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HDL-P subfractions may be prognostic in heart failure
In heart failure, derangements in HDL cholesterol particle (HDL-P) subfractions have prognostic implications beyond those of conventional cardiovascular risk factors, according to investigators who analyzed plasma samples from more than 6,500 patients.
The study revealed derangements that were shared and more severe in heart failure with reduced ejection fraction (HFrEF) as compared to heart failure with preserved ejection fraction (HFpEF), according to the researchers, who said their study is the largest to date of HDL-P subfractions in heart failure.
Both total HDL-P and small HDL-P had a strong inverse association with adverse outcomes, consistent with the conclusions of previous studies, they said in a report on their study in the Journal of the American College of Cardiology.
“Altogether, our findings support total and small HDL-P as important markers of residual risk in both HFrEF and HFpEF,” said the investigators, led by Wynn G. Hunter, MD, of Duke University, Durham, N.C.
Dr. Hunter and colleagues used the CATHGEN (Catheterization Genetics) biorepository to identify plasma samples obtained at catheterization for 782 patients with HFrEF, 1,004 with HFpEF, and 4,742 with no heart failure.
Lipoprotein profiling of the samples revealed that mean HDL-P size was greater in HFrEF than in HFpEF, and in both of those cases, mean HDL-P size was greater than in patients with no heart failure (P less than .0001), investigators reported.
Concentrations of small HDL-P and total HDL-P were by contrast lower in HFrEF versus HFpEF, and again, the values for both HFrEF and HFpEF were lower than in patients without heart failure (P less than .0001), they added.
Small HDL-P and total HDL-P had an inverse association with time to adverse events and all-cause mortality for both the HFrEF and HFpEF groups, according to investigators, who said those links remained robust even after multivariate adjustment for 14 cardiovascular risk factors, including diabetes, LDL particle, and GlycA, a marker of inflammation.
For example, small HDL-P and total HDL-P were inversely associated with all-cause mortality risk, with adjusted hazard ratios of 0.69-0.79 (P less than .0001), they reported. Similarly, a greater mean HDL-P size was associated with increased risk of all-cause mortality, yielding adjusted hazard ratios of 1.23-1.46 (P less than .0001).
Further studies are needed to clarify the role of HDL-P in the pathophysiology of heart failure, and to identify treatments that might increase total and small HDL-P in heart failure patients, Dr. Hunter and coauthors concluded.
Dr. Hunter reported no disclosures related to the study. Coauthors provided disclosures related to Amgen, Ostuka, Roche Diagnostics, Novartis, Trevena, Singulex, Medtronic, AstraZeneca, Bristol-Myers Squibb, Janssen, Portola, Boston Scientific, Gilead, GlaxoSmithKline, Merck, Alnylam, Ikaria Pharmaceuticals, Pfizer, Philips, LipoScience, and Pfizer, among others.
SOURCE: Hunter WG et al. J Am Coll Cardiol. 2019 Jan 22;73(2):177-86.
Although the study by Dr. Hunter and colleagues confirms the role of HDL cholesterol and HDL-P subfractions in heart failure, the immediate clinical implications of their findings are uncertain.
However, clinical use as a biomarker remains a “distant vision,” in part because a useful biomarker must be proven to provide an incremental benefit in terms of reducing disease-associated morbidity or mortality.
Even so, the present study could begin to inform future therapeutic studies looking at increasing specific HDL-P subfractions, rather than increasing HDL cholesterol across the board.
“Perhaps, this study will possibly serve to spur investigation into therapies designed to reduce derangements of [HDL cholesterol] metabolism and primarily target HDL-P as a regulator molecule, a promise that may keep the HDL story alive into the near future of scientific excursion.”
These comments were taken from an accompanying editorial by Hector O. Ventura, MD, and Carl J. Lavie, MD, of the University of Queensland Ochsner Clinical School, Brisbane, Australia, and New Orleans; and Mandeep R. Mehra, MD, of the Center of Advanced Heart Disease, Harvard University, Boston (J Am Coll Cardiol 2019 Jan 22;73[2]:187-9). Dr. Mehra reported that he is a consultant for Abbott, Medtronic, nupulseCV, Portola, Bayer, and FineHeart.
Although the study by Dr. Hunter and colleagues confirms the role of HDL cholesterol and HDL-P subfractions in heart failure, the immediate clinical implications of their findings are uncertain.
However, clinical use as a biomarker remains a “distant vision,” in part because a useful biomarker must be proven to provide an incremental benefit in terms of reducing disease-associated morbidity or mortality.
Even so, the present study could begin to inform future therapeutic studies looking at increasing specific HDL-P subfractions, rather than increasing HDL cholesterol across the board.
“Perhaps, this study will possibly serve to spur investigation into therapies designed to reduce derangements of [HDL cholesterol] metabolism and primarily target HDL-P as a regulator molecule, a promise that may keep the HDL story alive into the near future of scientific excursion.”
These comments were taken from an accompanying editorial by Hector O. Ventura, MD, and Carl J. Lavie, MD, of the University of Queensland Ochsner Clinical School, Brisbane, Australia, and New Orleans; and Mandeep R. Mehra, MD, of the Center of Advanced Heart Disease, Harvard University, Boston (J Am Coll Cardiol 2019 Jan 22;73[2]:187-9). Dr. Mehra reported that he is a consultant for Abbott, Medtronic, nupulseCV, Portola, Bayer, and FineHeart.
Although the study by Dr. Hunter and colleagues confirms the role of HDL cholesterol and HDL-P subfractions in heart failure, the immediate clinical implications of their findings are uncertain.
However, clinical use as a biomarker remains a “distant vision,” in part because a useful biomarker must be proven to provide an incremental benefit in terms of reducing disease-associated morbidity or mortality.
Even so, the present study could begin to inform future therapeutic studies looking at increasing specific HDL-P subfractions, rather than increasing HDL cholesterol across the board.
“Perhaps, this study will possibly serve to spur investigation into therapies designed to reduce derangements of [HDL cholesterol] metabolism and primarily target HDL-P as a regulator molecule, a promise that may keep the HDL story alive into the near future of scientific excursion.”
These comments were taken from an accompanying editorial by Hector O. Ventura, MD, and Carl J. Lavie, MD, of the University of Queensland Ochsner Clinical School, Brisbane, Australia, and New Orleans; and Mandeep R. Mehra, MD, of the Center of Advanced Heart Disease, Harvard University, Boston (J Am Coll Cardiol 2019 Jan 22;73[2]:187-9). Dr. Mehra reported that he is a consultant for Abbott, Medtronic, nupulseCV, Portola, Bayer, and FineHeart.
In heart failure, derangements in HDL cholesterol particle (HDL-P) subfractions have prognostic implications beyond those of conventional cardiovascular risk factors, according to investigators who analyzed plasma samples from more than 6,500 patients.
The study revealed derangements that were shared and more severe in heart failure with reduced ejection fraction (HFrEF) as compared to heart failure with preserved ejection fraction (HFpEF), according to the researchers, who said their study is the largest to date of HDL-P subfractions in heart failure.
Both total HDL-P and small HDL-P had a strong inverse association with adverse outcomes, consistent with the conclusions of previous studies, they said in a report on their study in the Journal of the American College of Cardiology.
“Altogether, our findings support total and small HDL-P as important markers of residual risk in both HFrEF and HFpEF,” said the investigators, led by Wynn G. Hunter, MD, of Duke University, Durham, N.C.
Dr. Hunter and colleagues used the CATHGEN (Catheterization Genetics) biorepository to identify plasma samples obtained at catheterization for 782 patients with HFrEF, 1,004 with HFpEF, and 4,742 with no heart failure.
Lipoprotein profiling of the samples revealed that mean HDL-P size was greater in HFrEF than in HFpEF, and in both of those cases, mean HDL-P size was greater than in patients with no heart failure (P less than .0001), investigators reported.
Concentrations of small HDL-P and total HDL-P were by contrast lower in HFrEF versus HFpEF, and again, the values for both HFrEF and HFpEF were lower than in patients without heart failure (P less than .0001), they added.
Small HDL-P and total HDL-P had an inverse association with time to adverse events and all-cause mortality for both the HFrEF and HFpEF groups, according to investigators, who said those links remained robust even after multivariate adjustment for 14 cardiovascular risk factors, including diabetes, LDL particle, and GlycA, a marker of inflammation.
For example, small HDL-P and total HDL-P were inversely associated with all-cause mortality risk, with adjusted hazard ratios of 0.69-0.79 (P less than .0001), they reported. Similarly, a greater mean HDL-P size was associated with increased risk of all-cause mortality, yielding adjusted hazard ratios of 1.23-1.46 (P less than .0001).
Further studies are needed to clarify the role of HDL-P in the pathophysiology of heart failure, and to identify treatments that might increase total and small HDL-P in heart failure patients, Dr. Hunter and coauthors concluded.
Dr. Hunter reported no disclosures related to the study. Coauthors provided disclosures related to Amgen, Ostuka, Roche Diagnostics, Novartis, Trevena, Singulex, Medtronic, AstraZeneca, Bristol-Myers Squibb, Janssen, Portola, Boston Scientific, Gilead, GlaxoSmithKline, Merck, Alnylam, Ikaria Pharmaceuticals, Pfizer, Philips, LipoScience, and Pfizer, among others.
