabetes.
"The lesson of this study is that for those obese patients who also have uncontrolled diabetes, there is now another treatment option that may be very, very effective at getting them in good control," Dr. Philip R. Schauer declared in presenting the 1-year results of the STAMPEDE (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently) trial.
STAMPEDE was a single-center prospective study involving 150 randomized patients. The primary end point – hemoglobin A1c of 6.0% or less at 1 year – was achieved in 42% of patients in the Roux-en-Y gastric bypass group, 37% in the sleeve gastrectomy group, and 12% of patients assigned to state-of-the-art intensive medical management based upon American Diabetes Association guidelines, including a weight loss program, reported Dr. Schauer, professor of surgery and director of the Bariatric and Metabolic Institute at the Cleveland Clinic.
At enrollment the average HbA1c was 9.2% even though most patients were on three or more diabetes medications, and about half were taking insulin. The average baseline body mass index was 37 kg/m2. More than 60% of subjects had moderate to severe fatty liver disease.
Particularly noteworthy was the finding that all gastric bypass patients with an HbA1c of 6.0% or less at 1 year achieved that target despite having discontinued all diabetes medications, including insulin. So did 13 of 18 patients in the sleeve gastrectomy group who reached the primary end point.
"That’s as close to a definition of remission of diabetes as you can get to," the surgeon commented.
Improvements in secondary study end points related to cardiovascular risk were also far more impressive in the surgery arms.
Three patients in the gastric bypass group and one in the sleeve gastrectomy arm required redo operations. There were other serious complications in the surgical groups as well, but no deaths.
Follow-up of STAMPEDE participants will continue through 4 years. Dr. Schauer predicted that on the basis of the highly positive STAMPEDE findings, future studies will look at bariatric surgery versus intensive medical management in obese type 2 diabetic patients with lesser degrees of uncontrolled type 2 diabetes – say, HbA1cs between 7% and 9%.
Reaction to STAMPEDE was cautious.
"That’s a huge intervention in order to get control of diabetes. I’m just not sure it’s ready for prime time yet," former ACC President Dr. W. Douglas Weaver said in an interview.
"I would like to see some more outcomes data in patients who’ve been managed in this way. You’d like to see that it not only keeps the weight off and the glucose levels lower over the longer term, but that it actually improves outcomes in terms of cardiovascular events and diabetic complications. Then it becomes compelling. Right now, we just have these surrogate improvements," added Dr. Weaver, head of the division of cardiovascular medicine at the Henry Ford Health System, Detroit.
Cleveland Clinic endocrinologist Dr. Sangeeta Kashyap, who headed the STAMPEDE diabetology team, said medical therapy is not to be discounted. It’s titratable, even stoppable if need be. A surgical fix is not.
"Surgery works very well, but once it’s done, it’s done. If you want to eat an extra bite of food, you’re not going to be able to without getting violently ill," she observed in an interview.
"Even though our results strongly support bariatric surgery for diabetes, I don’t think it’s going to be right for everybody. I think more studies need to be done to figure out who the best candidates are, and for which procedures," Dr. Kashyap said.
The durability of surgery’s antidiabetic effect has yet to be established, she added.
Simultaneously with Dr. Schauer’s presentation of STAMPEDE in Chicago, the study was published online by the New England Journal of Medicine (N. Engl. J. Med. 2012 March 26 [10.1056/NEJMoa1200225]).
STAMPEDE was supported by Ethicon Endo-Surgery, the National Institutes of Health, and LifeScan. Dr. Schauer and Dr. Kashyap reported serving as consultants to Ethicon, and Dr. Schauer consults for other companies as well.
The randomized STAMPEDE trial from the Cleveland Clinic comparing the results of bariatric surgery to intensified medical therapy in obese patients with long-standing, poorly controlled type 2 diabetes is a seminal study. In contrast to most studies of bariatric surgery and diabetes, this study prospectively randomized patients to surgical treatments versus intensive medical therapy. The patients entering the study had long-standing diabetes, were poorly controlled on their current medical regimen, and had a high percentage of comorbidities. This is the population that could justify an invasive intervention that might be more effective in improving metabolic control and reducing complications.
The results of the surgical treatments were dramatic and far superior to the results of the intensified medical therapy. Patients undergoing gastric bypass surgery decreased mean HbA1c to 6.4 plus or minus 0.9 % compared with intensive medical therapy, 7.5 plus or minus 1.8 %. Additionally, 42% of those with the gastric bypass achieved an HbA1c below 6 % on no diabetes medications. The gastric bypass patients had greater reductions in triglycerides and high sensitivity C-reactive protein and increases in HDL cholesterol than did the medically treated patients, despite greater reductions in lipid lowering agents. Blood pressure and LDL cholesterol were the same between the surgical and medical patients, but were achieved with a decreased need for medications. The benefits from sleeve gastrectomy were similar to, but not as great as, those with gastric bypass.
|
Both surgical procedures resulted in much greater weight loss than the medical therapy. It is not possible to determine how much of the benefit of the surgical procedures was due to the greater weight loss and how much to non–weight loss mechanisms. A key question that is unanswered by the 1-year data, but may be resolved by the 5-year follow-up, is whether the better metabolic control from the surgical procedures will be matched by better improvements in clinical outcomes. Since surgical therapies are associated with significant morbidities, an evaluation of risk versus benefits compared with medical therapies in future long-term trials are necessary. This study is a very good start in beginning such an assessment.
Harold Lebovitz, M.D., is professor of medicine, State University of New York Health Science Center at Brooklyn. He is a consultant to Ethicon Endo-Surgery and serves on advisory boards for Amylin, Merck, Intarcia, and Medicure.
The randomized STAMPEDE trial from the Cleveland Clinic comparing the results of bariatric surgery to intensified medical therapy in obese patients with long-standing, poorly controlled type 2 diabetes is a seminal study. In contrast to most studies of bariatric surgery and diabetes, this study prospectively randomized patients to surgical treatments versus intensive medical therapy. The patients entering the study had long-standing diabetes, were poorly controlled on their current medical regimen, and had a high percentage of comorbidities. This is the population that could justify an invasive intervention that might be more effective in improving metabolic control and reducing complications.
