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Managing agitation in outpatient dementia
NEW ORLEANS – A reasonable stepwise approach to pharmacotherapy for agitation in outpatient dementia begins with a judiciously chosen SSRI as first-line therapy, with the second-line consisting of augmentation with a benzodiazepine, M. Philip Luber, MD, said at the annual meeting of the American College of Physicians.
If this combination doesn’t provide satisfactory improvement after adequate dosing for sufficient duration, only then is it time to turn to an atypical antipsychotic agent as a higher-risk/higher-reward third-line therapy, added Dr. Luber, professor of psychiatry and associate dean for graduate medical education at the University of Texas, San Antonio.
He emphasized, however, that medications are not the first-line therapy for agitation in outpatients with dementia. That distinction belongs to psychosocial interventions.
“Utilize a social worker to assist the family in modifying the environment: family settings and people, regular routines, consistently orienting the patient, keeping stimulation at a low to moderate level. When that’s done right, it can really dampen down a lot of agitation,” he said.
Dr. Luber noted that the formal randomized trial evidence base for SSRIs as first-line pharmacotherapy and benzodiazepines as second-line is quite limited. But in conversations with geriatric psychiatrists and other health care professionals around the country who are working in this area, he has found broad agreement that this is a good strategy.
“A lot of folks don’t realize that [SSRIs] are actually very useful in the treatment of agitation in dementia. But you want to choose one with fewer side effects and drug-drug interactions,” Dr. Luber said.
Two SSRIs that fit the bill are escitalopram (Lexapro) and sertraline (Zoloft). Start low and increase the dose slowly, provided circumstances allow. Expect a therapeutic response to emerge in weeks, not days. And, in this elderly population, be sure to monitor for hyponatremia.
When considering augmentation, remember that “using benzodiazepines in the elderly is controversial, particularly with agitation in dementia. There is very little randomized clinical trial data on benzodiazepines in dementia. Actually, though, there are lots of clinical trials of benzodiazepines in dementia that feature benzodiazepines as rescue medication. So, clinically, there’s an awareness that the drugs work, but they haven’t been studied except as rescue medication,” he explained.
The phenomenon of paradoxical agitation occurring in elderly patients on benzodiazepines “is something to be careful about, but in fact it’s pretty uncommon. Just watch for it,” he added.
Dr. Luber is among many geriatric psychiatrists who preferentially turn to clonazepam (Klonopin) because its relatively long half-life allows for twice-daily administration.
“Think about using it regularly rather than PRN. You want to stay ahead of the agitation rather than behind it,” he advised.
Patients with liver disease are better served by a shorter-acting benzodiazepine such as lorazepam (Ativan), which is not oxidized in the liver.
Also controversial is use of atypical antipsychotics as third-line pharmacotherapy, “but many geriatric psychiatrists would agree with me that the next step if the patient is still agitated despite an SSRI augmented with a benzodiazepine is to consider a trial of an atypical antipsychotic,” Dr. Luber said.
He pointed to risperidone (Risperdal) and aripiprazole (Abilify) as agents with a good track record for treatment of agitation in dementia. He urged primary care physicians to be familiar with the risk of serious and even potentially fatal side effects as described in the black box warning.
“There are tough choices involved in treating patients with this disorder. Use shared decision making with the patient or family,” Dr. Luber said.
He reported having no financial conflicts of interest regarding his presentation.
NEW ORLEANS – A reasonable stepwise approach to pharmacotherapy for agitation in outpatient dementia begins with a judiciously chosen SSRI as first-line therapy, with the second-line consisting of augmentation with a benzodiazepine, M. Philip Luber, MD, said at the annual meeting of the American College of Physicians.
If this combination doesn’t provide satisfactory improvement after adequate dosing for sufficient duration, only then is it time to turn to an atypical antipsychotic agent as a higher-risk/higher-reward third-line therapy, added Dr. Luber, professor of psychiatry and associate dean for graduate medical education at the University of Texas, San Antonio.
He emphasized, however, that medications are not the first-line therapy for agitation in outpatients with dementia. That distinction belongs to psychosocial interventions.
“Utilize a social worker to assist the family in modifying the environment: family settings and people, regular routines, consistently orienting the patient, keeping stimulation at a low to moderate level. When that’s done right, it can really dampen down a lot of agitation,” he said.
Dr. Luber noted that the formal randomized trial evidence base for SSRIs as first-line pharmacotherapy and benzodiazepines as second-line is quite limited. But in conversations with geriatric psychiatrists and other health care professionals around the country who are working in this area, he has found broad agreement that this is a good strategy.
“A lot of folks don’t realize that [SSRIs] are actually very useful in the treatment of agitation in dementia. But you want to choose one with fewer side effects and drug-drug interactions,” Dr. Luber said.
Two SSRIs that fit the bill are escitalopram (Lexapro) and sertraline (Zoloft). Start low and increase the dose slowly, provided circumstances allow. Expect a therapeutic response to emerge in weeks, not days. And, in this elderly population, be sure to monitor for hyponatremia.
When considering augmentation, remember that “using benzodiazepines in the elderly is controversial, particularly with agitation in dementia. There is very little randomized clinical trial data on benzodiazepines in dementia. Actually, though, there are lots of clinical trials of benzodiazepines in dementia that feature benzodiazepines as rescue medication. So, clinically, there’s an awareness that the drugs work, but they haven’t been studied except as rescue medication,” he explained.
The phenomenon of paradoxical agitation occurring in elderly patients on benzodiazepines “is something to be careful about, but in fact it’s pretty uncommon. Just watch for it,” he added.
Dr. Luber is among many geriatric psychiatrists who preferentially turn to clonazepam (Klonopin) because its relatively long half-life allows for twice-daily administration.
“Think about using it regularly rather than PRN. You want to stay ahead of the agitation rather than behind it,” he advised.
Patients with liver disease are better served by a shorter-acting benzodiazepine such as lorazepam (Ativan), which is not oxidized in the liver.
Also controversial is use of atypical antipsychotics as third-line pharmacotherapy, “but many geriatric psychiatrists would agree with me that the next step if the patient is still agitated despite an SSRI augmented with a benzodiazepine is to consider a trial of an atypical antipsychotic,” Dr. Luber said.
He pointed to risperidone (Risperdal) and aripiprazole (Abilify) as agents with a good track record for treatment of agitation in dementia. He urged primary care physicians to be familiar with the risk of serious and even potentially fatal side effects as described in the black box warning.
“There are tough choices involved in treating patients with this disorder. Use shared decision making with the patient or family,” Dr. Luber said.
He reported having no financial conflicts of interest regarding his presentation.
NEW ORLEANS – A reasonable stepwise approach to pharmacotherapy for agitation in outpatient dementia begins with a judiciously chosen SSRI as first-line therapy, with the second-line consisting of augmentation with a benzodiazepine, M. Philip Luber, MD, said at the annual meeting of the American College of Physicians.
If this combination doesn’t provide satisfactory improvement after adequate dosing for sufficient duration, only then is it time to turn to an atypical antipsychotic agent as a higher-risk/higher-reward third-line therapy, added Dr. Luber, professor of psychiatry and associate dean for graduate medical education at the University of Texas, San Antonio.
He emphasized, however, that medications are not the first-line therapy for agitation in outpatients with dementia. That distinction belongs to psychosocial interventions.
“Utilize a social worker to assist the family in modifying the environment: family settings and people, regular routines, consistently orienting the patient, keeping stimulation at a low to moderate level. When that’s done right, it can really dampen down a lot of agitation,” he said.
Dr. Luber noted that the formal randomized trial evidence base for SSRIs as first-line pharmacotherapy and benzodiazepines as second-line is quite limited. But in conversations with geriatric psychiatrists and other health care professionals around the country who are working in this area, he has found broad agreement that this is a good strategy.
“A lot of folks don’t realize that [SSRIs] are actually very useful in the treatment of agitation in dementia. But you want to choose one with fewer side effects and drug-drug interactions,” Dr. Luber said.
Two SSRIs that fit the bill are escitalopram (Lexapro) and sertraline (Zoloft). Start low and increase the dose slowly, provided circumstances allow. Expect a therapeutic response to emerge in weeks, not days. And, in this elderly population, be sure to monitor for hyponatremia.