SOURCE: Hunter WG et al. J Am Coll Cardiol. 2019 Jan 22;73(2):177-86.
In heart failure, derangements in HDL cholesterol particle (HDL-P) subfractions have prognostic implications beyond those of conventional cardiovascular risk factors, according to investigators who analyzed plasma samples from more than 6,500 patients.
The study revealed derangements that were shared and more severe in heart failure with reduced ejection fraction (HFrEF) as compared to heart failure with preserved ejection fraction (HFpEF), according to the researchers, who said their study is the largest to date of HDL-P subfractions in heart failure.
Both total HDL-P and small HDL-P had a strong inverse association with adverse outcomes, consistent with the conclusions of previous studies, they said in a report on their study in the Journal of the American College of Cardiology.
“Altogether, our findings support total and small HDL-P as important markers of residual risk in both HFrEF and HFpEF,” said the investigators, led by Wynn G. Hunter, MD, of Duke University, Durham, N.C.
Dr. Hunter and colleagues used the CATHGEN (Catheterization Genetics) biorepository to identify plasma samples obtained at catheterization for 782 patients with HFrEF, 1,004 with HFpEF, and 4,742 with no heart failure.
Lipoprotein profiling of the samples revealed that mean HDL-P size was greater in HFrEF than in HFpEF, and in both of those cases, mean HDL-P size was greater than in patients with no heart failure (P less than .0001), investigators reported.
Concentrations of small HDL-P and total HDL-P were by contrast lower in HFrEF versus HFpEF, and again, the values for both HFrEF and HFpEF were lower than in patients without heart failure (P less than .0001), they added.
Small HDL-P and total HDL-P had an inverse association with time to adverse events and all-cause mortality for both the HFrEF and HFpEF groups, according to investigators, who said those links remained robust even after multivariate adjustment for 14 cardiovascular risk factors, including diabetes, LDL particle, and GlycA, a marker of inflammation.
For example, small HDL-P and total HDL-P were inversely associated with all-cause mortality risk, with adjusted hazard ratios of 0.69-0.79 (P less than .0001), they reported. Similarly, a greater mean HDL-P size was associated with increased risk of all-cause mortality, yielding adjusted hazard ratios of 1.23-1.46 (P less than .0001).
Further studies are needed to clarify the role of HDL-P in the pathophysiology of heart failure, and to identify treatments that might increase total and small HDL-P in heart failure patients, Dr. Hunter and coauthors concluded.
Dr. Hunter reported no disclosures related to the study. Coauthors provided disclosures related to Amgen, Ostuka, Roche Diagnostics, Novartis, Trevena, Singulex, Medtronic, AstraZeneca, Bristol-Myers Squibb, Janssen, Portola, Boston Scientific, Gilead, GlaxoSmithKline, Merck, Alnylam, Ikaria Pharmaceuticals, Pfizer, Philips, LipoScience, and Pfizer, among others.
SOURCE: Hunter WG et al. J Am Coll Cardiol. 2019 Jan 22;73(2):177-86.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Key clinical point: Derangements in HDL particle (HDL-P) subfractions may have prognostic implications in patients with heart failure with reduced or preserved ejection fraction.
Major finding: (P less than .0001).
Study details: Study based on lipid profiling of more than 6,500 plasma samples obtained at catheterization.
Disclosures: Study authors provided disclosures related to Amgen, Ostuka, Roche Diagnostics, Novartis, Medtronic, and others.
Source: Hunter WG et al. J Am Coll Cardiol. 2019 Jan 22;73(2):177-86.
SGLT-2 inhibitors promising for heart failure prevention, not treatment
LOS ANGELES –
They also may play a role in the treatment of patients with known heart failure (HF), but further studies are required to prove definite treatment benefit.
“These trials enrolled a minority of patients with known heart failure, and, in those subgroups, the drugs seems to reduce the risk for hospitalization, opening the possibility of treatment benefit,” Javed Butler, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But there were not enough patients to conclude this. If you are treating diabetes with these agents in patients with heart failure, more power to you. But don’t think you are treating heart failure per se until the results of the dedicated heart failure trials come out.”
Good glycemic control has not been shown to affect heart failure outcomes per se, said Dr. Butler, professor and chairman of the department of medicine at the University of Mississippi Medical Center, Jackson.
“People seem to mix the concepts of prevention and treatment together,” he said. “We have now very good evidence across all trials with SGLT-2 inhibitors for prevention of heart failure. But for treatment, we need more data despite favorable early signals.
“Also, these trials include most patients with ischemic heart disease, but we don’t have data on nonischemic etiology for the development of heart failure from these trials,” Dr. Butler added.
The best available data from clinical trials suggest that patients with American College of Cardiology Foundation/American Heart Association heart failure classification stages A and B benefit the most from aggressive treatment to prevent HF.
“Either they have diseases like high blood pressure or diabetes, but their hearts are normal, or, perhaps, their hearts are abnormal, and they develop left ventricular hypertrophy or atrial fibrillation,” he said. “However, if someone is stage C – manifest heart failure – or stage D – advanced heart failure – we need further data on novel therapies to improve their outcomes.”
Dr. Butler emphasized that not all heart failure is associated with atherosclerotic vascular disease. In fact, the Health, Aging, and Body Composition Study showed that the incidence of heart failure increased progressively across age groups, both for those with and without a preceding vascular event (P = .03 and P less than .001, respectively; Eur J Heart Fail. 2014 May;16[5]:526-34). “There’s a whole other world of nonischemic heart failure that we also need to worry about,” he said. “There is a lot of microvascular endothelial dysfunction.”
The combination of heart failure and diabetes is especially lethal. “If you put them together, you’re looking at about a 10-fold higher risk of mortality, which is a horrible prognosis,” Dr. Butler said. “That means that we need to think about prevention and treatment separately.”
Data from the SAVOR-TIMI 53, EXAMINE, and TECOS trials show there is no protective effect of dipeptidyl peptidase–4 inhibitors when it comes to hospitalization for heart failure.
“The other classes of drugs either increase the risk, or we don’t have very good data,” Dr. Butler said. “So far, across the spectrum of therapies for diabetes, the effect on heart failure is neutral and perhaps confers some risk.”
SGLT-2 inhibitors convey a different story.
In the EMPA-REG OUTCOME Trial, one inclusion criterion was established cardiovascular disease (CVD) in the form of a prior MI, coronary artery disease, stroke, unstable angina, or occlusive peripheral artery disease, but not heart failure alone (N Engl J Med. 2015 Nov 26; 373[22]:2117-28). “This was not a heart failure study, so we don’t know what their New York Heart Association class was, or the details of their baseline HF treatment in the minority of patients who were enrolled who had a history of HF,” Dr. Butler cautioned.
However, the trial found that empagliflozin conferred an overall cardiovascular death risk reduction of 38%, compared with placebo. When the researchers assessed the impact of treatment on all modes of cardiovascular death, they found that death from heart failure benefited the most (hazard ratio, 0.32; P = .0008), while sudden death benefited as well. Empagliflozin also had a significant impact on reduced hospitalization for heart failure, compared with placebo (HR, 0.65).
“This is a large enough cohort that you should feel comfortable that this drug is preventing heart failure in those with HF at baseline,” said Dr. Butler, who was not involved with the study. “We can have a debate about whether this is a treatment for heart failure or not, but for prevention of heart failure, I feel comfortable that these drugs do that.”
A subsequent study of canagliflozin and cardiovascular and renal events in type 2 diabetes showed the same result (N Engl J Med. 2017 Aug 17; 377[7]:644-57). It reduced hospitalization for heart failure by 33% (HR, 0.67).
Then came the CVD-REAL study, which found low rates of hospitalization for heart failure and all-cause death in new users of SGLT-2 inhibitors. More recently, DECLARE-TIMI 58 yielded similar results.
“One of the criticisms of these findings is that heart failure characteristics were not well phenotyped in these studies,” Dr. Butler said. “I say it really does not matter. Heart failure hospitalizations are associated with a poor prognosis irrespective of whether the hospitalization occurred in patients without heart failure or in a patient with previously diagnosed heart failure, or whether the patient has reduced or preserved ejection fraction.
“Framingham and other classic studies show us that 5-year mortality for heart failure is about 50%,” he noted. “If you can prevent a disease that has a 5-year mortality of 50%, doesn’t that sound like a really good deal?”
A contemporary appraisal of the heart failure epidemic in Olmstead County, Minn., during 2000-2010 found that the mortality was 20.2% at 1 year after diagnosis, and 52.6% at 5 years after diagnosis. The data include new-onset HF in both inpatient and outpatient settings.
Specifically, new-onset HF hospitalization was associated with a 1-year post discharge mortality of 21.1% (JAMA Intern Med. 2015;175[6]:996-1004). “We cannot ignore prevention of heart failure,” Dr. Butler said. “Also, for treatment, once you get hospitalized for heart failure, the fundamental natural history of the disease changes. There is a 30% cumulative incremental death risk between the second and third hospitalizations.”