The results of the surgical treatments were dramatic and far superior to the results of the intensified medical therapy. Patients undergoing gastric bypass surgery decreased mean HbA1c to 6.4 plus or minus 0.9 % compared with intensive medical therapy, 7.5 plus or minus 1.8 %. Additionally, 42% of those with the gastric bypass achieved an HbA1c below 6 % on no diabetes medications. The gastric bypass patients had greater reductions in triglycerides and high sensitivity C-reactive protein and increases in HDL cholesterol than did the medically treated patients, despite greater reductions in lipid lowering agents. Blood pressure and LDL cholesterol were the same between the surgical and medical patients, but were achieved with a decreased need for medications. The benefits from sleeve gastrectomy were similar to, but not as great as, those with gastric bypass.
|
Both surgical procedures resulted in much greater weight loss than the medical therapy. It is not possible to determine how much of the benefit of the surgical procedures was due to the greater weight loss and how much to non–weight loss mechanisms. A key question that is unanswered by the 1-year data, but may be resolved by the 5-year follow-up, is whether the better metabolic control from the surgical procedures will be matched by better improvements in clinical outcomes. Since surgical therapies are associated with significant morbidities, an evaluation of risk versus benefits compared with medical therapies in future long-term trials are necessary. This study is a very good start in beginning such an assessment.
Harold Lebovitz, M.D., is professor of medicine, State University of New York Health Science Center at Brooklyn. He is a consultant to Ethicon Endo-Surgery and serves on advisory boards for Amylin, Merck, Intarcia, and Medicure.
The randomized STAMPEDE trial from the Cleveland Clinic comparing the results of bariatric surgery to intensified medical therapy in obese patients with long-standing, poorly controlled type 2 diabetes is a seminal study. In contrast to most studies of bariatric surgery and diabetes, this study prospectively randomized patients to surgical treatments versus intensive medical therapy. The patients entering the study had long-standing diabetes, were poorly controlled on their current medical regimen, and had a high percentage of comorbidities. This is the population that could justify an invasive intervention that might be more effective in improving metabolic control and reducing complications.
The results of the surgical treatments were dramatic and far superior to the results of the intensified medical therapy. Patients undergoing gastric bypass surgery decreased mean HbA1c to 6.4 plus or minus 0.9 % compared with intensive medical therapy, 7.5 plus or minus 1.8 %. Additionally, 42% of those with the gastric bypass achieved an HbA1c below 6 % on no diabetes medications. The gastric bypass patients had greater reductions in triglycerides and high sensitivity C-reactive protein and increases in HDL cholesterol than did the medically treated patients, despite greater reductions in lipid lowering agents. Blood pressure and LDL cholesterol were the same between the surgical and medical patients, but were achieved with a decreased need for medications. The benefits from sleeve gastrectomy were similar to, but not as great as, those with gastric bypass.
|
Both surgical procedures resulted in much greater weight loss than the medical therapy. It is not possible to determine how much of the benefit of the surgical procedures was due to the greater weight loss and how much to non–weight loss mechanisms. A key question that is unanswered by the 1-year data, but may be resolved by the 5-year follow-up, is whether the better metabolic control from the surgical procedures will be matched by better improvements in clinical outcomes. Since surgical therapies are associated with significant morbidities, an evaluation of risk versus benefits compared with medical therapies in future long-term trials are necessary. This study is a very good start in beginning such an assessment.
Harold Lebovitz, M.D., is professor of medicine, State University of New York Health Science Center at Brooklyn. He is a consultant to Ethicon Endo-Surgery and serves on advisory boards for Amylin, Merck, Intarcia, and Medicure.
CHICAGO – Bariatric surgery crushed intensive medical therapy for the management of hyperglycemia in a randomized trial involving obese patients with poorly controlled type 2 diabetes.
"The lesson of this study is that for those obese patients who also have uncontrolled diabetes, there is now another treatment option that may be very, very effective at getting them in good control," Dr. Philip R. Schauer declared in presenting the 1-year results of the STAMPEDE (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently) trial.
STAMPEDE was a single-center prospective study involving 150 randomized patients. The primary end point – hemoglobin A1c of 6.0% or less at 1 year – was achieved in 42% of patients in the Roux-en-Y gastric bypass group, 37% in the sleeve gastrectomy group, and 12% of patients assigned to state-of-the-art intensive medical management based upon American Diabetes Association guidelines, including a weight loss program, reported Dr. Schauer, professor of surgery and director of the Bariatric and Metabolic Institute at the Cleveland Clinic.
At enrollment the average HbA1c was 9.2% even though most patients were on three or more diabetes medications, and about half were taking insulin. The average baseline body mass index was 37 kg/m2. More than 60% of subjects had moderate to severe fatty liver disease.
Particularly noteworthy was the finding that all gastric bypass patients with an HbA1c of 6.0% or less at 1 year achieved that target despite having discontinued all diabetes medications, including insulin. So did 13 of 18 patients in the sleeve gastrectomy group who reached the primary end point.
"That’s as close to a definition of remission of diabetes as you can get to," the surgeon commented.
Improvements in secondary study end points related to cardiovascular risk were also far more impressive in the surgery arms.
Three patients in the gastric bypass group and one in the sleeve gastrectomy arm required redo operations. There were other serious complications in the surgical groups as well, but no deaths.
Follow-up of STAMPEDE participants will continue through 4 years. Dr. Schauer predicted that on the basis of the highly positive STAMPEDE findings, future studies will look at bariatric surgery versus intensive medical management in obese type 2 diabetic patients with lesser degrees of uncontrolled type 2 diabetes – say, HbA1cs between 7% and 9%.
Reaction to STAMPEDE was cautious.
"That’s a huge intervention in order to get control of diabetes. I’m just not sure it’s ready for prime time yet," former ACC President Dr. W. Douglas Weaver said in an interview.
"I would like to see some more outcomes data in patients who’ve been managed in this way. You’d like to see that it not only keeps the weight off and the glucose levels lower over the longer term, but that it actually improves outcomes in terms of cardiovascular events and diabetic complications. Then it becomes compelling. Right now, we just have these surrogate improvements," added Dr. Weaver, head of the division of cardiovascular medicine at the Henry Ford Health System, Detroit.
Cleveland Clinic endocrinologist Dr. Sangeeta Kashyap, who headed the STAMPEDE diabetology team, said medical therapy is not to be discounted. It’s titratable, even stoppable if need be. A surgical fix is not.
"Surgery works very well, but once it’s done, it’s done. If you want to eat an extra bite of food, you’re not going to be able to without getting violently ill," she observed in an interview.
"Even though our results strongly support bariatric surgery for diabetes, I don’t think it’s going to be right for everybody. I think more studies need to be done to figure out who the best candidates are, and for which procedures," Dr. Kashyap said.
The durability of surgery’s antidiabetic effect has yet to be established, she added.
Simultaneously with Dr. Schauer’s presentation of STAMPEDE in Chicago, the study was published online by the New England Journal of Medicine (N. Engl. J. Med. 2012 March 26 [10.1056/NEJMoa1200225]).