When considering augmentation, remember that “using benzodiazepines in the elderly is controversial, particularly with agitation in dementia. There is very little randomized clinical trial data on benzodiazepines in dementia. Actually, though, there are lots of clinical trials of benzodiazepines in dementia that feature benzodiazepines as rescue medication. So, clinically, there’s an awareness that the drugs work, but they haven’t been studied except as rescue medication,” he explained.
The phenomenon of paradoxical agitation occurring in elderly patients on benzodiazepines “is something to be careful about, but in fact it’s pretty uncommon. Just watch for it,” he added.
Dr. Luber is among many geriatric psychiatrists who preferentially turn to clonazepam (Klonopin) because its relatively long half-life allows for twice-daily administration.
“Think about using it regularly rather than PRN. You want to stay ahead of the agitation rather than behind it,” he advised.
Patients with liver disease are better served by a shorter-acting benzodiazepine such as lorazepam (Ativan), which is not oxidized in the liver.
Also controversial is use of atypical antipsychotics as third-line pharmacotherapy, “but many geriatric psychiatrists would agree with me that the next step if the patient is still agitated despite an SSRI augmented with a benzodiazepine is to consider a trial of an atypical antipsychotic,” Dr. Luber said.
He pointed to risperidone (Risperdal) and aripiprazole (Abilify) as agents with a good track record for treatment of agitation in dementia. He urged primary care physicians to be familiar with the risk of serious and even potentially fatal side effects as described in the black box warning.
“There are tough choices involved in treating patients with this disorder. Use shared decision making with the patient or family,” Dr. Luber said.
He reported having no financial conflicts of interest regarding his presentation.
REPORTING FROM ACP INTERNAL MEDICINE
When and how to suspect asthma misdiagnosis
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
REPORTING FROM ACP INTERNAL MEDICINE
Avoiding in-hospital acute kidney injury is a new imperative
NEW ORLEANS– Preventing acute kidney injury and its progression in hospitalized patients deserves to be a high priority – and now there is finally proof that it’s doable, Harold M. Szerlip, MD, declared at the annual meeting of the American College of Physicians.
The PrevAKI study, a recent randomized controlled clinical trial conducted by German investigators, has demonstrated that the use of renal biomarkers to identify patients at high risk for acute kidney injury (AKI) after major cardiac surgery and providing them with a range of internationally recommended supportive measures known as the KDIGO (Kidney Disease: Improving Global Outcomes) care bundle reduced the occurrence of moderate-to-severe AKI by 34% (Intensive Care Med. 2017 Nov;43[11]:1551-61).
The enthusiasm that greeted the PrevAKI trial findings is reflected in an editorial entitled, “AKI: the Myth of Inevitability is Finally Shattered,” by John A. Kellum, MD, professor of critical care medicine and director of the Center for Critical Care Nephrology at the University of Pittsburgh. Dr. Kellum noted that the renal biomarker-based approach to implementation of the KDIGO care bundle resulted in an attractively low number needed to treat (NNT) of only 6, whereas without biomarker-based enrichment of the target population, the NNT would have been more than 33.
“,” Dr. Kellum declared in the editorial (Nat Rev Nephrol. 2017 Mar;13[3]:140-1).
Indeed, another way to do it was recently demonstrated in the SALT-ED trial, in which 13,347 noncritically ill hospitalized patients requiring intravenous fluid administration were randomized to conventional saline or balanced crystalloids. The incidence of AKI and other major adverse kidney events was 4.7% in the balanced crystalloids group, for a significant 18% risk reduction relative to the 5.6% rate with saline (N Engl J Med. 2018 Mar 1;378[9]:819-28).
While that absolute 0.9% risk reduction might initially not sound like much, with 35 million people per year getting IV saline while in the hospital, it translates into 315,000 fewer major adverse kidney events as a result of a simple switch to balanced crystalloids, Dr. Szerlip observed.
The PrevAKI findings validate the concept of AKI ‘golden hours’ during which time potentially reversible early kidney injury detectable via renal biomarkers is occurring prior to the abrupt decline in kidney function measured by change in serum creatinine. “The problem with using change in creatinine to define AKI is the delay in diagnosis, which makes AKI more difficult to treat,” he explained.
The renal biomarkers utilized in PrevAKI were insulin-like growth factor binding protein-7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2), as incorporated in the commercially available urinary NephroCheck test, which was administered to study participants 4 hours after cardiopulmonary bypass. A test result of 0.3 or more identified a group at high risk for AKI for randomization to the KDIGO bundle or usual care. The KDIGO bundle consists of discontinuation of nephrotoxic agents when feasible, early optimization of fluid status, and maintenance of perfusion pressure.
Patients known to be at increased risk for in-hospital AKI include the elderly, those with diabetes, patients with heart failure or other conditions prone to volume contraction or overload, those undergoing major surgery, individuals with chronic kidney disease, and patients with sepsis.
Dr. Szerlip singled out as particularly nephrotoxic several drugs widely used in hospitalized patients, including the combination of vancomycin plus piperacillin-tazobactam, which in a recent metaanalysis was found to have a number needed to harm of 11 in terms of AKI in comparison to vancomycin monotherapy or vancomycin in combination with cefepime or carbapenem (Crit Care Med. 2018 Jan;46[1]:12-20). He was also critical of the American Society of Anesthesiologists practice parameter recommending that in-hospital pain management plans for surgical patients include continuous regimens of NSAIDs or COX-2 inhibitors as a means of combating the ongoing opioid epidemic.
“These are highly toxic drugs to the kidney and we shouldn’t be using them,” Dr. Szerlip said.
He reported receiving research grants from LaJolla, Bayer, Akebia, and BioPorto, serving on a speakers’ bureau for Astute Medical, and acting as a consultant to Zs Pharma, Amarin, and LaJolla.
NEW ORLEANS– Preventing acute kidney injury and its progression in hospitalized patients deserves to be a high priority – and now there is finally proof that it’s doable, Harold M. Szerlip, MD, declared at the annual meeting of the American College of Physicians.
The PrevAKI study, a recent randomized controlled clinical trial conducted by German investigators, has demonstrated that the use of renal biomarkers to identify patients at high risk for acute kidney injury (AKI) after major cardiac surgery and providing them with a range of internationally recommended supportive measures known as the KDIGO (Kidney Disease: Improving Global Outcomes) care bundle reduced the occurrence of moderate-to-severe AKI by 34% (Intensive Care Med. 2017 Nov;43[11]:1551-61).
The enthusiasm that greeted the PrevAKI trial findings is reflected in an editorial entitled, “AKI: the Myth of Inevitability is Finally Shattered,” by John A. Kellum, MD, professor of critical care medicine and director of the Center for Critical Care Nephrology at the University of Pittsburgh. Dr. Kellum noted that the renal biomarker-based approach to implementation of the KDIGO care bundle resulted in an attractively low number needed to treat (NNT) of only 6, whereas without biomarker-based enrichment of the target population, the NNT would have been more than 33.
“,” Dr. Kellum declared in the editorial (Nat Rev Nephrol. 2017 Mar;13[3]:140-1).
Indeed, another way to do it was recently demonstrated in the SALT-ED trial, in which 13,347 noncritically ill hospitalized patients requiring intravenous fluid administration were randomized to conventional saline or balanced crystalloids. The incidence of AKI and other major adverse kidney events was 4.7% in the balanced crystalloids group, for a significant 18% risk reduction relative to the 5.6% rate with saline (N Engl J Med. 2018 Mar 1;378[9]:819-28).
While that absolute 0.9% risk reduction might initially not sound like much, with 35 million people per year getting IV saline while in the hospital, it translates into 315,000 fewer major adverse kidney events as a result of a simple switch to balanced crystalloids, Dr. Szerlip observed.
The PrevAKI findings validate the concept of AKI ‘golden hours’ during which time potentially reversible early kidney injury detectable via renal biomarkers is occurring prior to the abrupt decline in kidney function measured by change in serum creatinine. “The problem with using change in creatinine to define AKI is the delay in diagnosis, which makes AKI more difficult to treat,” he explained.
The renal biomarkers utilized in PrevAKI were insulin-like growth factor binding protein-7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2), as incorporated in the commercially available urinary NephroCheck test, which was administered to study participants 4 hours after cardiopulmonary bypass. A test result of 0.3 or more identified a group at high risk for AKI for randomization to the KDIGO bundle or usual care. The KDIGO bundle consists of discontinuation of nephrotoxic agents when feasible, early optimization of fluid status, and maintenance of perfusion pressure.