Dr. Butler concluded his presentation by noting that five randomized, controlled trials evaluating SGLT-2 inhibitors in HF have been launched, and should help elucidate any effects the drugs may have in treating the condition. They include EMPEROR-Preserved (NCT03057951), EMPEROR-Reduced (NCT03057977), Dapa-HF (NCT03036124), and SOLOIST-WHF (NCT03521934) and DELIVER (NCT03619213).
Dr. Butler disclosed that he has received research support from the National Institutes of Health, the European Union, and the Patient-Centered Outcomes Research Institute. He has also been a consultant for numerous pharmaceutical companies, including Boehringer Ingelheim, Janssen, and AstraZeneca, which sponsored the EMPA-REG, CANVAS, and DECLARE TIMI 58 trials.
LOS ANGELES –
They also may play a role in the treatment of patients with known heart failure (HF), but further studies are required to prove definite treatment benefit.
“These trials enrolled a minority of patients with known heart failure, and, in those subgroups, the drugs seems to reduce the risk for hospitalization, opening the possibility of treatment benefit,” Javed Butler, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But there were not enough patients to conclude this. If you are treating diabetes with these agents in patients with heart failure, more power to you. But don’t think you are treating heart failure per se until the results of the dedicated heart failure trials come out.”
Good glycemic control has not been shown to affect heart failure outcomes per se, said Dr. Butler, professor and chairman of the department of medicine at the University of Mississippi Medical Center, Jackson.
“People seem to mix the concepts of prevention and treatment together,” he said. “We have now very good evidence across all trials with SGLT-2 inhibitors for prevention of heart failure. But for treatment, we need more data despite favorable early signals.
“Also, these trials include most patients with ischemic heart disease, but we don’t have data on nonischemic etiology for the development of heart failure from these trials,” Dr. Butler added.
The best available data from clinical trials suggest that patients with American College of Cardiology Foundation/American Heart Association heart failure classification stages A and B benefit the most from aggressive treatment to prevent HF.
“Either they have diseases like high blood pressure or diabetes, but their hearts are normal, or, perhaps, their hearts are abnormal, and they develop left ventricular hypertrophy or atrial fibrillation,” he said. “However, if someone is stage C – manifest heart failure – or stage D – advanced heart failure – we need further data on novel therapies to improve their outcomes.”
Dr. Butler emphasized that not all heart failure is associated with atherosclerotic vascular disease. In fact, the Health, Aging, and Body Composition Study showed that the incidence of heart failure increased progressively across age groups, both for those with and without a preceding vascular event (P = .03 and P less than .001, respectively; Eur J Heart Fail. 2014 May;16[5]:526-34). “There’s a whole other world of nonischemic heart failure that we also need to worry about,” he said. “There is a lot of microvascular endothelial dysfunction.”
The combination of heart failure and diabetes is especially lethal. “If you put them together, you’re looking at about a 10-fold higher risk of mortality, which is a horrible prognosis,” Dr. Butler said. “That means that we need to think about prevention and treatment separately.”
Data from the SAVOR-TIMI 53, EXAMINE, and TECOS trials show there is no protective effect of dipeptidyl peptidase–4 inhibitors when it comes to hospitalization for heart failure.
“The other classes of drugs either increase the risk, or we don’t have very good data,” Dr. Butler said. “So far, across the spectrum of therapies for diabetes, the effect on heart failure is neutral and perhaps confers some risk.”
SGLT-2 inhibitors convey a different story.
In the EMPA-REG OUTCOME Trial, one inclusion criterion was established cardiovascular disease (CVD) in the form of a prior MI, coronary artery disease, stroke, unstable angina, or occlusive peripheral artery disease, but not heart failure alone (N Engl J Med. 2015 Nov 26; 373[22]:2117-28). “This was not a heart failure study, so we don’t know what their New York Heart Association class was, or the details of their baseline HF treatment in the minority of patients who were enrolled who had a history of HF,” Dr. Butler cautioned.
However, the trial found that empagliflozin conferred an overall cardiovascular death risk reduction of 38%, compared with placebo. When the researchers assessed the impact of treatment on all modes of cardiovascular death, they found that death from heart failure benefited the most (hazard ratio, 0.32; P = .0008), while sudden death benefited as well. Empagliflozin also had a significant impact on reduced hospitalization for heart failure, compared with placebo (HR, 0.65).
“This is a large enough cohort that you should feel comfortable that this drug is preventing heart failure in those with HF at baseline,” said Dr. Butler, who was not involved with the study. “We can have a debate about whether this is a treatment for heart failure or not, but for prevention of heart failure, I feel comfortable that these drugs do that.”
A subsequent study of canagliflozin and cardiovascular and renal events in type 2 diabetes showed the same result (N Engl J Med. 2017 Aug 17; 377[7]:644-57). It reduced hospitalization for heart failure by 33% (HR, 0.67).
Then came the CVD-REAL study, which found low rates of hospitalization for heart failure and all-cause death in new users of SGLT-2 inhibitors. More recently, DECLARE-TIMI 58 yielded similar results.
“One of the criticisms of these findings is that heart failure characteristics were not well phenotyped in these studies,” Dr. Butler said. “I say it really does not matter. Heart failure hospitalizations are associated with a poor prognosis irrespective of whether the hospitalization occurred in patients without heart failure or in a patient with previously diagnosed heart failure, or whether the patient has reduced or preserved ejection fraction.
“Framingham and other classic studies show us that 5-year mortality for heart failure is about 50%,” he noted. “If you can prevent a disease that has a 5-year mortality of 50%, doesn’t that sound like a really good deal?”
A contemporary appraisal of the heart failure epidemic in Olmstead County, Minn., during 2000-2010 found that the mortality was 20.2% at 1 year after diagnosis, and 52.6% at 5 years after diagnosis. The data include new-onset HF in both inpatient and outpatient settings.
Specifically, new-onset HF hospitalization was associated with a 1-year post discharge mortality of 21.1% (JAMA Intern Med. 2015;175[6]:996-1004). “We cannot ignore prevention of heart failure,” Dr. Butler said. “Also, for treatment, once you get hospitalized for heart failure, the fundamental natural history of the disease changes. There is a 30% cumulative incremental death risk between the second and third hospitalizations.”
Dr. Butler concluded his presentation by noting that five randomized, controlled trials evaluating SGLT-2 inhibitors in HF have been launched, and should help elucidate any effects the drugs may have in treating the condition. They include EMPEROR-Preserved (NCT03057951), EMPEROR-Reduced (NCT03057977), Dapa-HF (NCT03036124), and SOLOIST-WHF (NCT03521934) and DELIVER (NCT03619213).
Dr. Butler disclosed that he has received research support from the National Institutes of Health, the European Union, and the Patient-Centered Outcomes Research Institute. He has also been a consultant for numerous pharmaceutical companies, including Boehringer Ingelheim, Janssen, and AstraZeneca, which sponsored the EMPA-REG, CANVAS, and DECLARE TIMI 58 trials.
LOS ANGELES –
They also may play a role in the treatment of patients with known heart failure (HF), but further studies are required to prove definite treatment benefit.
“These trials enrolled a minority of patients with known heart failure, and, in those subgroups, the drugs seems to reduce the risk for hospitalization, opening the possibility of treatment benefit,” Javed Butler, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But there were not enough patients to conclude this. If you are treating diabetes with these agents in patients with heart failure, more power to you. But don’t think you are treating heart failure per se until the results of the dedicated heart failure trials come out.”
Good glycemic control has not been shown to affect heart failure outcomes per se, said Dr. Butler, professor and chairman of the department of medicine at the University of Mississippi Medical Center, Jackson.
“People seem to mix the concepts of prevention and treatment together,” he said. “We have now very good evidence across all trials with SGLT-2 inhibitors for prevention of heart failure. But for treatment, we need more data despite favorable early signals.
“Also, these trials include most patients with ischemic heart disease, but we don’t have data on nonischemic etiology for the development of heart failure from these trials,” Dr. Butler added.
The best available data from clinical trials suggest that patients with American College of Cardiology Foundation/American Heart Association heart failure classification stages A and B benefit the most from aggressive treatment to prevent HF.
“Either they have diseases like high blood pressure or diabetes, but their hearts are normal, or, perhaps, their hearts are abnormal, and they develop left ventricular hypertrophy or atrial fibrillation,” he said. “However, if someone is stage C – manifest heart failure – or stage D – advanced heart failure – we need further data on novel therapies to improve their outcomes.”
Dr. Butler emphasized that not all heart failure is associated with atherosclerotic vascular disease. In fact, the Health, Aging, and Body Composition Study showed that the incidence of heart failure increased progressively across age groups, both for those with and without a preceding vascular event (P = .03 and P less than .001, respectively; Eur J Heart Fail. 2014 May;16[5]:526-34). “There’s a whole other world of nonischemic heart failure that we also need to worry about,” he said. “There is a lot of microvascular endothelial dysfunction.”