STAMPEDE was supported by Ethicon Endo-Surgery, the National Institutes of Health, and LifeScan. Dr. Schauer and Dr. Kashyap reported serving as consultants to Ethicon, and Dr. Schauer consults for other companies as well.
CHICAGO – Bariatric surgery crushed intensive medical therapy for the management of hyperglycemia in a randomized trial involving obese patients with poorly controlled type 2 diabetes.
"The lesson of this study is that for those obese patients who also have uncontrolled diabetes, there is now another treatment option that may be very, very effective at getting them in good control," Dr. Philip R. Schauer declared in presenting the 1-year results of the STAMPEDE (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently) trial.
STAMPEDE was a single-center prospective study involving 150 randomized patients. The primary end point – hemoglobin A1c of 6.0% or less at 1 year – was achieved in 42% of patients in the Roux-en-Y gastric bypass group, 37% in the sleeve gastrectomy group, and 12% of patients assigned to state-of-the-art intensive medical management based upon American Diabetes Association guidelines, including a weight loss program, reported Dr. Schauer, professor of surgery and director of the Bariatric and Metabolic Institute at the Cleveland Clinic.
At enrollment the average HbA1c was 9.2% even though most patients were on three or more diabetes medications, and about half were taking insulin. The average baseline body mass index was 37 kg/m2. More than 60% of subjects had moderate to severe fatty liver disease.
Particularly noteworthy was the finding that all gastric bypass patients with an HbA1c of 6.0% or less at 1 year achieved that target despite having discontinued all diabetes medications, including insulin. So did 13 of 18 patients in the sleeve gastrectomy group who reached the primary end point.
"That’s as close to a definition of remission of diabetes as you can get to," the surgeon commented.
Improvements in secondary study end points related to cardiovascular risk were also far more impressive in the surgery arms.
Three patients in the gastric bypass group and one in the sleeve gastrectomy arm required redo operations. There were other serious complications in the surgical groups as well, but no deaths.
Follow-up of STAMPEDE participants will continue through 4 years. Dr. Schauer predicted that on the basis of the highly positive STAMPEDE findings, future studies will look at bariatric surgery versus intensive medical management in obese type 2 diabetic patients with lesser degrees of uncontrolled type 2 diabetes – say, HbA1cs between 7% and 9%.
Reaction to STAMPEDE was cautious.
"That’s a huge intervention in order to get control of diabetes. I’m just not sure it’s ready for prime time yet," former ACC President Dr. W. Douglas Weaver said in an interview.
"I would like to see some more outcomes data in patients who’ve been managed in this way. You’d like to see that it not only keeps the weight off and the glucose levels lower over the longer term, but that it actually improves outcomes in terms of cardiovascular events and diabetic complications. Then it becomes compelling. Right now, we just have these surrogate improvements," added Dr. Weaver, head of the division of cardiovascular medicine at the Henry Ford Health System, Detroit.
Cleveland Clinic endocrinologist Dr. Sangeeta Kashyap, who headed the STAMPEDE diabetology team, said medical therapy is not to be discounted. It’s titratable, even stoppable if need be. A surgical fix is not.
"Surgery works very well, but once it’s done, it’s done. If you want to eat an extra bite of food, you’re not going to be able to without getting violently ill," she observed in an interview.
"Even though our results strongly support bariatric surgery for diabetes, I don’t think it’s going to be right for everybody. I think more studies need to be done to figure out who the best candidates are, and for which procedures," Dr. Kashyap said.
The durability of surgery’s antidiabetic effect has yet to be established, she added.
Simultaneously with Dr. Schauer’s presentation of STAMPEDE in Chicago, the study was published online by the New England Journal of Medicine (N. Engl. J. Med. 2012 March 26 [10.1056/NEJMoa1200225]).
STAMPEDE was supported by Ethicon Endo-Surgery, the National Institutes of Health, and LifeScan. Dr. Schauer and Dr. Kashyap reported serving as consultants to Ethicon, and Dr. Schauer consults for other companies as well.
FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY
Major Finding: In obese patients with poorly controlled type 2 diabetes, 1 year of intensive medical management yielded an HbA1c of 6.0% or lower in 12%, compared with 42% of gastric bypass recipients and 37% of patients undergoing sleeve gastrectomy.
Data Source: A three-armed randomized trial of 150 patients assigned to gastric bypass, sleeve gastrectomy, or intensive medical management and followed quarterly for 1 year.
Disclosures: STAMPEDE was supported by Ethicon Endo-Surgery, the National Institutes of Health, and LifeScan. Dr. Schauer and Dr. Kashyap reported serving as consultants to Ethicon, and Dr. Schauer consults for other companies as well.
Intracoronary Abciximab Reduces Size of Large Myocardial Infarcts
CHICAGO – Bolus intracoronary abciximab delivered directly to the infarct lesion site in patients undergoing primary percutaneous coronary intervention for a large anterior myocardial infarction significantly reduced infarct size at 30 days in the INFUSE-AMI randomized trial.
In contrast, manual aspiration thrombectomy, also studied in INFUSE-AMI, proved to have no impact on infarct size, Dr. Gregg W. Stone reported at the annual meeting of the American College of Cardiology.
INFUSE-AMI was a 37-site, 6-nation prospective clinical trial. It involved 452 patients who presented within 4 hours after onset of symptoms, because of an ST-segment elevation MI involving occlusion of the proximal or midleft anterior descending coronary artery with no or minimal flow.
Participants underwent primary percutaneous coronary intervention (PCI) with bivalirudin anticoagulation. Under the 2 x 2 factorial study design, patients were randomized to aspiration plus a 0.25-mg/kg bolus of intracoronary abciximab, aspiration without abciximab, abciximab with no aspiration, or neither intervention. The goal was to find out whether either or both interventions reduce distal embolization of atherothrombotic debris resulting from primary PCI, which can lead to large infarcts despite prompt revascularization.
The primary endpoint in INFUSE-AMI was infarct size at 30 days as assessed by cardiac MRI. Most prior trials have measured infarct size at 3-5 days, when transitory myocardial edema typically makes the infarcts more than twice as large as they are at 30 days, explained Dr. Stone, director of cardiovascular research and education at Columbia University Medical Center/New York–Presbyterian Hospital.
The median 30-day infarct size in patients who got intracoronary abciximab was 15.1%, compared with 17.9% in those who did not. That’s roughly a 15% relative reduction. The abciximab group also had a significantly smaller median absolute infarct mass: 18.4 g, compared with 24 g. In addition, they showed a trend for a lower abnormal wall motion score that didn’t reach significance.
In contrast, 30-day infarct size and the other endpoints were almost identical, regardless of whether patients got aspiration thrombectomy or not.