Patients known to be at increased risk for in-hospital AKI include the elderly, those with diabetes, patients with heart failure or other conditions prone to volume contraction or overload, those undergoing major surgery, individuals with chronic kidney disease, and patients with sepsis.
Dr. Szerlip singled out as particularly nephrotoxic several drugs widely used in hospitalized patients, including the combination of vancomycin plus piperacillin-tazobactam, which in a recent metaanalysis was found to have a number needed to harm of 11 in terms of AKI in comparison to vancomycin monotherapy or vancomycin in combination with cefepime or carbapenem (Crit Care Med. 2018 Jan;46[1]:12-20). He was also critical of the American Society of Anesthesiologists practice parameter recommending that in-hospital pain management plans for surgical patients include continuous regimens of NSAIDs or COX-2 inhibitors as a means of combating the ongoing opioid epidemic.
“These are highly toxic drugs to the kidney and we shouldn’t be using them,” Dr. Szerlip said.
He reported receiving research grants from LaJolla, Bayer, Akebia, and BioPorto, serving on a speakers’ bureau for Astute Medical, and acting as a consultant to Zs Pharma, Amarin, and LaJolla.
NEW ORLEANS– Preventing acute kidney injury and its progression in hospitalized patients deserves to be a high priority – and now there is finally proof that it’s doable, Harold M. Szerlip, MD, declared at the annual meeting of the American College of Physicians.
The PrevAKI study, a recent randomized controlled clinical trial conducted by German investigators, has demonstrated that the use of renal biomarkers to identify patients at high risk for acute kidney injury (AKI) after major cardiac surgery and providing them with a range of internationally recommended supportive measures known as the KDIGO (Kidney Disease: Improving Global Outcomes) care bundle reduced the occurrence of moderate-to-severe AKI by 34% (Intensive Care Med. 2017 Nov;43[11]:1551-61).
The enthusiasm that greeted the PrevAKI trial findings is reflected in an editorial entitled, “AKI: the Myth of Inevitability is Finally Shattered,” by John A. Kellum, MD, professor of critical care medicine and director of the Center for Critical Care Nephrology at the University of Pittsburgh. Dr. Kellum noted that the renal biomarker-based approach to implementation of the KDIGO care bundle resulted in an attractively low number needed to treat (NNT) of only 6, whereas without biomarker-based enrichment of the target population, the NNT would have been more than 33.
“,” Dr. Kellum declared in the editorial (Nat Rev Nephrol. 2017 Mar;13[3]:140-1).
Indeed, another way to do it was recently demonstrated in the SALT-ED trial, in which 13,347 noncritically ill hospitalized patients requiring intravenous fluid administration were randomized to conventional saline or balanced crystalloids. The incidence of AKI and other major adverse kidney events was 4.7% in the balanced crystalloids group, for a significant 18% risk reduction relative to the 5.6% rate with saline (N Engl J Med. 2018 Mar 1;378[9]:819-28).
While that absolute 0.9% risk reduction might initially not sound like much, with 35 million people per year getting IV saline while in the hospital, it translates into 315,000 fewer major adverse kidney events as a result of a simple switch to balanced crystalloids, Dr. Szerlip observed.
The PrevAKI findings validate the concept of AKI ‘golden hours’ during which time potentially reversible early kidney injury detectable via renal biomarkers is occurring prior to the abrupt decline in kidney function measured by change in serum creatinine. “The problem with using change in creatinine to define AKI is the delay in diagnosis, which makes AKI more difficult to treat,” he explained.
The renal biomarkers utilized in PrevAKI were insulin-like growth factor binding protein-7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2), as incorporated in the commercially available urinary NephroCheck test, which was administered to study participants 4 hours after cardiopulmonary bypass. A test result of 0.3 or more identified a group at high risk for AKI for randomization to the KDIGO bundle or usual care. The KDIGO bundle consists of discontinuation of nephrotoxic agents when feasible, early optimization of fluid status, and maintenance of perfusion pressure.
Patients known to be at increased risk for in-hospital AKI include the elderly, those with diabetes, patients with heart failure or other conditions prone to volume contraction or overload, those undergoing major surgery, individuals with chronic kidney disease, and patients with sepsis.
Dr. Szerlip singled out as particularly nephrotoxic several drugs widely used in hospitalized patients, including the combination of vancomycin plus piperacillin-tazobactam, which in a recent metaanalysis was found to have a number needed to harm of 11 in terms of AKI in comparison to vancomycin monotherapy or vancomycin in combination with cefepime or carbapenem (Crit Care Med. 2018 Jan;46[1]:12-20). He was also critical of the American Society of Anesthesiologists practice parameter recommending that in-hospital pain management plans for surgical patients include continuous regimens of NSAIDs or COX-2 inhibitors as a means of combating the ongoing opioid epidemic.
“These are highly toxic drugs to the kidney and we shouldn’t be using them,” Dr. Szerlip said.
He reported receiving research grants from LaJolla, Bayer, Akebia, and BioPorto, serving on a speakers’ bureau for Astute Medical, and acting as a consultant to Zs Pharma, Amarin, and LaJolla.
EXPERT ANALYSIS FROM ACP INTERNAL MECICINE
Key to MGUS and myeloma may lie in Iceland
NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.
This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.
The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).
The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.
In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.
Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.
In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.
Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.
An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.
When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.
A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).
CRAB vs. SLiM CRAB
Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).
If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).
“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”
The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.
Not all MGUS needs a bone marrow biopsy
A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.
The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.
“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”
Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.
NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.
This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.
The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).
The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.
In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.
Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.
In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.
Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.
An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.
When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.
A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).
CRAB vs. SLiM CRAB
Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).
If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).
“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”
The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.
Not all MGUS needs a bone marrow biopsy
A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.
The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.
“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”
Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.
NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.
This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.
The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).
The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.
In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.
Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.
In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.
Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.
An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.
When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.
A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).
CRAB vs. SLiM CRAB
Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).
If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).
“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”
The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.
Not all MGUS needs a bone marrow biopsy
A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.
The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.
“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”
Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.
EXPERT ANALYSIS FROM ACP INTERNAL MEDICINE
Beware nonopiate meds with high street value
NEW ORLEANS – Gabapentin heads the short list of prescription drugs other than opioids and benzodiazepines with substantial black-market abuse potential, according to Alexander Y. Walley, MD.
“At least in Massachusetts, where I see patients, these are the pills that people are using and trading on the street. Your part of the country might have others,” noted Dr. Walley, director of the addiction medicine fellowship program at Boston Medical Center.
“I’m not telling you to never prescribe these medications – they are clinically indicated in certain cases and should certainly be used,” Dr. Walley said at the annual meeting of the American College of Physicians. “But now that you know that they might be misused, you should use safeguards.
“A lot of these medications – gabapentin is an example – are a problem primarily in people with other substance use disorders,” he added. “That’s really where I think you need to have the greatest caution.”
Gabapentinoids
Gabapentin and pregabalin are not addictive in the sense that it’s easy to get laboratory animals or healthy volunteers to self-administer them. However, gabapentinoid use disorder is extremely common among people with opioid use disorder, who report that the combination boosts the euphoric effects of opioids and reduces opioid withdrawal symptoms without causing side effects.
Indeed, a recent systematic review of 106 studies found that gabapentinoid use disorder was present in up to 26% of opioid users (Eur Neuropsychopharmacol. 2017 Dec;27[12]:1185-1215).
Overdoses involving gabapentinoids alone are uncommon because they require consumption at up to 25 times the maximum recommended dose. Moreover, these overdoses are rarely fatal.
“You almost can’t overdose on a gabapentinoid, because you have to take lots and lots of it to do so, and you’ll usually survive. But if you add it to an opioid or other sedative, then you’re really in dangerous territory. That’s where all the deaths are clustered,” Dr. Walley explained.
A recent Canadian/Dutch population-based, nested, case-control study concluded that concomitant prescription of opioids and gabapentin was associated with a 49% greater chance of fatal overdose, compared with opioid prescription alone, in an analysis extensively adjusted for potential confounders. A dose-response effect was noted, such that coprescription of high-dose gabapentin was linked to an adjusted 58% increased risk (PLoS Med. 2017 Oct 3;14[10]:e1002396).