The combination of heart failure and diabetes is especially lethal. “If you put them together, you’re looking at about a 10-fold higher risk of mortality, which is a horrible prognosis,” Dr. Butler said. “That means that we need to think about prevention and treatment separately.”
Data from the SAVOR-TIMI 53, EXAMINE, and TECOS trials show there is no protective effect of dipeptidyl peptidase–4 inhibitors when it comes to hospitalization for heart failure.
“The other classes of drugs either increase the risk, or we don’t have very good data,” Dr. Butler said. “So far, across the spectrum of therapies for diabetes, the effect on heart failure is neutral and perhaps confers some risk.”
SGLT-2 inhibitors convey a different story.
In the EMPA-REG OUTCOME Trial, one inclusion criterion was established cardiovascular disease (CVD) in the form of a prior MI, coronary artery disease, stroke, unstable angina, or occlusive peripheral artery disease, but not heart failure alone (N Engl J Med. 2015 Nov 26; 373[22]:2117-28). “This was not a heart failure study, so we don’t know what their New York Heart Association class was, or the details of their baseline HF treatment in the minority of patients who were enrolled who had a history of HF,” Dr. Butler cautioned.
However, the trial found that empagliflozin conferred an overall cardiovascular death risk reduction of 38%, compared with placebo. When the researchers assessed the impact of treatment on all modes of cardiovascular death, they found that death from heart failure benefited the most (hazard ratio, 0.32; P = .0008), while sudden death benefited as well. Empagliflozin also had a significant impact on reduced hospitalization for heart failure, compared with placebo (HR, 0.65).
“This is a large enough cohort that you should feel comfortable that this drug is preventing heart failure in those with HF at baseline,” said Dr. Butler, who was not involved with the study. “We can have a debate about whether this is a treatment for heart failure or not, but for prevention of heart failure, I feel comfortable that these drugs do that.”
A subsequent study of canagliflozin and cardiovascular and renal events in type 2 diabetes showed the same result (N Engl J Med. 2017 Aug 17; 377[7]:644-57). It reduced hospitalization for heart failure by 33% (HR, 0.67).
Then came the CVD-REAL study, which found low rates of hospitalization for heart failure and all-cause death in new users of SGLT-2 inhibitors. More recently, DECLARE-TIMI 58 yielded similar results.
“One of the criticisms of these findings is that heart failure characteristics were not well phenotyped in these studies,” Dr. Butler said. “I say it really does not matter. Heart failure hospitalizations are associated with a poor prognosis irrespective of whether the hospitalization occurred in patients without heart failure or in a patient with previously diagnosed heart failure, or whether the patient has reduced or preserved ejection fraction.
“Framingham and other classic studies show us that 5-year mortality for heart failure is about 50%,” he noted. “If you can prevent a disease that has a 5-year mortality of 50%, doesn’t that sound like a really good deal?”
A contemporary appraisal of the heart failure epidemic in Olmstead County, Minn., during 2000-2010 found that the mortality was 20.2% at 1 year after diagnosis, and 52.6% at 5 years after diagnosis. The data include new-onset HF in both inpatient and outpatient settings.
Specifically, new-onset HF hospitalization was associated with a 1-year post discharge mortality of 21.1% (JAMA Intern Med. 2015;175[6]:996-1004). “We cannot ignore prevention of heart failure,” Dr. Butler said. “Also, for treatment, once you get hospitalized for heart failure, the fundamental natural history of the disease changes. There is a 30% cumulative incremental death risk between the second and third hospitalizations.”
Dr. Butler concluded his presentation by noting that five randomized, controlled trials evaluating SGLT-2 inhibitors in HF have been launched, and should help elucidate any effects the drugs may have in treating the condition. They include EMPEROR-Preserved (NCT03057951), EMPEROR-Reduced (NCT03057977), Dapa-HF (NCT03036124), and SOLOIST-WHF (NCT03521934) and DELIVER (NCT03619213).
Dr. Butler disclosed that he has received research support from the National Institutes of Health, the European Union, and the Patient-Centered Outcomes Research Institute. He has also been a consultant for numerous pharmaceutical companies, including Boehringer Ingelheim, Janssen, and AstraZeneca, which sponsored the EMPA-REG, CANVAS, and DECLARE TIMI 58 trials.
EXPERT ANALYSIS FROM WCIRDC 2018
Flu season showing signs of decline
The 2018-2019 flu season may have peaked as measures of influenza-like illness (ILI) activity dropped in the first week of the new year, according to the U.S. Centers for Disease Control and Prevention.
The proportion of outpatients visits for ILI dropped to 3.5% for the week ending Jan. 5, 2019, after reaching 4.0% the previous week. Outpatient ILI visits first topped the national baseline of 2.2% during the week ending Dec. 8, 2018, and have remained above that value for 5 consecutive weeks, the CDC’s influenza division said on Jan. 11.
Flu activity reported by the states reflects the national drop: 10 states came in at level 10 on the CDC’s 1-10 scale of activity for the week ending Jan. 5 – down from 12 the week before – and a total of 15 were in the high range from 8 to 10, compared with 19 the previous week, the CDC said. Two states, Mississippi and Texas, dropped from level 10 to level 7, which the CDC categorizes as moderate activity.
A total of 73 ILI-related deaths were reported during the week ending Dec. 29 (the latest with data available; reporting less than 68% complete), which already exceeds the 71 deaths reported for the week ending Dec. 22 (reporting 85% complete). Flu deaths totaled 437 through the first 13 weeks of the 2018-2019 season, compared with the 1,659 that occurred during weeks 1-13 of the very severe 2017-2018 season, CDC data show.
For the week ending Jan. 5, the CDC received reports of three flu-related pediatric deaths, all of which occurred the previous week. For the season so far, there have been 16 pediatric deaths, compared with 20 at this point in the 2017-2018 season.
Estimates released during the flu season for the first time show that between 6 and 7 million Americans have been infected since Oct. 1, 2018, and that 69,000-84,000 people have been hospitalized with the flu through Jan. 5, 2019. These cumulative totals have previously been available only at the end of the season, the CDC noted.
The 2018-2019 flu season may have peaked as measures of influenza-like illness (ILI) activity dropped in the first week of the new year, according to the U.S. Centers for Disease Control and Prevention.
The proportion of outpatients visits for ILI dropped to 3.5% for the week ending Jan. 5, 2019, after reaching 4.0% the previous week. Outpatient ILI visits first topped the national baseline of 2.2% during the week ending Dec. 8, 2018, and have remained above that value for 5 consecutive weeks, the CDC’s influenza division said on Jan. 11.
Flu activity reported by the states reflects the national drop: 10 states came in at level 10 on the CDC’s 1-10 scale of activity for the week ending Jan. 5 – down from 12 the week before – and a total of 15 were in the high range from 8 to 10, compared with 19 the previous week, the CDC said. Two states, Mississippi and Texas, dropped from level 10 to level 7, which the CDC categorizes as moderate activity.
A total of 73 ILI-related deaths were reported during the week ending Dec. 29 (the latest with data available; reporting less than 68% complete), which already exceeds the 71 deaths reported for the week ending Dec. 22 (reporting 85% complete). Flu deaths totaled 437 through the first 13 weeks of the 2018-2019 season, compared with the 1,659 that occurred during weeks 1-13 of the very severe 2017-2018 season, CDC data show.
For the week ending Jan. 5, the CDC received reports of three flu-related pediatric deaths, all of which occurred the previous week. For the season so far, there have been 16 pediatric deaths, compared with 20 at this point in the 2017-2018 season.
Estimates released during the flu season for the first time show that between 6 and 7 million Americans have been infected since Oct. 1, 2018, and that 69,000-84,000 people have been hospitalized with the flu through Jan. 5, 2019. These cumulative totals have previously been available only at the end of the season, the CDC noted.
The 2018-2019 flu season may have peaked as measures of influenza-like illness (ILI) activity dropped in the first week of the new year, according to the U.S. Centers for Disease Control and Prevention.
The proportion of outpatients visits for ILI dropped to 3.5% for the week ending Jan. 5, 2019, after reaching 4.0% the previous week. Outpatient ILI visits first topped the national baseline of 2.2% during the week ending Dec. 8, 2018, and have remained above that value for 5 consecutive weeks, the CDC’s influenza division said on Jan. 11.
Flu activity reported by the states reflects the national drop: 10 states came in at level 10 on the CDC’s 1-10 scale of activity for the week ending Jan. 5 – down from 12 the week before – and a total of 15 were in the high range from 8 to 10, compared with 19 the previous week, the CDC said. Two states, Mississippi and Texas, dropped from level 10 to level 7, which the CDC categorizes as moderate activity.
A total of 73 ILI-related deaths were reported during the week ending Dec. 29 (the latest with data available; reporting less than 68% complete), which already exceeds the 71 deaths reported for the week ending Dec. 22 (reporting 85% complete). Flu deaths totaled 437 through the first 13 weeks of the 2018-2019 season, compared with the 1,659 that occurred during weeks 1-13 of the very severe 2017-2018 season, CDC data show.