The combined rate of TIMI (Thrombolysis in Myocardial Infarction) major or minor bleeding was 2.2% in patients who received intracoronary abciximab and 1.8% in those who did not, a nonsignificant difference.
Dr. Stone said that while it might now be reasonable based on the INFUSE-AMI findings to use an intracoronary bolus of abciximab during primary PCI in a highly select patient subset – those who present early with a particularly large occlusion of the proximal left anterior descending artery and are at low bleeding risk – he doesn’t consider INFUSE-AMI to be a definitive trial.
"The reduction in infarct size, while significant, was modest. Going into the study we considered that an absolute 6% reduction would be clinically relevant. We got about half of that. We really need a large outcomes trial to see if that amount of infarct size reduction improves clinical outcomes," the cardiologist said.
Currently, there are no plans for such a study, since INFUSE-AMI was just completed, and the findings are still being scrutinized. But Dr. Stone indicated that a decision to undertake a big clinical outcomes trial is by no means a slam dunk.
"If you studied 10,000 patients and you had exactly these results, there probably would be a clinical benefit, but it would be modest. And there is the possibility that bleeding would offset some of that," he commented.
Discussant Dr. Erik Magnus Ohman of Duke University, Durham, N.C., noted that a recent report from the AIDA STEMI (Abciximab IV versus IC in ST-Elevation Myocardial Infarction) trial, which with 2,065 randomized patients was powered for clinical outcomes, reported nearly identical infarct sizes and cardiovascular event rates with bolus intracoronary abciximab, compared with intravenous abciximab (Lancet 2012;379:875-7).
Dr. Stone replied that AIDA-STEMI and all other studies prior to INFUSE-AMI had a major limitation: Intracoronary abciximab was infused through the guide catheter. That’s highly inefficient in terms of getting the agent into the thrombus.
"Most of the drug probably goes down the circumflex artery or just blows back into the aorta," he explained.
In contrast, INFUSE-AMI utilized the ClearWay Rx local therapeutic infusion catheter, a low-profile "weeping" balloon that delivers abciximab directly to the infarct lesion.
As for aspiration thrombectomy, a practice now encouraged with a IIb recommendation in the ACC/American Heart Association guidelines, Dr. Stone noted that this intervention is the subject of two ongoing multithousand-patient randomized trials, TOTAL and TASTE, which should provide the final word on this procedure.
"I will say, though, that it’s hard for me to understand how aspiration can work as a routine therapy if it doesn’t decrease infarct size. I would predict that these trials might not be positive," Dr. Stone said.
The INFUSE-AMI trial was published in JAMA (2012;307([7];doi:10.1001/jama.2012.421) at the same time the study results were presented at the ACC meeting.
INFUSE-AMI was sponsored by Atrium Medical with support from Medtronic and the Medicines Co. Dr. Stone reported having served as a consultant to those three companies and more than a dozen others.
CHICAGO – Bolus intracoronary abciximab delivered directly to the infarct lesion site in patients undergoing primary percutaneous coronary intervention for a large anterior myocardial infarction significantly reduced infarct size at 30 days in the INFUSE-AMI randomized trial.
In contrast, manual aspiration thrombectomy, also studied in INFUSE-AMI, proved to have no impact on infarct size, Dr. Gregg W. Stone reported at the annual meeting of the American College of Cardiology.
INFUSE-AMI was a 37-site, 6-nation prospective clinical trial. It involved 452 patients who presented within 4 hours after onset of symptoms, because of an ST-segment elevation MI involving occlusion of the proximal or midleft anterior descending coronary artery with no or minimal flow.
Participants underwent primary percutaneous coronary intervention (PCI) with bivalirudin anticoagulation. Under the 2 x 2 factorial study design, patients were randomized to aspiration plus a 0.25-mg/kg bolus of intracoronary abciximab, aspiration without abciximab, abciximab with no aspiration, or neither intervention. The goal was to find out whether either or both interventions reduce distal embolization of atherothrombotic debris resulting from primary PCI, which can lead to large infarcts despite prompt revascularization.
The primary endpoint in INFUSE-AMI was infarct size at 30 days as assessed by cardiac MRI. Most prior trials have measured infarct size at 3-5 days, when transitory myocardial edema typically makes the infarcts more than twice as large as they are at 30 days, explained Dr. Stone, director of cardiovascular research and education at Columbia University Medical Center/New York–Presbyterian Hospital.
The median 30-day infarct size in patients who got intracoronary abciximab was 15.1%, compared with 17.9% in those who did not. That’s roughly a 15% relative reduction. The abciximab group also had a significantly smaller median absolute infarct mass: 18.4 g, compared with 24 g. In addition, they showed a trend for a lower abnormal wall motion score that didn’t reach significance.
In contrast, 30-day infarct size and the other endpoints were almost identical, regardless of whether patients got aspiration thrombectomy or not.
The combined rate of TIMI (Thrombolysis in Myocardial Infarction) major or minor bleeding was 2.2% in patients who received intracoronary abciximab and 1.8% in those who did not, a nonsignificant difference.
Dr. Stone said that while it might now be reasonable based on the INFUSE-AMI findings to use an intracoronary bolus of abciximab during primary PCI in a highly select patient subset – those who present early with a particularly large occlusion of the proximal left anterior descending artery and are at low bleeding risk – he doesn’t consider INFUSE-AMI to be a definitive trial.
"The reduction in infarct size, while significant, was modest. Going into the study we considered that an absolute 6% reduction would be clinically relevant. We got about half of that. We really need a large outcomes trial to see if that amount of infarct size reduction improves clinical outcomes," the cardiologist said.
Currently, there are no plans for such a study, since INFUSE-AMI was just completed, and the findings are still being scrutinized. But Dr. Stone indicated that a decision to undertake a big clinical outcomes trial is by no means a slam dunk.
"If you studied 10,000 patients and you had exactly these results, there probably would be a clinical benefit, but it would be modest. And there is the possibility that bleeding would offset some of that," he commented.
Discussant Dr. Erik Magnus Ohman of Duke University, Durham, N.C., noted that a recent report from the AIDA STEMI (Abciximab IV versus IC in ST-Elevation Myocardial Infarction) trial, which with 2,065 randomized patients was powered for clinical outcomes, reported nearly identical infarct sizes and cardiovascular event rates with bolus intracoronary abciximab, compared with intravenous abciximab (Lancet 2012;379:875-7).
Dr. Stone replied that AIDA-STEMI and all other studies prior to INFUSE-AMI had a major limitation: Intracoronary abciximab was infused through the guide catheter. That’s highly inefficient in terms of getting the agent into the thrombus.