Complicating the picture, however, is solid evidence from a randomized, placebo-controlled, crossover trial that gabapentin and opioids are synergistic for relief from neuropathic pain, which can be notoriously difficult to control (N Engl J Med. 2005 Mar 31;352[13]:1324-34).
“It’s tricky, because you can potentially spare having to use high-dose opioids by adding gabapentin,” Dr. Walley observed. “So, as prescribers, you’re in a difficult position, because there’s a mixed message here: When gabapentin is combined with opioids, that’s when it’s dangerous – but that’s also when they’re potentially more effective for pain.”
Promethazine
This drug has a host of neurobiologic actions, which collectively provide sedative and antiemetic effects. Promethazine jacks up opioid-induced euphoria and alleviates withdrawal symptoms. It’s commonly detected in toxicology testing of patients on prescription opioids for chronic pain or on methadone therapy for opioid use disorder.
National Poison Data System figures show an unwelcome trend: A sharp uptick in promethazine abuse/misuse beginning in 2008, even while the total number of poisoning events of all kinds reported to the system began a steady decline (J Addict Med. 2015 May-Jun;9[3]:233-7).
Clonidine
This centrally acting alpha2-adrenoreceptor and imidazoline-receptor agonist is indicated for treatment of hypertension. However, it’s also extensively used off-label to treat anxiety, as well as for alcohol and opioid withdrawal symptoms. The problem is, clonidine boosts opioid-induced euphoria.
A retrospective study of clonidine-overdose patients characterized the clonidine overdose syndrome as marked by sedation, hypotension, bradycardia, and excessive pupillary constriction (Clin Toxicol [Phila]. 2017 Mar;55[3]:187-92).
“The combination of clonidine and opioids is particularly dangerous,” according to Dr. Walley. “Even though it mimics what an opioid overdose looks like, a clonidine overdose is not responsive to naloxone.”
Stimulants
One-quarter of patients who are prescribed methylphenidate or amphetamine for ADHD report being asked to divert their medication, and 11%-29% sell or give it to others seeking to use it recreationally or as a performance aid.
It’s common for prescription seekers to misrepresent symptoms of ADHD, and this play-acting is often tough to detect. In contrast, the nonstimulant atomoxetine (Strattera) and the alpha-adrenergic agonists prescribed for ADHD aren’t linked to misuse or diversion (Postgrad Med. 2014 Sep;126[5]:64-81).
Bupropion
This norepinephrine and dopamine reuptake inhibitor is generally assumed to have low abuse potential. That’s usually true – except in jail and prisons.
“In my patient population, where I have a keen eye to what’s being used on the street, bupropion is not one of the medications that I see very often in my patients who are not incarcerated,” Dr. Walley said. “But in incarcerated settings, it does have a street value.”
Consider safeguards
None of the prescription drugs on Dr. Walley’s problem list is included in prescription monitoring programs, nor are they detectable with standard toxicology testing. This poses a challenge for prescribing physicians.
Before prescribing any of these potentially abusable medications for a given patient, therefore, Dr. Walley considers the underlying risks. For example, an addiction history is a big red flag. So is coprescription of an opioid or another drug that might have synergistic adverse effects. Dr. Walley makes sure there is a solid indication for the medication, and, having prescribed the drug, he wants to see and document clear functional benefit.
Drug-specific toxicology screening is worthy of consideration as a means of confirming the presence of the prescribed medication, along with the absence of opioids or other drugs that shouldn’t be on board.
“I do this with gabapentin, because I see a lot of diversion,” he explained. “If gabapentin doesn’t show up in the toxicology screen, I stop prescribing it. Or if I detect it and it hasn’t been prescribed, that allows me to have a safety discussion with the patient.”
Dr. Walley reported no financial conflicts of interest regarding his presentation.
NEW ORLEANS – Gabapentin heads the short list of prescription drugs other than opioids and benzodiazepines with substantial black-market abuse potential, according to Alexander Y. Walley, MD.
“At least in Massachusetts, where I see patients, these are the pills that people are using and trading on the street. Your part of the country might have others,” noted Dr. Walley, director of the addiction medicine fellowship program at Boston Medical Center.
“I’m not telling you to never prescribe these medications – they are clinically indicated in certain cases and should certainly be used,” Dr. Walley said at the annual meeting of the American College of Physicians. “But now that you know that they might be misused, you should use safeguards.
“A lot of these medications – gabapentin is an example – are a problem primarily in people with other substance use disorders,” he added. “That’s really where I think you need to have the greatest caution.”
Gabapentinoids
Gabapentin and pregabalin are not addictive in the sense that it’s easy to get laboratory animals or healthy volunteers to self-administer them. However, gabapentinoid use disorder is extremely common among people with opioid use disorder, who report that the combination boosts the euphoric effects of opioids and reduces opioid withdrawal symptoms without causing side effects.
Indeed, a recent systematic review of 106 studies found that gabapentinoid use disorder was present in up to 26% of opioid users (Eur Neuropsychopharmacol. 2017 Dec;27[12]:1185-1215).
Overdoses involving gabapentinoids alone are uncommon because they require consumption at up to 25 times the maximum recommended dose. Moreover, these overdoses are rarely fatal.
“You almost can’t overdose on a gabapentinoid, because you have to take lots and lots of it to do so, and you’ll usually survive. But if you add it to an opioid or other sedative, then you’re really in dangerous territory. That’s where all the deaths are clustered,” Dr. Walley explained.
A recent Canadian/Dutch population-based, nested, case-control study concluded that concomitant prescription of opioids and gabapentin was associated with a 49% greater chance of fatal overdose, compared with opioid prescription alone, in an analysis extensively adjusted for potential confounders. A dose-response effect was noted, such that coprescription of high-dose gabapentin was linked to an adjusted 58% increased risk (PLoS Med. 2017 Oct 3;14[10]:e1002396).
Complicating the picture, however, is solid evidence from a randomized, placebo-controlled, crossover trial that gabapentin and opioids are synergistic for relief from neuropathic pain, which can be notoriously difficult to control (N Engl J Med. 2005 Mar 31;352[13]:1324-34).
“It’s tricky, because you can potentially spare having to use high-dose opioids by adding gabapentin,” Dr. Walley observed. “So, as prescribers, you’re in a difficult position, because there’s a mixed message here: When gabapentin is combined with opioids, that’s when it’s dangerous – but that’s also when they’re potentially more effective for pain.”
Promethazine
This drug has a host of neurobiologic actions, which collectively provide sedative and antiemetic effects. Promethazine jacks up opioid-induced euphoria and alleviates withdrawal symptoms. It’s commonly detected in toxicology testing of patients on prescription opioids for chronic pain or on methadone therapy for opioid use disorder.
National Poison Data System figures show an unwelcome trend: A sharp uptick in promethazine abuse/misuse beginning in 2008, even while the total number of poisoning events of all kinds reported to the system began a steady decline (J Addict Med. 2015 May-Jun;9[3]:233-7).
Clonidine
This centrally acting alpha2-adrenoreceptor and imidazoline-receptor agonist is indicated for treatment of hypertension. However, it’s also extensively used off-label to treat anxiety, as well as for alcohol and opioid withdrawal symptoms. The problem is, clonidine boosts opioid-induced euphoria.
A retrospective study of clonidine-overdose patients characterized the clonidine overdose syndrome as marked by sedation, hypotension, bradycardia, and excessive pupillary constriction (Clin Toxicol [Phila]. 2017 Mar;55[3]:187-92).
“The combination of clonidine and opioids is particularly dangerous,” according to Dr. Walley. “Even though it mimics what an opioid overdose looks like, a clonidine overdose is not responsive to naloxone.”
Stimulants
One-quarter of patients who are prescribed methylphenidate or amphetamine for ADHD report being asked to divert their medication, and 11%-29% sell or give it to others seeking to use it recreationally or as a performance aid.
It’s common for prescription seekers to misrepresent symptoms of ADHD, and this play-acting is often tough to detect. In contrast, the nonstimulant atomoxetine (Strattera) and the alpha-adrenergic agonists prescribed for ADHD aren’t linked to misuse or diversion (Postgrad Med. 2014 Sep;126[5]:64-81).