For the week ending Jan. 5, the CDC received reports of three flu-related pediatric deaths, all of which occurred the previous week. For the season so far, there have been 16 pediatric deaths, compared with 20 at this point in the 2017-2018 season.
Estimates released during the flu season for the first time show that between 6 and 7 million Americans have been infected since Oct. 1, 2018, and that 69,000-84,000 people have been hospitalized with the flu through Jan. 5, 2019. These cumulative totals have previously been available only at the end of the season, the CDC noted.
RE-SPECT ESUS: Dabigatran matched aspirin for second stroke prevention
MONTREAL – For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.
“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.
More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.
The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.
During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.
The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.
A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).
RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.
SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.
MONTREAL – For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.
“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.
More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.
The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.
During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.
The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.
A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).
RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.
SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.
MONTREAL – For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.
“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.
More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.
The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.
During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.
The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.
A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).
RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.
SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.
REPORTING FROM THE WORLD STROKE CONGRESS
Key clinical point:
Major finding: A second stroke occurred at 4.1%/year with dabigatran and 4.8%/year with aspirin, not a statistically significant difference.
Study details: RE-SPECT ESUS, an international randomized trial with 5,390 ESUS patients.
Disclosures: RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.
Source: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.
AAN publishes position statement on brain death
In a position statement published online ahead of print Jan. 2 in Neurology, Such uniformity would reduce uncertainty and improve patient care, according to the authors. The statement, which was drafted by the AAN’s Brain Death Working Group, also supports the development of uniform policies regarding brain death and its determination within American medical institutions. Finally, the document provides neurologists with guidance for responding to requests for accommodation, including objections to the determination of brain death and to the withdrawal of organ-sustaining technology.
The AAN defines brain death as death resulting from irreversible loss of function of the entire brain. The Uniform Determination of Death Act of 1981 held that brain death and circulatory death (that is, death resulting from irreversible loss of function of the circulatory system) are equivalent, and the AAN acknowledges this equivalence.
The two current medical standards for brain death are the AAN’s 2010 Evidence-Based Guideline Update: Determining Brain Death in Adults and the 2011 Guidelines for the Determination of Brain Death in Infants and Children, which was published by the pediatric section of the Society of Critical Care Medicine, the sections of neurology and critical care of the American Academy of Pediatrics, and the Child Neurology Society. “The AAN is unaware of any cases in which compliant application of the brain death guidelines led to inaccurate determination of death with return of any brain function, including consciousness, brainstem reflexes, or ventilatory effort,” according to their 2019 statement.
The only jurisdiction with laws that specifically defer to these standards, however, is Nevada. The vagueness of most states’ laws has contributed to divergent legal interpretations and idiosyncratic standards for determining brain death, according to the statement.
“The AAN believes that a specific, uniform standard for the determination of brain death is critically important to provide the highest quality patient-centered neurologic and end-of-life care,” said James Russell, DO, MS, a neurologist at Lahey Hospital and Medical Center in Burlington, Mass., and lead author of the position statement. “The AAN supports the development of legislation in every state modeled after the Nevada statute, which specifically defers to these current adult and pediatric brain death guidelines and any future updates.”
In addition to uniform institutional policies for determining brain death within U.S. medical facilities, the AAN calls for the development of training programs and credentialing mechanisms for physicians who determine brain death, regardless of their specialties. The association also supports research that enhances understanding of brain death and enhanced professional and public education.
While expressing respect and sympathy for requests for limited accommodation, the AAN asserts that these requests “must be based on the values of the patient, and not those of loved ones or other surrogate decision makers.” The association further observes that physicians have no ethical obligation to provide medical treatment to a deceased patient. New Jersey is the only state that legally obliges physicians to provide indefinite accommodation and continued application of organ-sustaining technology.
“The AAN believes that its members have both the moral authority and professional responsibility, when lawful, to perform a brain death evaluation, including apnea testing, after informing a patient’s loved ones or lawful surrogates of that intention, but without obligation to obtain informed consent,” according to the statement. “This position is analogous to the authority and responsibility historically granted to the medical profession to determine circulatory death without the requirement for additional informed consent.”
If a dispute about indefinite accommodation cannot be resolved, it is acceptable for a physician to withdraw organ-sustaining technology unilaterally over the objection of loved ones when legally permitted, according to the AAN. Such unilateral action is a measure of last resort and does not apply when the patient is a pregnant woman, said the authors. In the latter case, the ethical analysis should focus mainly on the welfare of the fetus.
The AAN provided financial support for the Brain Death Working Group’s efforts. The statement’s authors reported no relevant disclosures. The American Neurological Association and the Child Neurology Society have endorsed the AAN’s position statement.
SOURCE: Russell JA et al. Neurology. 2018 Jan 2. doi: 10.1212/WNL.0000000000006750.
In a position statement published online ahead of print Jan. 2 in Neurology, Such uniformity would reduce uncertainty and improve patient care, according to the authors. The statement, which was drafted by the AAN’s Brain Death Working Group, also supports the development of uniform policies regarding brain death and its determination within American medical institutions. Finally, the document provides neurologists with guidance for responding to requests for accommodation, including objections to the determination of brain death and to the withdrawal of organ-sustaining technology.
The AAN defines brain death as death resulting from irreversible loss of function of the entire brain. The Uniform Determination of Death Act of 1981 held that brain death and circulatory death (that is, death resulting from irreversible loss of function of the circulatory system) are equivalent, and the AAN acknowledges this equivalence.
The two current medical standards for brain death are the AAN’s 2010 Evidence-Based Guideline Update: Determining Brain Death in Adults and the 2011 Guidelines for the Determination of Brain Death in Infants and Children, which was published by the pediatric section of the Society of Critical Care Medicine, the sections of neurology and critical care of the American Academy of Pediatrics, and the Child Neurology Society. “The AAN is unaware of any cases in which compliant application of the brain death guidelines led to inaccurate determination of death with return of any brain function, including consciousness, brainstem reflexes, or ventilatory effort,” according to their 2019 statement.
The only jurisdiction with laws that specifically defer to these standards, however, is Nevada. The vagueness of most states’ laws has contributed to divergent legal interpretations and idiosyncratic standards for determining brain death, according to the statement.
“The AAN believes that a specific, uniform standard for the determination of brain death is critically important to provide the highest quality patient-centered neurologic and end-of-life care,” said James Russell, DO, MS, a neurologist at Lahey Hospital and Medical Center in Burlington, Mass., and lead author of the position statement. “The AAN supports the development of legislation in every state modeled after the Nevada statute, which specifically defers to these current adult and pediatric brain death guidelines and any future updates.”
In addition to uniform institutional policies for determining brain death within U.S. medical facilities, the AAN calls for the development of training programs and credentialing mechanisms for physicians who determine brain death, regardless of their specialties. The association also supports research that enhances understanding of brain death and enhanced professional and public education.
While expressing respect and sympathy for requests for limited accommodation, the AAN asserts that these requests “must be based on the values of the patient, and not those of loved ones or other surrogate decision makers.” The association further observes that physicians have no ethical obligation to provide medical treatment to a deceased patient. New Jersey is the only state that legally obliges physicians to provide indefinite accommodation and continued application of organ-sustaining technology.
“The AAN believes that its members have both the moral authority and professional responsibility, when lawful, to perform a brain death evaluation, including apnea testing, after informing a patient’s loved ones or lawful surrogates of that intention, but without obligation to obtain informed consent,” according to the statement. “This position is analogous to the authority and responsibility historically granted to the medical profession to determine circulatory death without the requirement for additional informed consent.”
If a dispute about indefinite accommodation cannot be resolved, it is acceptable for a physician to withdraw organ-sustaining technology unilaterally over the objection of loved ones when legally permitted, according to the AAN. Such unilateral action is a measure of last resort and does not apply when the patient is a pregnant woman, said the authors. In the latter case, the ethical analysis should focus mainly on the welfare of the fetus.
The AAN provided financial support for the Brain Death Working Group’s efforts. The statement’s authors reported no relevant disclosures. The American Neurological Association and the Child Neurology Society have endorsed the AAN’s position statement.
SOURCE: Russell JA et al. Neurology. 2018 Jan 2. doi: 10.1212/WNL.0000000000006750.
In a position statement published online ahead of print Jan. 2 in Neurology, Such uniformity would reduce uncertainty and improve patient care, according to the authors. The statement, which was drafted by the AAN’s Brain Death Working Group, also supports the development of uniform policies regarding brain death and its determination within American medical institutions. Finally, the document provides neurologists with guidance for responding to requests for accommodation, including objections to the determination of brain death and to the withdrawal of organ-sustaining technology.
The AAN defines brain death as death resulting from irreversible loss of function of the entire brain. The Uniform Determination of Death Act of 1981 held that brain death and circulatory death (that is, death resulting from irreversible loss of function of the circulatory system) are equivalent, and the AAN acknowledges this equivalence.
The two current medical standards for brain death are the AAN’s 2010 Evidence-Based Guideline Update: Determining Brain Death in Adults and the 2011 Guidelines for the Determination of Brain Death in Infants and Children, which was published by the pediatric section of the Society of Critical Care Medicine, the sections of neurology and critical care of the American Academy of Pediatrics, and the Child Neurology Society. “The AAN is unaware of any cases in which compliant application of the brain death guidelines led to inaccurate determination of death with return of any brain function, including consciousness, brainstem reflexes, or ventilatory effort,” according to their 2019 statement.