"Most of the drug probably goes down the circumflex artery or just blows back into the aorta," he explained.
In contrast, INFUSE-AMI utilized the ClearWay Rx local therapeutic infusion catheter, a low-profile "weeping" balloon that delivers abciximab directly to the infarct lesion.
As for aspiration thrombectomy, a practice now encouraged with a IIb recommendation in the ACC/American Heart Association guidelines, Dr. Stone noted that this intervention is the subject of two ongoing multithousand-patient randomized trials, TOTAL and TASTE, which should provide the final word on this procedure.
"I will say, though, that it’s hard for me to understand how aspiration can work as a routine therapy if it doesn’t decrease infarct size. I would predict that these trials might not be positive," Dr. Stone said.
The INFUSE-AMI trial was published in JAMA (2012;307([7];doi:10.1001/jama.2012.421) at the same time the study results were presented at the ACC meeting.
INFUSE-AMI was sponsored by Atrium Medical with support from Medtronic and the Medicines Co. Dr. Stone reported having served as a consultant to those three companies and more than a dozen others.
CHICAGO – Bolus intracoronary abciximab delivered directly to the infarct lesion site in patients undergoing primary percutaneous coronary intervention for a large anterior myocardial infarction significantly reduced infarct size at 30 days in the INFUSE-AMI randomized trial.
In contrast, manual aspiration thrombectomy, also studied in INFUSE-AMI, proved to have no impact on infarct size, Dr. Gregg W. Stone reported at the annual meeting of the American College of Cardiology.
INFUSE-AMI was a 37-site, 6-nation prospective clinical trial. It involved 452 patients who presented within 4 hours after onset of symptoms, because of an ST-segment elevation MI involving occlusion of the proximal or midleft anterior descending coronary artery with no or minimal flow.
Participants underwent primary percutaneous coronary intervention (PCI) with bivalirudin anticoagulation. Under the 2 x 2 factorial study design, patients were randomized to aspiration plus a 0.25-mg/kg bolus of intracoronary abciximab, aspiration without abciximab, abciximab with no aspiration, or neither intervention. The goal was to find out whether either or both interventions reduce distal embolization of atherothrombotic debris resulting from primary PCI, which can lead to large infarcts despite prompt revascularization.
The primary endpoint in INFUSE-AMI was infarct size at 30 days as assessed by cardiac MRI. Most prior trials have measured infarct size at 3-5 days, when transitory myocardial edema typically makes the infarcts more than twice as large as they are at 30 days, explained Dr. Stone, director of cardiovascular research and education at Columbia University Medical Center/New York–Presbyterian Hospital.
The median 30-day infarct size in patients who got intracoronary abciximab was 15.1%, compared with 17.9% in those who did not. That’s roughly a 15% relative reduction. The abciximab group also had a significantly smaller median absolute infarct mass: 18.4 g, compared with 24 g. In addition, they showed a trend for a lower abnormal wall motion score that didn’t reach significance.
In contrast, 30-day infarct size and the other endpoints were almost identical, regardless of whether patients got aspiration thrombectomy or not.
The combined rate of TIMI (Thrombolysis in Myocardial Infarction) major or minor bleeding was 2.2% in patients who received intracoronary abciximab and 1.8% in those who did not, a nonsignificant difference.
Dr. Stone said that while it might now be reasonable based on the INFUSE-AMI findings to use an intracoronary bolus of abciximab during primary PCI in a highly select patient subset – those who present early with a particularly large occlusion of the proximal left anterior descending artery and are at low bleeding risk – he doesn’t consider INFUSE-AMI to be a definitive trial.
"The reduction in infarct size, while significant, was modest. Going into the study we considered that an absolute 6% reduction would be clinically relevant. We got about half of that. We really need a large outcomes trial to see if that amount of infarct size reduction improves clinical outcomes," the cardiologist said.
Currently, there are no plans for such a study, since INFUSE-AMI was just completed, and the findings are still being scrutinized. But Dr. Stone indicated that a decision to undertake a big clinical outcomes trial is by no means a slam dunk.
"If you studied 10,000 patients and you had exactly these results, there probably would be a clinical benefit, but it would be modest. And there is the possibility that bleeding would offset some of that," he commented.
Discussant Dr. Erik Magnus Ohman of Duke University, Durham, N.C., noted that a recent report from the AIDA STEMI (Abciximab IV versus IC in ST-Elevation Myocardial Infarction) trial, which with 2,065 randomized patients was powered for clinical outcomes, reported nearly identical infarct sizes and cardiovascular event rates with bolus intracoronary abciximab, compared with intravenous abciximab (Lancet 2012;379:875-7).
Dr. Stone replied that AIDA-STEMI and all other studies prior to INFUSE-AMI had a major limitation: Intracoronary abciximab was infused through the guide catheter. That’s highly inefficient in terms of getting the agent into the thrombus.
"Most of the drug probably goes down the circumflex artery or just blows back into the aorta," he explained.
In contrast, INFUSE-AMI utilized the ClearWay Rx local therapeutic infusion catheter, a low-profile "weeping" balloon that delivers abciximab directly to the infarct lesion.
As for aspiration thrombectomy, a practice now encouraged with a IIb recommendation in the ACC/American Heart Association guidelines, Dr. Stone noted that this intervention is the subject of two ongoing multithousand-patient randomized trials, TOTAL and TASTE, which should provide the final word on this procedure.
"I will say, though, that it’s hard for me to understand how aspiration can work as a routine therapy if it doesn’t decrease infarct size. I would predict that these trials might not be positive," Dr. Stone said.
The INFUSE-AMI trial was published in JAMA (2012;307([7];doi:10.1001/jama.2012.421) at the same time the study results were presented at the ACC meeting.
INFUSE-AMI was sponsored by Atrium Medical with support from Medtronic and the Medicines Co. Dr. Stone reported having served as a consultant to those three companies and more than a dozen others.
FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY
Major Finding: Median infarct size at 30 days, as measured by cardiac MRI, was 15.1% in patients who received intracoronary abciximab in conjunction with primary PCI for a large ST-elevation MI, significantly less than the 17.9% in those who did not.
Data Source: This was a 452-patient, randomized, prospective, multicenter, international clinical trial with a 2 x 2 factorial design.
Disclosures: INFUSE-AMI was sponsored by Atrium Medical with support from Medtronic and the Medicines Co. Dr. Stone reported having served as a consultant to those three companies and more than a dozen others.
Prasugrel Bests Double-Dose Clopidogrel in Clopidogrel Nonresponders
CHICAGO – Patients with high platelet reactivity on standard-dose clopidogrel in conjunction with a drug-eluting stent for stable coronary disease obtain markedly greater platelet inhibition by switching to prasugrel at 10 mg/day than by doubling the clopidogrel dose to 150 mg/day, according to the Italian RESET trial.