Bupropion
This norepinephrine and dopamine reuptake inhibitor is generally assumed to have low abuse potential. That’s usually true – except in jail and prisons.
“In my patient population, where I have a keen eye to what’s being used on the street, bupropion is not one of the medications that I see very often in my patients who are not incarcerated,” Dr. Walley said. “But in incarcerated settings, it does have a street value.”
Consider safeguards
None of the prescription drugs on Dr. Walley’s problem list is included in prescription monitoring programs, nor are they detectable with standard toxicology testing. This poses a challenge for prescribing physicians.
Before prescribing any of these potentially abusable medications for a given patient, therefore, Dr. Walley considers the underlying risks. For example, an addiction history is a big red flag. So is coprescription of an opioid or another drug that might have synergistic adverse effects. Dr. Walley makes sure there is a solid indication for the medication, and, having prescribed the drug, he wants to see and document clear functional benefit.
Drug-specific toxicology screening is worthy of consideration as a means of confirming the presence of the prescribed medication, along with the absence of opioids or other drugs that shouldn’t be on board.
“I do this with gabapentin, because I see a lot of diversion,” he explained. “If gabapentin doesn’t show up in the toxicology screen, I stop prescribing it. Or if I detect it and it hasn’t been prescribed, that allows me to have a safety discussion with the patient.”
Dr. Walley reported no financial conflicts of interest regarding his presentation.
NEW ORLEANS – Gabapentin heads the short list of prescription drugs other than opioids and benzodiazepines with substantial black-market abuse potential, according to Alexander Y. Walley, MD.
“At least in Massachusetts, where I see patients, these are the pills that people are using and trading on the street. Your part of the country might have others,” noted Dr. Walley, director of the addiction medicine fellowship program at Boston Medical Center.
“I’m not telling you to never prescribe these medications – they are clinically indicated in certain cases and should certainly be used,” Dr. Walley said at the annual meeting of the American College of Physicians. “But now that you know that they might be misused, you should use safeguards.
“A lot of these medications – gabapentin is an example – are a problem primarily in people with other substance use disorders,” he added. “That’s really where I think you need to have the greatest caution.”
Gabapentinoids
Gabapentin and pregabalin are not addictive in the sense that it’s easy to get laboratory animals or healthy volunteers to self-administer them. However, gabapentinoid use disorder is extremely common among people with opioid use disorder, who report that the combination boosts the euphoric effects of opioids and reduces opioid withdrawal symptoms without causing side effects.
Indeed, a recent systematic review of 106 studies found that gabapentinoid use disorder was present in up to 26% of opioid users (Eur Neuropsychopharmacol. 2017 Dec;27[12]:1185-1215).
Overdoses involving gabapentinoids alone are uncommon because they require consumption at up to 25 times the maximum recommended dose. Moreover, these overdoses are rarely fatal.
“You almost can’t overdose on a gabapentinoid, because you have to take lots and lots of it to do so, and you’ll usually survive. But if you add it to an opioid or other sedative, then you’re really in dangerous territory. That’s where all the deaths are clustered,” Dr. Walley explained.
A recent Canadian/Dutch population-based, nested, case-control study concluded that concomitant prescription of opioids and gabapentin was associated with a 49% greater chance of fatal overdose, compared with opioid prescription alone, in an analysis extensively adjusted for potential confounders. A dose-response effect was noted, such that coprescription of high-dose gabapentin was linked to an adjusted 58% increased risk (PLoS Med. 2017 Oct 3;14[10]:e1002396).
Complicating the picture, however, is solid evidence from a randomized, placebo-controlled, crossover trial that gabapentin and opioids are synergistic for relief from neuropathic pain, which can be notoriously difficult to control (N Engl J Med. 2005 Mar 31;352[13]:1324-34).
“It’s tricky, because you can potentially spare having to use high-dose opioids by adding gabapentin,” Dr. Walley observed. “So, as prescribers, you’re in a difficult position, because there’s a mixed message here: When gabapentin is combined with opioids, that’s when it’s dangerous – but that’s also when they’re potentially more effective for pain.”
Promethazine
This drug has a host of neurobiologic actions, which collectively provide sedative and antiemetic effects. Promethazine jacks up opioid-induced euphoria and alleviates withdrawal symptoms. It’s commonly detected in toxicology testing of patients on prescription opioids for chronic pain or on methadone therapy for opioid use disorder.
National Poison Data System figures show an unwelcome trend: A sharp uptick in promethazine abuse/misuse beginning in 2008, even while the total number of poisoning events of all kinds reported to the system began a steady decline (J Addict Med. 2015 May-Jun;9[3]:233-7).
Clonidine
This centrally acting alpha2-adrenoreceptor and imidazoline-receptor agonist is indicated for treatment of hypertension. However, it’s also extensively used off-label to treat anxiety, as well as for alcohol and opioid withdrawal symptoms. The problem is, clonidine boosts opioid-induced euphoria.
A retrospective study of clonidine-overdose patients characterized the clonidine overdose syndrome as marked by sedation, hypotension, bradycardia, and excessive pupillary constriction (Clin Toxicol [Phila]. 2017 Mar;55[3]:187-92).
“The combination of clonidine and opioids is particularly dangerous,” according to Dr. Walley. “Even though it mimics what an opioid overdose looks like, a clonidine overdose is not responsive to naloxone.”
Stimulants
One-quarter of patients who are prescribed methylphenidate or amphetamine for ADHD report being asked to divert their medication, and 11%-29% sell or give it to others seeking to use it recreationally or as a performance aid.
It’s common for prescription seekers to misrepresent symptoms of ADHD, and this play-acting is often tough to detect. In contrast, the nonstimulant atomoxetine (Strattera) and the alpha-adrenergic agonists prescribed for ADHD aren’t linked to misuse or diversion (Postgrad Med. 2014 Sep;126[5]:64-81).
Bupropion
This norepinephrine and dopamine reuptake inhibitor is generally assumed to have low abuse potential. That’s usually true – except in jail and prisons.
“In my patient population, where I have a keen eye to what’s being used on the street, bupropion is not one of the medications that I see very often in my patients who are not incarcerated,” Dr. Walley said. “But in incarcerated settings, it does have a street value.”
Consider safeguards
None of the prescription drugs on Dr. Walley’s problem list is included in prescription monitoring programs, nor are they detectable with standard toxicology testing. This poses a challenge for prescribing physicians.
Before prescribing any of these potentially abusable medications for a given patient, therefore, Dr. Walley considers the underlying risks. For example, an addiction history is a big red flag. So is coprescription of an opioid or another drug that might have synergistic adverse effects. Dr. Walley makes sure there is a solid indication for the medication, and, having prescribed the drug, he wants to see and document clear functional benefit.
Drug-specific toxicology screening is worthy of consideration as a means of confirming the presence of the prescribed medication, along with the absence of opioids or other drugs that shouldn’t be on board.
“I do this with gabapentin, because I see a lot of diversion,” he explained. “If gabapentin doesn’t show up in the toxicology screen, I stop prescribing it. Or if I detect it and it hasn’t been prescribed, that allows me to have a safety discussion with the patient.”
Dr. Walley reported no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM ACP INTERNAL MEDICINE
VIDEO: Fix physician burnout? You need more than yoga
NEW ORLEANS – Among a growing number of physicians, the words of a Righteous Brothers’ song ring true about their careers: They’ve lost that loving feeling.
For burned-out physicians, “they’ve lost that sense that they’re making a difference,” explained Susan Thompson Hingle, MD, of Southern Illinois University in Springfield. And the solutions aren’t simple. “You can’t yoga your way out of this,” Dr. Hingle cautioned.
At the annual meeting of the American College of Physicians, Dr. Hingle and Daisy Smith, MD, vice president of clinical programs at the ACP, talked about solutions to burnout, including how more traditional approaches can boost physician well-being, such as team-based care, physician champions, and increasing the pool of primary care providers.
But they also detailed ways that struggling physicians can find support from an unlikely source: their patients.
Dr. Smith’s video interview:
Dr. Hingle’s video interview:
NEW ORLEANS – Among a growing number of physicians, the words of a Righteous Brothers’ song ring true about their careers: They’ve lost that loving feeling.