The only jurisdiction with laws that specifically defer to these standards, however, is Nevada. The vagueness of most states’ laws has contributed to divergent legal interpretations and idiosyncratic standards for determining brain death, according to the statement.
“The AAN believes that a specific, uniform standard for the determination of brain death is critically important to provide the highest quality patient-centered neurologic and end-of-life care,” said James Russell, DO, MS, a neurologist at Lahey Hospital and Medical Center in Burlington, Mass., and lead author of the position statement. “The AAN supports the development of legislation in every state modeled after the Nevada statute, which specifically defers to these current adult and pediatric brain death guidelines and any future updates.”
In addition to uniform institutional policies for determining brain death within U.S. medical facilities, the AAN calls for the development of training programs and credentialing mechanisms for physicians who determine brain death, regardless of their specialties. The association also supports research that enhances understanding of brain death and enhanced professional and public education.
While expressing respect and sympathy for requests for limited accommodation, the AAN asserts that these requests “must be based on the values of the patient, and not those of loved ones or other surrogate decision makers.” The association further observes that physicians have no ethical obligation to provide medical treatment to a deceased patient. New Jersey is the only state that legally obliges physicians to provide indefinite accommodation and continued application of organ-sustaining technology.
“The AAN believes that its members have both the moral authority and professional responsibility, when lawful, to perform a brain death evaluation, including apnea testing, after informing a patient’s loved ones or lawful surrogates of that intention, but without obligation to obtain informed consent,” according to the statement. “This position is analogous to the authority and responsibility historically granted to the medical profession to determine circulatory death without the requirement for additional informed consent.”
If a dispute about indefinite accommodation cannot be resolved, it is acceptable for a physician to withdraw organ-sustaining technology unilaterally over the objection of loved ones when legally permitted, according to the AAN. Such unilateral action is a measure of last resort and does not apply when the patient is a pregnant woman, said the authors. In the latter case, the ethical analysis should focus mainly on the welfare of the fetus.
The AAN provided financial support for the Brain Death Working Group’s efforts. The statement’s authors reported no relevant disclosures. The American Neurological Association and the Child Neurology Society have endorsed the AAN’s position statement.
SOURCE: Russell JA et al. Neurology. 2018 Jan 2. doi: 10.1212/WNL.0000000000006750.
FROM NEUROLOGY
Key clinical point: The AAN calls for uniform brain death laws, policies, and practices.
Major finding: The association published a position statement online on January 2.
Study details: The AAN’s Brain Death Working Group drafted the statement.
Disclosures: The authors reported no relevant disclosures, and the American Academy of Neurology funded their work.
Source: Russell JA et al. Neurology. 2018 Jan 2. doi: 10.1212/WNL.0000000000006750.
Appropriate use criteria for imaging in nonvalvular heart disease released
The American College of Cardiology, the American Heart Association, and other groups have jointly released an appropriate use criteria (AUC) document regarding the use of imaging modalities in diagnosing nonvalvular (that is, structural) heart disease.
Imaging plays an important role in diagnosing both valvular and nonvalvular heart diseases, so the goal of the document was to help clinicians provide high-quality care by standardizing the decision-making process. To do so, a committee was formed to devise scenarios that reflected situations in real-world practice; these scenarios were considered within categories to prevent the list from being too exhaustive. The scenarios were then reviewed by a rating panel in terms of how appropriate certain modalities were in each situation. The panel members first evaluated the scenarios independently then face to face as a panel before giving their final scores (from 1 to 9) independently.
For example, for the indication of nonsustained ventricular tachycardia, the panelists rated transthoracic echocardiography with or without 3-D and with contrast as needed as a 8, which means it’s an “appropriate test,” whereas they gave CT for the same indication a 3, which means “rarely appropriate.” For sustained ventricular tachycardia or ventricular fibrillation, they gave a 9 and a 6, respectively; this latter score indicates the test “may be appropriate.” These scenarios and the respective scores for any given test are organized into tables, such as initial evaluation or follow-up.
This AUC document “signals a shift from documents evaluating a single modality in various disease states to documents evaluating multiple imaging modalities and focusing on evidence and clinical experience within a given disease category,” the authors wrote. “We believe this approach better reflects clinical decision making in real-world scenarios and offers the diagnostic choices available to the clinician.”
The full document can be viewed in JACC.
The American College of Cardiology, the American Heart Association, and other groups have jointly released an appropriate use criteria (AUC) document regarding the use of imaging modalities in diagnosing nonvalvular (that is, structural) heart disease.
Imaging plays an important role in diagnosing both valvular and nonvalvular heart diseases, so the goal of the document was to help clinicians provide high-quality care by standardizing the decision-making process. To do so, a committee was formed to devise scenarios that reflected situations in real-world practice; these scenarios were considered within categories to prevent the list from being too exhaustive. The scenarios were then reviewed by a rating panel in terms of how appropriate certain modalities were in each situation. The panel members first evaluated the scenarios independently then face to face as a panel before giving their final scores (from 1 to 9) independently.
For example, for the indication of nonsustained ventricular tachycardia, the panelists rated transthoracic echocardiography with or without 3-D and with contrast as needed as a 8, which means it’s an “appropriate test,” whereas they gave CT for the same indication a 3, which means “rarely appropriate.” For sustained ventricular tachycardia or ventricular fibrillation, they gave a 9 and a 6, respectively; this latter score indicates the test “may be appropriate.” These scenarios and the respective scores for any given test are organized into tables, such as initial evaluation or follow-up.
This AUC document “signals a shift from documents evaluating a single modality in various disease states to documents evaluating multiple imaging modalities and focusing on evidence and clinical experience within a given disease category,” the authors wrote. “We believe this approach better reflects clinical decision making in real-world scenarios and offers the diagnostic choices available to the clinician.”
The full document can be viewed in JACC.
The American College of Cardiology, the American Heart Association, and other groups have jointly released an appropriate use criteria (AUC) document regarding the use of imaging modalities in diagnosing nonvalvular (that is, structural) heart disease.
Imaging plays an important role in diagnosing both valvular and nonvalvular heart diseases, so the goal of the document was to help clinicians provide high-quality care by standardizing the decision-making process. To do so, a committee was formed to devise scenarios that reflected situations in real-world practice; these scenarios were considered within categories to prevent the list from being too exhaustive. The scenarios were then reviewed by a rating panel in terms of how appropriate certain modalities were in each situation. The panel members first evaluated the scenarios independently then face to face as a panel before giving their final scores (from 1 to 9) independently.
For example, for the indication of nonsustained ventricular tachycardia, the panelists rated transthoracic echocardiography with or without 3-D and with contrast as needed as a 8, which means it’s an “appropriate test,” whereas they gave CT for the same indication a 3, which means “rarely appropriate.” For sustained ventricular tachycardia or ventricular fibrillation, they gave a 9 and a 6, respectively; this latter score indicates the test “may be appropriate.” These scenarios and the respective scores for any given test are organized into tables, such as initial evaluation or follow-up.
This AUC document “signals a shift from documents evaluating a single modality in various disease states to documents evaluating multiple imaging modalities and focusing on evidence and clinical experience within a given disease category,” the authors wrote. “We believe this approach better reflects clinical decision making in real-world scenarios and offers the diagnostic choices available to the clinician.”
The full document can be viewed in JACC.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
New diabetes drugs solidify their cardiovascular and renal benefits
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Hospital Readmissions Reduction Program may be doing more harm than good
A Medicare program aimed at lowering readmissions to hospitals could be having an adverse effect on mortality.
Results from a retrospective cohort study of hospitalizations for heart failure, acute myocardial infarction, and pneumonia among Medicare beneficiaries aged 65 years and older between April 1, 2005 and March 31, 2015 (covering the period before and after the Medicare Hospital Readmissions Reduction Program was announced in April 2010 and implemented in October 2012) found a significant increase in 30-day post discharge mortality among heart failure and pneumonia patients.
“Most concerning, however, is the possibility that the relationship between the HRRP and postdischarge mortality for heart failure and pneumonia is causal, indicating that the HRRP led to changes in quality of care that adversely affected patients,” Rishi Wadhera, MD, Harvard Medical School, Boston, and his colleagues wrote in a report published Dec. 25, 2018, in JAMA.
They looked at 8.3 million hospitalizations for heart failure, acute MI, and pneumonia, among whom 7.9 million were alive at the time of discharge. There were roughly 270,000 deaths within 30 days of discharge for heart failure; 128,000 for acute MI; and 246,000 for pneumonia.
To examine trends, the timing was divided into four periods: two prior to the announcement of the HRRP (April 2005–September 2007 and October 2007–March 2010); a third covering the time when the HRRP was announced (April 2010–September 2012); and the fourth when HRRP was implemented (October 2012–March 2015).