This was a central finding in RESET. Another key finding was that high platelet reactivity on standard maintenance-dose clopidogrel was a common occurrence, affecting 23% of the 180 patients screened for the study, Dr. Gennaro Sardella, professor of cardiology at the University of Rome, reported at the annual meeting of the American College of Cardiology.
Thirty-two nonresponders to clopidogrel at 75 mg/day participated in the crossover portion of the study. They were randomized to 15 days of prasugrel at the standard dose of 10 mg/day or to clopidogrel at 150 mg/day, then underwent platelet activity testing using the Multiplate P2Y12 assay. Next came crossover to 15 days on the opposite therapy, followed by repeat platelet activity testing.
Twenty-eight percent of subjects were poor responders to double-dose clopidogrel as defined by high platelet reactivity, with an area under the curve in excess of 450/minute. In contrast, none of the subjects displayed high platelet reactivity while on prasugrel.
Moreover, inhibition of platelet aggregation was significantly greater during prasugrel therapy: 50% compared with 9% during double-dose clopidogrel therapy, the cardiologist continued.
Fourteen subjects were hetero- or homozygous for the allelic variant of CYP2C19 previously linked to high platelet reactivity in patients on clopidogrel. These were the patients who experienced high platelet reactivity on clopidogrel at 150 mg/day. Noncarriers had a similarly low level of platelet reactivity whether on prasugrel or clopidogrel.
An area under the curve greater than 600/minute on the Multiplate assay had 75% sensitivity and 72% specificity for the presence of genetic variation of the CYP2C19 allele. This is a novel observation which, if confirmed in larger studies, might obviate the need for genotyping of clopidogrel candidates, according to Dr. Sardella.
Session cochair Dr. George D. Dangas noted that while RESET and other small studies show that variants in CYP2C19 are related to clopidogrel responsiveness, a large meta-analysis by investigators at University College London found no significant association between genotype and cardiovascular events. The meta-analysis (JAMA 2011;306:2704-14) included more than 42,000 patients in 32 studies with 3,545 cardiovascular events, observed Dr. Dangas, professor of medicine at Mount Sinai School of Medicine, New York.
Dr. Sardella reported having no financial disclosures. Dr. Dangas serves as a consultant to Johnson & Johnson and Astra-Zeneca.
CHICAGO – Patients with high platelet reactivity on standard-dose clopidogrel in conjunction with a drug-eluting stent for stable coronary disease obtain markedly greater platelet inhibition by switching to prasugrel at 10 mg/day than by doubling the clopidogrel dose to 150 mg/day, according to the Italian RESET trial.
This was a central finding in RESET. Another key finding was that high platelet reactivity on standard maintenance-dose clopidogrel was a common occurrence, affecting 23% of the 180 patients screened for the study, Dr. Gennaro Sardella, professor of cardiology at the University of Rome, reported at the annual meeting of the American College of Cardiology.
Thirty-two nonresponders to clopidogrel at 75 mg/day participated in the crossover portion of the study. They were randomized to 15 days of prasugrel at the standard dose of 10 mg/day or to clopidogrel at 150 mg/day, then underwent platelet activity testing using the Multiplate P2Y12 assay. Next came crossover to 15 days on the opposite therapy, followed by repeat platelet activity testing.
Twenty-eight percent of subjects were poor responders to double-dose clopidogrel as defined by high platelet reactivity, with an area under the curve in excess of 450/minute. In contrast, none of the subjects displayed high platelet reactivity while on prasugrel.
Moreover, inhibition of platelet aggregation was significantly greater during prasugrel therapy: 50% compared with 9% during double-dose clopidogrel therapy, the cardiologist continued.
Fourteen subjects were hetero- or homozygous for the allelic variant of CYP2C19 previously linked to high platelet reactivity in patients on clopidogrel. These were the patients who experienced high platelet reactivity on clopidogrel at 150 mg/day. Noncarriers had a similarly low level of platelet reactivity whether on prasugrel or clopidogrel.
An area under the curve greater than 600/minute on the Multiplate assay had 75% sensitivity and 72% specificity for the presence of genetic variation of the CYP2C19 allele. This is a novel observation which, if confirmed in larger studies, might obviate the need for genotyping of clopidogrel candidates, according to Dr. Sardella.
Session cochair Dr. George D. Dangas noted that while RESET and other small studies show that variants in CYP2C19 are related to clopidogrel responsiveness, a large meta-analysis by investigators at University College London found no significant association between genotype and cardiovascular events. The meta-analysis (JAMA 2011;306:2704-14) included more than 42,000 patients in 32 studies with 3,545 cardiovascular events, observed Dr. Dangas, professor of medicine at Mount Sinai School of Medicine, New York.
Dr. Sardella reported having no financial disclosures. Dr. Dangas serves as a consultant to Johnson & Johnson and Astra-Zeneca.
CHICAGO – Patients with high platelet reactivity on standard-dose clopidogrel in conjunction with a drug-eluting stent for stable coronary disease obtain markedly greater platelet inhibition by switching to prasugrel at 10 mg/day than by doubling the clopidogrel dose to 150 mg/day, according to the Italian RESET trial.
This was a central finding in RESET. Another key finding was that high platelet reactivity on standard maintenance-dose clopidogrel was a common occurrence, affecting 23% of the 180 patients screened for the study, Dr. Gennaro Sardella, professor of cardiology at the University of Rome, reported at the annual meeting of the American College of Cardiology.
Thirty-two nonresponders to clopidogrel at 75 mg/day participated in the crossover portion of the study. They were randomized to 15 days of prasugrel at the standard dose of 10 mg/day or to clopidogrel at 150 mg/day, then underwent platelet activity testing using the Multiplate P2Y12 assay. Next came crossover to 15 days on the opposite therapy, followed by repeat platelet activity testing.
Twenty-eight percent of subjects were poor responders to double-dose clopidogrel as defined by high platelet reactivity, with an area under the curve in excess of 450/minute. In contrast, none of the subjects displayed high platelet reactivity while on prasugrel.
Moreover, inhibition of platelet aggregation was significantly greater during prasugrel therapy: 50% compared with 9% during double-dose clopidogrel therapy, the cardiologist continued.
Fourteen subjects were hetero- or homozygous for the allelic variant of CYP2C19 previously linked to high platelet reactivity in patients on clopidogrel. These were the patients who experienced high platelet reactivity on clopidogrel at 150 mg/day. Noncarriers had a similarly low level of platelet reactivity whether on prasugrel or clopidogrel.