For burned-out physicians, “they’ve lost that sense that they’re making a difference,” explained Susan Thompson Hingle, MD, of Southern Illinois University in Springfield. And the solutions aren’t simple. “You can’t yoga your way out of this,” Dr. Hingle cautioned.
At the annual meeting of the American College of Physicians, Dr. Hingle and Daisy Smith, MD, vice president of clinical programs at the ACP, talked about solutions to burnout, including how more traditional approaches can boost physician well-being, such as team-based care, physician champions, and increasing the pool of primary care providers.
But they also detailed ways that struggling physicians can find support from an unlikely source: their patients.
Dr. Smith’s video interview:
Dr. Hingle’s video interview:
NEW ORLEANS – Among a growing number of physicians, the words of a Righteous Brothers’ song ring true about their careers: They’ve lost that loving feeling.
For burned-out physicians, “they’ve lost that sense that they’re making a difference,” explained Susan Thompson Hingle, MD, of Southern Illinois University in Springfield. And the solutions aren’t simple. “You can’t yoga your way out of this,” Dr. Hingle cautioned.
At the annual meeting of the American College of Physicians, Dr. Hingle and Daisy Smith, MD, vice president of clinical programs at the ACP, talked about solutions to burnout, including how more traditional approaches can boost physician well-being, such as team-based care, physician champions, and increasing the pool of primary care providers.
But they also detailed ways that struggling physicians can find support from an unlikely source: their patients.
Dr. Smith’s video interview:
Dr. Hingle’s video interview:
REPORTING FROM ACP INTERNAL MEDICINE
VIDEO: A treatment plan for medicine’s gender inequities
NEW ORLEANS – Gender inequities may pervade the medical profession, but a new generation of younger physicians – women and men – can help reshape medicine’s mindsets and workplaces.
At the annual meeting of the American College of Physicians, Sue Bornstein, MD, former chief of staff at Baylor University Medical Center in Dallas, and Darilyn Moyer, MD, CEO of the American College of Physicians, talked about the challenges to closing medicine’s gender-equity gaps, from structural bias to backlash. And they outlined strategies for women to broaden career opportunities and achieve fair payment – from mentoring and sponsoring, to leading change from the top of organizations.
The ACP published a position paper on achieving gender equity in the Annals of Internal Medicine.
Dr. Bornstein’s interview:
Dr. Moyer’s interview:
SOURCE: Ann Intern Med. 2018 Apr 17. doi: 10.7326/M17-3438.
NEW ORLEANS – Gender inequities may pervade the medical profession, but a new generation of younger physicians – women and men – can help reshape medicine’s mindsets and workplaces.
At the annual meeting of the American College of Physicians, Sue Bornstein, MD, former chief of staff at Baylor University Medical Center in Dallas, and Darilyn Moyer, MD, CEO of the American College of Physicians, talked about the challenges to closing medicine’s gender-equity gaps, from structural bias to backlash. And they outlined strategies for women to broaden career opportunities and achieve fair payment – from mentoring and sponsoring, to leading change from the top of organizations.
The ACP published a position paper on achieving gender equity in the Annals of Internal Medicine.
Dr. Bornstein’s interview:
Dr. Moyer’s interview:
SOURCE: Ann Intern Med. 2018 Apr 17. doi: 10.7326/M17-3438.
NEW ORLEANS – Gender inequities may pervade the medical profession, but a new generation of younger physicians – women and men – can help reshape medicine’s mindsets and workplaces.
At the annual meeting of the American College of Physicians, Sue Bornstein, MD, former chief of staff at Baylor University Medical Center in Dallas, and Darilyn Moyer, MD, CEO of the American College of Physicians, talked about the challenges to closing medicine’s gender-equity gaps, from structural bias to backlash. And they outlined strategies for women to broaden career opportunities and achieve fair payment – from mentoring and sponsoring, to leading change from the top of organizations.
The ACP published a position paper on achieving gender equity in the Annals of Internal Medicine.
Dr. Bornstein’s interview:
Dr. Moyer’s interview:
SOURCE: Ann Intern Med. 2018 Apr 17. doi: 10.7326/M17-3438.
REPORTING FROM ACP Internal Medicine
Statin-associated muscle symptoms? Rechallenge!
New Orleans – An effective and well-tolerated, evidence-based strategy for managing statin-associated muscle complaints is to rechallenge with the same statin, Douglas S. Paauw, MD, said at the annual meeting of the American College of Physicians.
That being said, it must be recognized that statin-associated muscle symptoms remain an enigma. This was underscored in a recent study by investigators at Hartford (Conn.) Hospital, which suggested a need to reassess the whole concept of statin-associated muscle symptoms, according to Dr. Paauw, professor of medicine at the University of Washington, Seattle.
“This study just blows my mind,” Dr. Paauw said. “The bottom line here is we just don’t know. A third of our patients might have true statin-associated muscle symptoms, but the other two-thirds would fall into these other groups, where they don’t have symptoms if we give them a statin again or they might get worse with placebo. So, we’ve got to rethink this.”
First things first
Before embarking on same-statin rechallenge, several things should first be done. Step 1 is to check the patient’s thyroid-stimulating hormone, creatine kinase, and serum vitamin D levels. Step 2 is to look for possible explanatory drug interactions, with verapamil and diltiazem being particularly common offenders in statin users.
If a patient with statin-associated muscle symptoms has a low serum vitamin D level, Dr. Paauw will give high-dose supplemental vitamin D. This strategy is supported by a University of Cincinnati prospective study of 146 patients with intolerable muscle symptoms on two or more statins, all of whom had a serum vitamin D below 32 ng/mL. They were placed on long-term vitamin D2 at 50,000-100,000 units per week and rechallenged with a statin. At 2 years of follow-up while still on supplemental vitamin D, 91% of patients had a normal serum vitamin D, and 95% of these previously statin-intolerant patients were on statin therapy without muscle complaints (N Am J Med Sci. 2015 Mar;7[3]:86-93).
Hypothyroidism increases statin toxicity. “I can’t overstate how important it is to check the thyroid-stimulating hormone to see if we’re dealing with something really simple,” Dr. Paauw said, “because trust me, treating hypothyroidism is much easier than treating statin-associated muscle symptoms.”
It has long been known that fibrates increase the risk of statin toxicity. Much less well recognized is that not all fibrates are the same in this regard: The risk is 15 times greater with gemfibrozil than with fenofibrate. The risk is also higher with verapamil or diltiazem than with nifedipine or amlodipine. Other important causes of drug interactions that increase statin toxicity include amiodarone, azole antifungals, protease inhibitors, erythromycin, and clarithromycin, but not azithromycin.
“Simvastatin and lovastatin are probably the worst as far as drug interactions,” Dr. Paauw cautioned. “They’re cheap, they’ve been generic for a long, long time, and a lot of times insurance companies want to move people to them. I try to move patients away from those two, because they are the dirtiest of the statins as far as side effects and drug interactions.”
When a drug interaction simply cannot be avoided, it’s best to have patients take the drugs 12 hours apart so peak levels don’t overlap, he added.
Same-statin rechallenge
If the checks of TSH, vitamin D, and possible drug interactions don’t turn up anything that needs fixing, it makes sense to launch same-statin rechallenge.
This management strategy was greenlighted by Canadian investigators in a retrospective study of 118 patients who presented to a tertiary lipid clinic with a history of muscle-related symptoms on at least two different statins.
At a median follow-up of 17 months, 71% of rechallenged patients were tolerating the same statin, compared with 53% of those who were switched to a different statin and 57% who were switched to ezetimibe or another nonstatin LDL-lowering drug. Moreover, 50% of patients in the same-statin rechallenge group achieved their target LDL, compared with only 15% switched to nonstatin therapy (Can J Cardiol. 2017 May;33[5]:666-73).
“I like this study; it helps a lot,” Dr. Paauw noted. “I think it’s worthwhile the first time they have muscle pain to get them off the statin and see if they feel better, so you become convinced that the statin may have had something to do with it. Then tell the patient, ‘Let’s just give it another try.’ ”
Alternative strategies
In the event of recurrent symptoms after same-statin rechallenge, it’s reasonable to switch to extended-release fluvastatin at 80 mg/day or low-dose rosuvastatin daily. Only if the patient remains symptomatic after trials of a couple of other statins does Dr. Paauw recommend turning to 5 mg of rosuvastatin twice weekly as a last resort.