They found that among patients discharged with heart failure, 30-day mortality was rising even before the announcement of the HRRP, by 0.27% from the first period to the second period. That baseline trend continued when the HRRP was announced, by 0.49%, from second period to third. The difference in change between those periods was 0.22%. After implementation, 30-day mortality increased by 0.52%, with a difference in change from the third period of 0.25%. Both changes were statistically significant.
Among pneumonia patients, postdischarge mortality was stable before HRRP, but significantly increased after HRRP announcement, by 0.26%, with a difference in change from the second period to the third period of 0.22%. After implementation, the 30-day postdischarge mortality was 0.44%, with a significant difference in change of 0.40%.
Acute MI was a different story. Postdischarge mortality decreased significantly after the implementation of the HRRP, by 0.22%. The difference in change was –0.26%.
The authors suggested that “some hospitals may have focused more resources and efforts on reducing or avoiding readmissions than on prioritizing survival.” They add that the increases in heart failure morbidity could be related to patients with more severe heart conditions.
They noted that “although hospitals that reduce readmissions also appear to reduce mortality, this hospital-level concordance does not reflect the change in readmissions and mortality at the level of the patient population, which is arguably of greater importance to individual patients and to public health.”
Further research is needed to understand whether the increase in 30-day postdischarge mortality is a result of the HRRP, the authors concluded.
SOURCE: Wadhera R et al. JAMA. 2018 Dec 25. doi: 10.1001/jama.2018.19232.
Evidence in this study shows that while the Hospital Readmissions Reduction Program my be succeeding in reducing hospital admissions, little evidence is available to show that it is having a positive effect on patient outcomes.
The Centers for Medicare & Medicaid Services needs to reexamine the program and find alternative methods that are both effective at reducing hospital readmissions while at the same time protect patients from unintentional harm, including death.
Gregg C. Fonarow, MD , University of California Medical Center, Los Angeles, in an editorial published in JAMA, Dec. 25, 2018. doi:10.1001/jama.2018.19325 .
Evidence in this study shows that while the Hospital Readmissions Reduction Program my be succeeding in reducing hospital admissions, little evidence is available to show that it is having a positive effect on patient outcomes.
The Centers for Medicare & Medicaid Services needs to reexamine the program and find alternative methods that are both effective at reducing hospital readmissions while at the same time protect patients from unintentional harm, including death.
Gregg C. Fonarow, MD , University of California Medical Center, Los Angeles, in an editorial published in JAMA, Dec. 25, 2018. doi:10.1001/jama.2018.19325 .
Evidence in this study shows that while the Hospital Readmissions Reduction Program my be succeeding in reducing hospital admissions, little evidence is available to show that it is having a positive effect on patient outcomes.
The Centers for Medicare & Medicaid Services needs to reexamine the program and find alternative methods that are both effective at reducing hospital readmissions while at the same time protect patients from unintentional harm, including death.
Gregg C. Fonarow, MD , University of California Medical Center, Los Angeles, in an editorial published in JAMA, Dec. 25, 2018. doi:10.1001/jama.2018.19325 .
A Medicare program aimed at lowering readmissions to hospitals could be having an adverse effect on mortality.
Results from a retrospective cohort study of hospitalizations for heart failure, acute myocardial infarction, and pneumonia among Medicare beneficiaries aged 65 years and older between April 1, 2005 and March 31, 2015 (covering the period before and after the Medicare Hospital Readmissions Reduction Program was announced in April 2010 and implemented in October 2012) found a significant increase in 30-day post discharge mortality among heart failure and pneumonia patients.
“Most concerning, however, is the possibility that the relationship between the HRRP and postdischarge mortality for heart failure and pneumonia is causal, indicating that the HRRP led to changes in quality of care that adversely affected patients,” Rishi Wadhera, MD, Harvard Medical School, Boston, and his colleagues wrote in a report published Dec. 25, 2018, in JAMA.
They looked at 8.3 million hospitalizations for heart failure, acute MI, and pneumonia, among whom 7.9 million were alive at the time of discharge. There were roughly 270,000 deaths within 30 days of discharge for heart failure; 128,000 for acute MI; and 246,000 for pneumonia.
To examine trends, the timing was divided into four periods: two prior to the announcement of the HRRP (April 2005–September 2007 and October 2007–March 2010); a third covering the time when the HRRP was announced (April 2010–September 2012); and the fourth when HRRP was implemented (October 2012–March 2015).
They found that among patients discharged with heart failure, 30-day mortality was rising even before the announcement of the HRRP, by 0.27% from the first period to the second period. That baseline trend continued when the HRRP was announced, by 0.49%, from second period to third. The difference in change between those periods was 0.22%. After implementation, 30-day mortality increased by 0.52%, with a difference in change from the third period of 0.25%. Both changes were statistically significant.
Among pneumonia patients, postdischarge mortality was stable before HRRP, but significantly increased after HRRP announcement, by 0.26%, with a difference in change from the second period to the third period of 0.22%. After implementation, the 30-day postdischarge mortality was 0.44%, with a significant difference in change of 0.40%.
Acute MI was a different story. Postdischarge mortality decreased significantly after the implementation of the HRRP, by 0.22%. The difference in change was –0.26%.
The authors suggested that “some hospitals may have focused more resources and efforts on reducing or avoiding readmissions than on prioritizing survival.” They add that the increases in heart failure morbidity could be related to patients with more severe heart conditions.
They noted that “although hospitals that reduce readmissions also appear to reduce mortality, this hospital-level concordance does not reflect the change in readmissions and mortality at the level of the patient population, which is arguably of greater importance to individual patients and to public health.”
Further research is needed to understand whether the increase in 30-day postdischarge mortality is a result of the HRRP, the authors concluded.
SOURCE: Wadhera R et al. JAMA. 2018 Dec 25. doi: 10.1001/jama.2018.19232.
A Medicare program aimed at lowering readmissions to hospitals could be having an adverse effect on mortality.
Results from a retrospective cohort study of hospitalizations for heart failure, acute myocardial infarction, and pneumonia among Medicare beneficiaries aged 65 years and older between April 1, 2005 and March 31, 2015 (covering the period before and after the Medicare Hospital Readmissions Reduction Program was announced in April 2010 and implemented in October 2012) found a significant increase in 30-day post discharge mortality among heart failure and pneumonia patients.
“Most concerning, however, is the possibility that the relationship between the HRRP and postdischarge mortality for heart failure and pneumonia is causal, indicating that the HRRP led to changes in quality of care that adversely affected patients,” Rishi Wadhera, MD, Harvard Medical School, Boston, and his colleagues wrote in a report published Dec. 25, 2018, in JAMA.
They looked at 8.3 million hospitalizations for heart failure, acute MI, and pneumonia, among whom 7.9 million were alive at the time of discharge. There were roughly 270,000 deaths within 30 days of discharge for heart failure; 128,000 for acute MI; and 246,000 for pneumonia.
To examine trends, the timing was divided into four periods: two prior to the announcement of the HRRP (April 2005–September 2007 and October 2007–March 2010); a third covering the time when the HRRP was announced (April 2010–September 2012); and the fourth when HRRP was implemented (October 2012–March 2015).
They found that among patients discharged with heart failure, 30-day mortality was rising even before the announcement of the HRRP, by 0.27% from the first period to the second period. That baseline trend continued when the HRRP was announced, by 0.49%, from second period to third. The difference in change between those periods was 0.22%. After implementation, 30-day mortality increased by 0.52%, with a difference in change from the third period of 0.25%. Both changes were statistically significant.
Among pneumonia patients, postdischarge mortality was stable before HRRP, but significantly increased after HRRP announcement, by 0.26%, with a difference in change from the second period to the third period of 0.22%. After implementation, the 30-day postdischarge mortality was 0.44%, with a significant difference in change of 0.40%.
Acute MI was a different story. Postdischarge mortality decreased significantly after the implementation of the HRRP, by 0.22%. The difference in change was –0.26%.
The authors suggested that “some hospitals may have focused more resources and efforts on reducing or avoiding readmissions than on prioritizing survival.” They add that the increases in heart failure morbidity could be related to patients with more severe heart conditions.
They noted that “although hospitals that reduce readmissions also appear to reduce mortality, this hospital-level concordance does not reflect the change in readmissions and mortality at the level of the patient population, which is arguably of greater importance to individual patients and to public health.”
Further research is needed to understand whether the increase in 30-day postdischarge mortality is a result of the HRRP, the authors concluded.
SOURCE: Wadhera R et al. JAMA. 2018 Dec 25. doi: 10.1001/jama.2018.19232.
FROM JAMA
Key clinical point:
Major finding: Heart failure patients saw mortality increase 0.52% after HRRP launched.
Study details: A retrospective cohort study across 10 years, including time before and after the implementation of the HRRP.
Disclosures: The Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology funded the study. No relevant conflicts of interest were disclosed.
Source: Wadhera R et al. JAMA 2018 Dec 25. doi: 10.1001/jama.2018.19232.