An area under the curve greater than 600/minute on the Multiplate assay had 75% sensitivity and 72% specificity for the presence of genetic variation of the CYP2C19 allele. This is a novel observation which, if confirmed in larger studies, might obviate the need for genotyping of clopidogrel candidates, according to Dr. Sardella.
Session cochair Dr. George D. Dangas noted that while RESET and other small studies show that variants in CYP2C19 are related to clopidogrel responsiveness, a large meta-analysis by investigators at University College London found no significant association between genotype and cardiovascular events. The meta-analysis (JAMA 2011;306:2704-14) included more than 42,000 patients in 32 studies with 3,545 cardiovascular events, observed Dr. Dangas, professor of medicine at Mount Sinai School of Medicine, New York.
Dr. Sardella reported having no financial disclosures. Dr. Dangas serves as a consultant to Johnson & Johnson and Astra-Zeneca.
FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY
Major Finding: High platelet reactivity in nonresponders to standard-dose clopidogrel was documented in 28% of patients on double-dose clopidogrel but 0% when crossed to prasugrel.
Data Source: RESET was a randomized, prospective, double crossover trial including 32 patients.
Disclosures: Dr. Sardella reported having no financial disclosures.
Pain Medications Relieve Agitation in Demented Patients
DENVER – A structured approach to giving pain medications to agitated nursing home residents with moderate to severe dementia – regardless of their pain scores – significantly reduced their agitation and aggression in a randomized trial.
"The assumption is that their agitation was related to pain and because they had cognitive impairment they couldn’t really express [their condition]," Dr. Nathan E. Goldstein of Mount Sinai School of Medicine, New York, said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.
He was one of several experts at the meeting who singled out the Norwegian nursing home study as one of the most important scientific advances in palliative care during the past year.
Agitation and other behavioral disturbances are common in patients with dementia. Haloperidol or another antipsychotic agent is often employed as first-line therapy, but these drugs have significant side effects, particularly in elderly demented patients who are often already on many other medications.
Investigators at the University of Bergen (Norway) opted to think outside the box. They randomized 352 subjects in 60 nursing home units within 18 nursing homes to 8 weeks of pain medication delivered according to a structured protocol or to usual care. Participants had moderate to severe dementia, with a median Mini-Mental State Examination score of 7. Cluster randomization was utilized, such that all patients in a given nursing home unit were randomized to the same study arm.
The primary study end point was agitation as measured by the Cohen-Mansfield Agitation Inventory. This instrument requires nurses to rate each of 29 behaviors on a 1-7 scale, with 1 indicating the behavior is not present and 7 meaning the behavior occurs several times per hour. A score of 39 or more is considered clinically significant agitation.
The mean agitation score in the pain medication group dropped steadily from a baseline of 56.2 to a nadir of 46.9 at week 8, when the intervention ended. The mean score as assessed by blinded evaluators rebounded to 50.3 at week 12, after 4 weeks off the intervention. Agitation scores in the control group didn’t change significantly over time.
The pain treatment group also demonstrated significant decreases in overall aggression and pain scores, but no significant changes in cognition or activities of daily living. The lower a patient’s pain score at the end of treatment, the lower the aggression score.
The stepwise pain treatment protocol was based upon American Geriatrics Society guidelines. Patients who were on no analgesics or only on low-dose acetaminophen at baseline were bumped up to full-dose oral acetaminophen at a maximum of 3 g/day. Those who were on full-dose acetaminophen or low-dose morphine at baseline received short-acting oral morphine to a maximum of 20 mg/day. Patients on low-dose buprenorphine at baseline or who were unable to swallow were placed on transdermal buprenorphine at 5-10 mcg/hour. And subjects with neuropathic pain were placed on adjuvant pregabalin at a maximum daily dose of 300 mg (BMJ 2011;343:d4065 [doi: 10.1136/bmj.d4065]).
Dr. Goldstein praised the Norwegian analgesia protocol as straightforward and easy to implement.
"It could be standardized and used routinely by nursing staff based upon their assessment. This means they wouldn’t have to wait for a physician order," he observed.
The only possible hang-up is that staff education and reorientation would definitely be required to make this work, and the Norwegian investigators did not discuss how they accomplished this.
"All patients in the intervention arm received the pain medication regardless of their pain assessment. There would need to be quite a bit of culture change in nursing homes to actually implement a protocol like this," the geriatrician noted.
Dr. Eric Widera of the University of California, San Francisco, said ample evidence indicates that pain in patients with dementia is common, underrecognized, and undertreated. The Norwegian pain medication protocol overcomes these barriers in novel fashion by treating everybody.
He stressed that the reduction in agitation and aggressive behavior wasn’t accomplished by merely sedating participants. After all, 69% of subjects in the intervention arm received only full-dose acetaminophen. And of the roughly one-quarter of patients who got opioids, only three withdrew from the study due to nausea or sedation.
The randomized trial was funded by the Norwegian Research Council, the University of Bergen, and Kavli’s Center for Aging and Dementia. Dr. Goldstein and Dr. Widera reported having no financial conflicts.
DENVER – A structured approach to giving pain medications to agitated nursing home residents with moderate to severe dementia – regardless of their pain scores – significantly reduced their agitation and aggression in a randomized trial.
"The assumption is that their agitation was related to pain and because they had cognitive impairment they couldn’t really express [their condition]," Dr. Nathan E. Goldstein of Mount Sinai School of Medicine, New York, said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.
He was one of several experts at the meeting who singled out the Norwegian nursing home study as one of the most important scientific advances in palliative care during the past year.
Agitation and other behavioral disturbances are common in patients with dementia. Haloperidol or another antipsychotic agent is often employed as first-line therapy, but these drugs have significant side effects, particularly in elderly demented patients who are often already on many other medications.
Investigators at the University of Bergen (Norway) opted to think outside the box. They randomized 352 subjects in 60 nursing home units within 18 nursing homes to 8 weeks of pain medication delivered according to a structured protocol or to usual care. Participants had moderate to severe dementia, with a median Mini-Mental State Examination score of 7. Cluster randomization was utilized, such that all patients in a given nursing home unit were randomized to the same study arm.
The primary study end point was agitation as measured by the Cohen-Mansfield Agitation Inventory. This instrument requires nurses to rate each of 29 behaviors on a 1-7 scale, with 1 indicating the behavior is not present and 7 meaning the behavior occurs several times per hour. A score of 39 or more is considered clinically significant agitation.
The mean agitation score in the pain medication group dropped steadily from a baseline of 56.2 to a nadir of 46.9 at week 8, when the intervention ended. The mean score as assessed by blinded evaluators rebounded to 50.3 at week 12, after 4 weeks off the intervention. Agitation scores in the control group didn’t change significantly over time.