Twice-weekly rosuvastatin is a popular treatment strategy in patients with intolerable muscle complaints on daily statin therapy. In a study of 40 such patients, twice-weekly rosuvastatin proved to be tolerated by 80% of them (Am J Cardiol. 2008 Jun 15;101[12]:1747-8). But the long-term effectiveness remains unknown.
“I think this is a really good option for our very statin-intolerant patients when nothing else works,” Dr. Paauw explained. “My only concern about this is we have no outcome data. Is twice-weekly rosuvastatin going to help reduce MI risk, especially if we give it for secondary prevention, as well as a daily statin? We know from this study that twice-weekly rosuvastatin can lower the lipids, but we also believe statins do more than just lower lipids. So, daily statin therapy is preferential.”
What about giving coenzyme Q10? It makes sense mechanistically: Coenzyme Q10 is an antioxidant, ubiquinone, and patients with statin-associated muscle symptoms are ubiquinone depleted.
But while oral coenzyme Q10 is a popular OTC treatment for statin-associated muscle complaints, it’s not supported by any good evidence. A meta-analysis of six randomized trials totaling 302 participants found coenzyme Q10 had no impact on symptoms (Mayo Clin Proc. 2015;90[1]:24-34).
In Dr. Paauw’s view, however, those trials didn’t address the proper question.
“The studies that have been done aren’t the right study,“ he said. “The study that needs to be done is for prevention: Do patients who start a statin and coenzyme Q10 at the same time stay on the statin and feel better?”
He reported having no financial conflicts of interest regarding his presentation.
New Orleans – An effective and well-tolerated, evidence-based strategy for managing statin-associated muscle complaints is to rechallenge with the same statin, Douglas S. Paauw, MD, said at the annual meeting of the American College of Physicians.
That being said, it must be recognized that statin-associated muscle symptoms remain an enigma. This was underscored in a recent study by investigators at Hartford (Conn.) Hospital, which suggested a need to reassess the whole concept of statin-associated muscle symptoms, according to Dr. Paauw, professor of medicine at the University of Washington, Seattle.
“This study just blows my mind,” Dr. Paauw said. “The bottom line here is we just don’t know. A third of our patients might have true statin-associated muscle symptoms, but the other two-thirds would fall into these other groups, where they don’t have symptoms if we give them a statin again or they might get worse with placebo. So, we’ve got to rethink this.”
First things first
Before embarking on same-statin rechallenge, several things should first be done. Step 1 is to check the patient’s thyroid-stimulating hormone, creatine kinase, and serum vitamin D levels. Step 2 is to look for possible explanatory drug interactions, with verapamil and diltiazem being particularly common offenders in statin users.
If a patient with statin-associated muscle symptoms has a low serum vitamin D level, Dr. Paauw will give high-dose supplemental vitamin D. This strategy is supported by a University of Cincinnati prospective study of 146 patients with intolerable muscle symptoms on two or more statins, all of whom had a serum vitamin D below 32 ng/mL. They were placed on long-term vitamin D2 at 50,000-100,000 units per week and rechallenged with a statin. At 2 years of follow-up while still on supplemental vitamin D, 91% of patients had a normal serum vitamin D, and 95% of these previously statin-intolerant patients were on statin therapy without muscle complaints (N Am J Med Sci. 2015 Mar;7[3]:86-93).
Hypothyroidism increases statin toxicity. “I can’t overstate how important it is to check the thyroid-stimulating hormone to see if we’re dealing with something really simple,” Dr. Paauw said, “because trust me, treating hypothyroidism is much easier than treating statin-associated muscle symptoms.”
It has long been known that fibrates increase the risk of statin toxicity. Much less well recognized is that not all fibrates are the same in this regard: The risk is 15 times greater with gemfibrozil than with fenofibrate. The risk is also higher with verapamil or diltiazem than with nifedipine or amlodipine. Other important causes of drug interactions that increase statin toxicity include amiodarone, azole antifungals, protease inhibitors, erythromycin, and clarithromycin, but not azithromycin.
“Simvastatin and lovastatin are probably the worst as far as drug interactions,” Dr. Paauw cautioned. “They’re cheap, they’ve been generic for a long, long time, and a lot of times insurance companies want to move people to them. I try to move patients away from those two, because they are the dirtiest of the statins as far as side effects and drug interactions.”
When a drug interaction simply cannot be avoided, it’s best to have patients take the drugs 12 hours apart so peak levels don’t overlap, he added.
Same-statin rechallenge
If the checks of TSH, vitamin D, and possible drug interactions don’t turn up anything that needs fixing, it makes sense to launch same-statin rechallenge.
This management strategy was greenlighted by Canadian investigators in a retrospective study of 118 patients who presented to a tertiary lipid clinic with a history of muscle-related symptoms on at least two different statins.
At a median follow-up of 17 months, 71% of rechallenged patients were tolerating the same statin, compared with 53% of those who were switched to a different statin and 57% who were switched to ezetimibe or another nonstatin LDL-lowering drug. Moreover, 50% of patients in the same-statin rechallenge group achieved their target LDL, compared with only 15% switched to nonstatin therapy (Can J Cardiol. 2017 May;33[5]:666-73).
“I like this study; it helps a lot,” Dr. Paauw noted. “I think it’s worthwhile the first time they have muscle pain to get them off the statin and see if they feel better, so you become convinced that the statin may have had something to do with it. Then tell the patient, ‘Let’s just give it another try.’ ”
Alternative strategies
In the event of recurrent symptoms after same-statin rechallenge, it’s reasonable to switch to extended-release fluvastatin at 80 mg/day or low-dose rosuvastatin daily. Only if the patient remains symptomatic after trials of a couple of other statins does Dr. Paauw recommend turning to 5 mg of rosuvastatin twice weekly as a last resort.
Twice-weekly rosuvastatin is a popular treatment strategy in patients with intolerable muscle complaints on daily statin therapy. In a study of 40 such patients, twice-weekly rosuvastatin proved to be tolerated by 80% of them (Am J Cardiol. 2008 Jun 15;101[12]:1747-8). But the long-term effectiveness remains unknown.
“I think this is a really good option for our very statin-intolerant patients when nothing else works,” Dr. Paauw explained. “My only concern about this is we have no outcome data. Is twice-weekly rosuvastatin going to help reduce MI risk, especially if we give it for secondary prevention, as well as a daily statin? We know from this study that twice-weekly rosuvastatin can lower the lipids, but we also believe statins do more than just lower lipids. So, daily statin therapy is preferential.”
What about giving coenzyme Q10? It makes sense mechanistically: Coenzyme Q10 is an antioxidant, ubiquinone, and patients with statin-associated muscle symptoms are ubiquinone depleted.
But while oral coenzyme Q10 is a popular OTC treatment for statin-associated muscle complaints, it’s not supported by any good evidence. A meta-analysis of six randomized trials totaling 302 participants found coenzyme Q10 had no impact on symptoms (Mayo Clin Proc. 2015;90[1]:24-34).
In Dr. Paauw’s view, however, those trials didn’t address the proper question.
“The studies that have been done aren’t the right study,“ he said. “The study that needs to be done is for prevention: Do patients who start a statin and coenzyme Q10 at the same time stay on the statin and feel better?”
He reported having no financial conflicts of interest regarding his presentation.
New Orleans – An effective and well-tolerated, evidence-based strategy for managing statin-associated muscle complaints is to rechallenge with the same statin, Douglas S. Paauw, MD, said at the annual meeting of the American College of Physicians.
That being said, it must be recognized that statin-associated muscle symptoms remain an enigma. This was underscored in a recent study by investigators at Hartford (Conn.) Hospital, which suggested a need to reassess the whole concept of statin-associated muscle symptoms, according to Dr. Paauw, professor of medicine at the University of Washington, Seattle.
“This study just blows my mind,” Dr. Paauw said. “The bottom line here is we just don’t know. A third of our patients might have true statin-associated muscle symptoms, but the other two-thirds would fall into these other groups, where they don’t have symptoms if we give them a statin again or they might get worse with placebo. So, we’ve got to rethink this.”
First things first
Before embarking on same-statin rechallenge, several things should first be done. Step 1 is to check the patient’s thyroid-stimulating hormone, creatine kinase, and serum vitamin D levels. Step 2 is to look for possible explanatory drug interactions, with verapamil and diltiazem being particularly common offenders in statin users.