The pain treatment group also demonstrated significant decreases in overall aggression and pain scores, but no significant changes in cognition or activities of daily living. The lower a patient’s pain score at the end of treatment, the lower the aggression score.
The stepwise pain treatment protocol was based upon American Geriatrics Society guidelines. Patients who were on no analgesics or only on low-dose acetaminophen at baseline were bumped up to full-dose oral acetaminophen at a maximum of 3 g/day. Those who were on full-dose acetaminophen or low-dose morphine at baseline received short-acting oral morphine to a maximum of 20 mg/day. Patients on low-dose buprenorphine at baseline or who were unable to swallow were placed on transdermal buprenorphine at 5-10 mcg/hour. And subjects with neuropathic pain were placed on adjuvant pregabalin at a maximum daily dose of 300 mg (BMJ 2011;343:d4065 [doi: 10.1136/bmj.d4065]).
Dr. Goldstein praised the Norwegian analgesia protocol as straightforward and easy to implement.
"It could be standardized and used routinely by nursing staff based upon their assessment. This means they wouldn’t have to wait for a physician order," he observed.
The only possible hang-up is that staff education and reorientation would definitely be required to make this work, and the Norwegian investigators did not discuss how they accomplished this.
"All patients in the intervention arm received the pain medication regardless of their pain assessment. There would need to be quite a bit of culture change in nursing homes to actually implement a protocol like this," the geriatrician noted.
Dr. Eric Widera of the University of California, San Francisco, said ample evidence indicates that pain in patients with dementia is common, underrecognized, and undertreated. The Norwegian pain medication protocol overcomes these barriers in novel fashion by treating everybody.
He stressed that the reduction in agitation and aggressive behavior wasn’t accomplished by merely sedating participants. After all, 69% of subjects in the intervention arm received only full-dose acetaminophen. And of the roughly one-quarter of patients who got opioids, only three withdrew from the study due to nausea or sedation.
The randomized trial was funded by the Norwegian Research Council, the University of Bergen, and Kavli’s Center for Aging and Dementia. Dr. Goldstein and Dr. Widera reported having no financial conflicts.
DENVER – A structured approach to giving pain medications to agitated nursing home residents with moderate to severe dementia – regardless of their pain scores – significantly reduced their agitation and aggression in a randomized trial.
"The assumption is that their agitation was related to pain and because they had cognitive impairment they couldn’t really express [their condition]," Dr. Nathan E. Goldstein of Mount Sinai School of Medicine, New York, said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.
He was one of several experts at the meeting who singled out the Norwegian nursing home study as one of the most important scientific advances in palliative care during the past year.
Agitation and other behavioral disturbances are common in patients with dementia. Haloperidol or another antipsychotic agent is often employed as first-line therapy, but these drugs have significant side effects, particularly in elderly demented patients who are often already on many other medications.
Investigators at the University of Bergen (Norway) opted to think outside the box. They randomized 352 subjects in 60 nursing home units within 18 nursing homes to 8 weeks of pain medication delivered according to a structured protocol or to usual care. Participants had moderate to severe dementia, with a median Mini-Mental State Examination score of 7. Cluster randomization was utilized, such that all patients in a given nursing home unit were randomized to the same study arm.
The primary study end point was agitation as measured by the Cohen-Mansfield Agitation Inventory. This instrument requires nurses to rate each of 29 behaviors on a 1-7 scale, with 1 indicating the behavior is not present and 7 meaning the behavior occurs several times per hour. A score of 39 or more is considered clinically significant agitation.
The mean agitation score in the pain medication group dropped steadily from a baseline of 56.2 to a nadir of 46.9 at week 8, when the intervention ended. The mean score as assessed by blinded evaluators rebounded to 50.3 at week 12, after 4 weeks off the intervention. Agitation scores in the control group didn’t change significantly over time.
The pain treatment group also demonstrated significant decreases in overall aggression and pain scores, but no significant changes in cognition or activities of daily living. The lower a patient’s pain score at the end of treatment, the lower the aggression score.
The stepwise pain treatment protocol was based upon American Geriatrics Society guidelines. Patients who were on no analgesics or only on low-dose acetaminophen at baseline were bumped up to full-dose oral acetaminophen at a maximum of 3 g/day. Those who were on full-dose acetaminophen or low-dose morphine at baseline received short-acting oral morphine to a maximum of 20 mg/day. Patients on low-dose buprenorphine at baseline or who were unable to swallow were placed on transdermal buprenorphine at 5-10 mcg/hour. And subjects with neuropathic pain were placed on adjuvant pregabalin at a maximum daily dose of 300 mg (BMJ 2011;343:d4065 [doi: 10.1136/bmj.d4065]).
Dr. Goldstein praised the Norwegian analgesia protocol as straightforward and easy to implement.
"It could be standardized and used routinely by nursing staff based upon their assessment. This means they wouldn’t have to wait for a physician order," he observed.
The only possible hang-up is that staff education and reorientation would definitely be required to make this work, and the Norwegian investigators did not discuss how they accomplished this.
"All patients in the intervention arm received the pain medication regardless of their pain assessment. There would need to be quite a bit of culture change in nursing homes to actually implement a protocol like this," the geriatrician noted.
Dr. Eric Widera of the University of California, San Francisco, said ample evidence indicates that pain in patients with dementia is common, underrecognized, and undertreated. The Norwegian pain medication protocol overcomes these barriers in novel fashion by treating everybody.
He stressed that the reduction in agitation and aggressive behavior wasn’t accomplished by merely sedating participants. After all, 69% of subjects in the intervention arm received only full-dose acetaminophen. And of the roughly one-quarter of patients who got opioids, only three withdrew from the study due to nausea or sedation.
The randomized trial was funded by the Norwegian Research Council, the University of Bergen, and Kavli’s Center for Aging and Dementia. Dr. Goldstein and Dr. Widera reported having no financial conflicts.
EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF HOSPICE AND PALLIATIVE CARE MEDICINE
'Scrambler' Device Reduces Refractory Neuropathic Pain
DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.
"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.
The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.
"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."
Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.
Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).
"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."
Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.
Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).
Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.
The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).
With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.
The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.
"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."
Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.
"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.
Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.
Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.
DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.
"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.
The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.
"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."
Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.
Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).
"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."
Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.
Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).
Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.
The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).
With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.
The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.
"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."
Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.
"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.
Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.
Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.
DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.
"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.
The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.
"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."
Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.
Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).
"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."
Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.
Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).
Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.
The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).
With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.
The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.
"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."
Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.
"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.
Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.
Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.
EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF HOSPICE AND PALLIATIVE CARE MEDICINE