If a patient with statin-associated muscle symptoms has a low serum vitamin D level, Dr. Paauw will give high-dose supplemental vitamin D. This strategy is supported by a University of Cincinnati prospective study of 146 patients with intolerable muscle symptoms on two or more statins, all of whom had a serum vitamin D below 32 ng/mL. They were placed on long-term vitamin D2 at 50,000-100,000 units per week and rechallenged with a statin. At 2 years of follow-up while still on supplemental vitamin D, 91% of patients had a normal serum vitamin D, and 95% of these previously statin-intolerant patients were on statin therapy without muscle complaints (N Am J Med Sci. 2015 Mar;7[3]:86-93).
Hypothyroidism increases statin toxicity. “I can’t overstate how important it is to check the thyroid-stimulating hormone to see if we’re dealing with something really simple,” Dr. Paauw said, “because trust me, treating hypothyroidism is much easier than treating statin-associated muscle symptoms.”
It has long been known that fibrates increase the risk of statin toxicity. Much less well recognized is that not all fibrates are the same in this regard: The risk is 15 times greater with gemfibrozil than with fenofibrate. The risk is also higher with verapamil or diltiazem than with nifedipine or amlodipine. Other important causes of drug interactions that increase statin toxicity include amiodarone, azole antifungals, protease inhibitors, erythromycin, and clarithromycin, but not azithromycin.
“Simvastatin and lovastatin are probably the worst as far as drug interactions,” Dr. Paauw cautioned. “They’re cheap, they’ve been generic for a long, long time, and a lot of times insurance companies want to move people to them. I try to move patients away from those two, because they are the dirtiest of the statins as far as side effects and drug interactions.”
When a drug interaction simply cannot be avoided, it’s best to have patients take the drugs 12 hours apart so peak levels don’t overlap, he added.
Same-statin rechallenge
If the checks of TSH, vitamin D, and possible drug interactions don’t turn up anything that needs fixing, it makes sense to launch same-statin rechallenge.
This management strategy was greenlighted by Canadian investigators in a retrospective study of 118 patients who presented to a tertiary lipid clinic with a history of muscle-related symptoms on at least two different statins.
At a median follow-up of 17 months, 71% of rechallenged patients were tolerating the same statin, compared with 53% of those who were switched to a different statin and 57% who were switched to ezetimibe or another nonstatin LDL-lowering drug. Moreover, 50% of patients in the same-statin rechallenge group achieved their target LDL, compared with only 15% switched to nonstatin therapy (Can J Cardiol. 2017 May;33[5]:666-73).
“I like this study; it helps a lot,” Dr. Paauw noted. “I think it’s worthwhile the first time they have muscle pain to get them off the statin and see if they feel better, so you become convinced that the statin may have had something to do with it. Then tell the patient, ‘Let’s just give it another try.’ ”
Alternative strategies
In the event of recurrent symptoms after same-statin rechallenge, it’s reasonable to switch to extended-release fluvastatin at 80 mg/day or low-dose rosuvastatin daily. Only if the patient remains symptomatic after trials of a couple of other statins does Dr. Paauw recommend turning to 5 mg of rosuvastatin twice weekly as a last resort.
Twice-weekly rosuvastatin is a popular treatment strategy in patients with intolerable muscle complaints on daily statin therapy. In a study of 40 such patients, twice-weekly rosuvastatin proved to be tolerated by 80% of them (Am J Cardiol. 2008 Jun 15;101[12]:1747-8). But the long-term effectiveness remains unknown.
“I think this is a really good option for our very statin-intolerant patients when nothing else works,” Dr. Paauw explained. “My only concern about this is we have no outcome data. Is twice-weekly rosuvastatin going to help reduce MI risk, especially if we give it for secondary prevention, as well as a daily statin? We know from this study that twice-weekly rosuvastatin can lower the lipids, but we also believe statins do more than just lower lipids. So, daily statin therapy is preferential.”
What about giving coenzyme Q10? It makes sense mechanistically: Coenzyme Q10 is an antioxidant, ubiquinone, and patients with statin-associated muscle symptoms are ubiquinone depleted.
But while oral coenzyme Q10 is a popular OTC treatment for statin-associated muscle complaints, it’s not supported by any good evidence. A meta-analysis of six randomized trials totaling 302 participants found coenzyme Q10 had no impact on symptoms (Mayo Clin Proc. 2015;90[1]:24-34).
In Dr. Paauw’s view, however, those trials didn’t address the proper question.
“The studies that have been done aren’t the right study,“ he said. “The study that needs to be done is for prevention: Do patients who start a statin and coenzyme Q10 at the same time stay on the statin and feel better?”
He reported having no financial conflicts of interest regarding his presentation.
REPORTING FROM ACP INTERNAL MEDICINE
VIDEO: ZIP code, not gene code – Social factors shape patients’ health
NEW ORLEANS – What happens outside the exam room often plays a crucial, and crucially overlooked, role in how well or poorly patients respond to medical therapy.
Social determinants – from the bus ride to a clinic to fitting medication compliance into a three-job work day – are at the center of a new push by the American College of Physicians to improve patient care and awaken physicians to the nonmedical factors that frustrate treatment and fuel outcomes failures.
When it comes to patients’ health, American College of Physicians President Jack Ende, MD, says it’s often ZIP code, not gene code, that can make all the difference.
At the annual meeting of the American College of Physicians, Dr. Ende of the University of Pennsylvania, Philadelphia; Sarah Candler, MD, of Baylor College of Medicine, Houston; and Karen DeSalvo, MD, of the University of Texas, Austin, outlined how physicians can look beyond biology and into patients’ social environments, and they shared resources physicians can use to counter social determinants that harm health.
The ACP published a position paper on social determinants of health in the Annals of Internal Medicine.
Dr. Candler's interview:
Dr. DeSalvo's interview:
Dr. Ende's interview:
SOURCE: Ann Intern Med. 2018 Apr 17;168(8):577-8.
NEW ORLEANS – What happens outside the exam room often plays a crucial, and crucially overlooked, role in how well or poorly patients respond to medical therapy.
Social determinants – from the bus ride to a clinic to fitting medication compliance into a three-job work day – are at the center of a new push by the American College of Physicians to improve patient care and awaken physicians to the nonmedical factors that frustrate treatment and fuel outcomes failures.
When it comes to patients’ health, American College of Physicians President Jack Ende, MD, says it’s often ZIP code, not gene code, that can make all the difference.
At the annual meeting of the American College of Physicians, Dr. Ende of the University of Pennsylvania, Philadelphia; Sarah Candler, MD, of Baylor College of Medicine, Houston; and Karen DeSalvo, MD, of the University of Texas, Austin, outlined how physicians can look beyond biology and into patients’ social environments, and they shared resources physicians can use to counter social determinants that harm health.
The ACP published a position paper on social determinants of health in the Annals of Internal Medicine.
Dr. Candler's interview:
Dr. DeSalvo's interview:
Dr. Ende's interview:
SOURCE: Ann Intern Med. 2018 Apr 17;168(8):577-8.
NEW ORLEANS – What happens outside the exam room often plays a crucial, and crucially overlooked, role in how well or poorly patients respond to medical therapy.
Social determinants – from the bus ride to a clinic to fitting medication compliance into a three-job work day – are at the center of a new push by the American College of Physicians to improve patient care and awaken physicians to the nonmedical factors that frustrate treatment and fuel outcomes failures.
When it comes to patients’ health, American College of Physicians President Jack Ende, MD, says it’s often ZIP code, not gene code, that can make all the difference.
At the annual meeting of the American College of Physicians, Dr. Ende of the University of Pennsylvania, Philadelphia; Sarah Candler, MD, of Baylor College of Medicine, Houston; and Karen DeSalvo, MD, of the University of Texas, Austin, outlined how physicians can look beyond biology and into patients’ social environments, and they shared resources physicians can use to counter social determinants that harm health.
The ACP published a position paper on social determinants of health in the Annals of Internal Medicine.
Dr. Candler's interview:
Dr. DeSalvo's interview:
Dr. Ende's interview:
SOURCE: Ann Intern Med. 2018 Apr 17;168(8):577-8.
REPORTING FROM ACP INTERNAL MEDICINE