Synthetic opioids drive spike in U.S. fatal drug overdoses
New federal statistics suggest that the opioid epidemic in the United States is evolving as physicians crack down on the use of prescription painkillers: Fatal drug overdose deaths rose by 12% from 2016 to 2017, boosted by a wave of fatalities linked to illicit synthetic opioids like fentanyl that are now linked to an estimated 60% of opioid-related deaths.
“Overall, the overdose epidemic continues to worsen, and it has grown increasingly complex by coinvolvement of prescription and illicit drugs,” Lawrence Scholl, PhD, MPH, and his associates at the Centers for Disease Control & Prevention wrote in the Morbidity and Mortality Weekly Report.
The new statistics provide more evidence that 2017 marked “a sharp increase in what has characterized as the third wave of the opioid epidemic,” said drug and health policy researcher Stephen Crystal, PhD, of Rutgers University, New Brunswick, N.J., in an interview. He was referring to a wave that experts believe started in 2013 amid a spike in U.S. overdose deaths from fentanyl and other synthetic opioids.
The new report analyzes fatal drug overdose data from 2013 to 2017. According to the findings, the total number of those overdoses rose to 70,237 in 2017, up from 63,632 in 2016. The highest drug overdose death rates in 2017 were in West Virginia, followed by Ohio, Pennsylvania, and the District of Columbia.
Some statistics did not change much from 2016 to 2017: About two-thirds of the drug overdose deaths were linked to opioids in both years, and the death rate of cases linked to prescription drugs and heroin remained steady. (Death rates in the report were age adjusted.)
However, the percentage of fatal overdose cases linked to synthetic opioids grew 45% from 2016 to 2017. Overall, 60% of opioid-related fatal overdoses in 2017 involved synthetic opioids.
The report identifies increases in several areas from 2016 to 2017. Opioid-related drug overdose deaths among black people rose by 25%, and an analysis of data from 34 states and the District of Columbia found the highest increases in death rates in North Carolina (29%), Ohio (19%), and Maine (19%).
In regard to deaths linked to synthetic opioids specifically, the highest death rates in 2017 were in West Virginia (37 per 100,000), Ohio (32 per 100,000), and New Hampshire (30 per 100,000).
“Part of what we’re seeing in these increased numbers are individuals who have pain, can’t get prescribed opioids, and turn to street drugs,” Dr. Crystal said, adding that “abruptly cutting patients off is not good, and leaving patients with a lot of untreated pain is not good. If people are going to be discontinued [from opioids] or have their doses reduced, the taper needs to be done very slowly and carefully.”
Synthetic opioids were not the only drugs that are driving up fatal overdoses, as the death rates of cases linked to cocaine and psychostimulants (such as methamphetamine) jumped by more than a third in 2017.
“The most important thing these numbers are telling me is that it’s becoming more and more attractive to drug dealers to put fentanyl in the heroin, cocaine, and other drugs they sell,” Dr. Crystal said. “When that happens, dependence on street drugs becomes much more deadly. It’s almost impossible to get the dose right. Every time you shoot up, you’re taking a chance that you’ll overdose.”
The report had limitations, including the fact that details about drug use were missing from 12% (2016) and 15% (2017) of death certificates in fatal overdose cases. By state, the percentages of those death certificates that included drug information ranged from as little as 55% to 99%.
There’s some possible positive news: The report points to preliminary data from 2018 suggesting that the number of annual drug overdose deaths may be leveling off – although it says more analysis is needed to confirm the trend.
Dr. Crystal, however, is not celebrating. “I don’t see this as a good news story, really,” he said, adding that there’s “a little too much of people patting themselves on the back” because they’re proud of cutbacks in opioid prescriptions.
“This doesn’t have to do with the huge number of people who got started with opioids years ago” and are now at risk of using street drugs, he said. “We haven’t engaged that population at the rate we need to. And flattening out at 70,000 drug overdoses a year is not a good news story.”
Dr. Crystal reported no relevant disclosures.
SOURCE: Scholl L et al. MMWR. 2019 Jan 4;67(5152):1419-27.
New federal statistics suggest that the opioid epidemic in the United States is evolving as physicians crack down on the use of prescription painkillers: Fatal drug overdose deaths rose by 12% from 2016 to 2017, boosted by a wave of fatalities linked to illicit synthetic opioids like fentanyl that are now linked to an estimated 60% of opioid-related deaths.
“Overall, the overdose epidemic continues to worsen, and it has grown increasingly complex by coinvolvement of prescription and illicit drugs,” Lawrence Scholl, PhD, MPH, and his associates at the Centers for Disease Control & Prevention wrote in the Morbidity and Mortality Weekly Report.
The new statistics provide more evidence that 2017 marked “a sharp increase in what has characterized as the third wave of the opioid epidemic,” said drug and health policy researcher Stephen Crystal, PhD, of Rutgers University, New Brunswick, N.J., in an interview. He was referring to a wave that experts believe started in 2013 amid a spike in U.S. overdose deaths from fentanyl and other synthetic opioids.
The new report analyzes fatal drug overdose data from 2013 to 2017. According to the findings, the total number of those overdoses rose to 70,237 in 2017, up from 63,632 in 2016. The highest drug overdose death rates in 2017 were in West Virginia, followed by Ohio, Pennsylvania, and the District of Columbia.
Some statistics did not change much from 2016 to 2017: About two-thirds of the drug overdose deaths were linked to opioids in both years, and the death rate of cases linked to prescription drugs and heroin remained steady. (Death rates in the report were age adjusted.)
However, the percentage of fatal overdose cases linked to synthetic opioids grew 45% from 2016 to 2017. Overall, 60% of opioid-related fatal overdoses in 2017 involved synthetic opioids.
The report identifies increases in several areas from 2016 to 2017. Opioid-related drug overdose deaths among black people rose by 25%, and an analysis of data from 34 states and the District of Columbia found the highest increases in death rates in North Carolina (29%), Ohio (19%), and Maine (19%).
In regard to deaths linked to synthetic opioids specifically, the highest death rates in 2017 were in West Virginia (37 per 100,000), Ohio (32 per 100,000), and New Hampshire (30 per 100,000).
“Part of what we’re seeing in these increased numbers are individuals who have pain, can’t get prescribed opioids, and turn to street drugs,” Dr. Crystal said, adding that “abruptly cutting patients off is not good, and leaving patients with a lot of untreated pain is not good. If people are going to be discontinued [from opioids] or have their doses reduced, the taper needs to be done very slowly and carefully.”
Synthetic opioids were not the only drugs that are driving up fatal overdoses, as the death rates of cases linked to cocaine and psychostimulants (such as methamphetamine) jumped by more than a third in 2017.
“The most important thing these numbers are telling me is that it’s becoming more and more attractive to drug dealers to put fentanyl in the heroin, cocaine, and other drugs they sell,” Dr. Crystal said. “When that happens, dependence on street drugs becomes much more deadly. It’s almost impossible to get the dose right. Every time you shoot up, you’re taking a chance that you’ll overdose.”
The report had limitations, including the fact that details about drug use were missing from 12% (2016) and 15% (2017) of death certificates in fatal overdose cases. By state, the percentages of those death certificates that included drug information ranged from as little as 55% to 99%.
There’s some possible positive news: The report points to preliminary data from 2018 suggesting that the number of annual drug overdose deaths may be leveling off – although it says more analysis is needed to confirm the trend.
Dr. Crystal, however, is not celebrating. “I don’t see this as a good news story, really,” he said, adding that there’s “a little too much of people patting themselves on the back” because they’re proud of cutbacks in opioid prescriptions.
“This doesn’t have to do with the huge number of people who got started with opioids years ago” and are now at risk of using street drugs, he said. “We haven’t engaged that population at the rate we need to. And flattening out at 70,000 drug overdoses a year is not a good news story.”
Dr. Crystal reported no relevant disclosures.
SOURCE: Scholl L et al. MMWR. 2019 Jan 4;67(5152):1419-27.
New federal statistics suggest that the opioid epidemic in the United States is evolving as physicians crack down on the use of prescription painkillers: Fatal drug overdose deaths rose by 12% from 2016 to 2017, boosted by a wave of fatalities linked to illicit synthetic opioids like fentanyl that are now linked to an estimated 60% of opioid-related deaths.
“Overall, the overdose epidemic continues to worsen, and it has grown increasingly complex by coinvolvement of prescription and illicit drugs,” Lawrence Scholl, PhD, MPH, and his associates at the Centers for Disease Control & Prevention wrote in the Morbidity and Mortality Weekly Report.
The new statistics provide more evidence that 2017 marked “a sharp increase in what has characterized as the third wave of the opioid epidemic,” said drug and health policy researcher Stephen Crystal, PhD, of Rutgers University, New Brunswick, N.J., in an interview. He was referring to a wave that experts believe started in 2013 amid a spike in U.S. overdose deaths from fentanyl and other synthetic opioids.
The new report analyzes fatal drug overdose data from 2013 to 2017. According to the findings, the total number of those overdoses rose to 70,237 in 2017, up from 63,632 in 2016. The highest drug overdose death rates in 2017 were in West Virginia, followed by Ohio, Pennsylvania, and the District of Columbia.
Some statistics did not change much from 2016 to 2017: About two-thirds of the drug overdose deaths were linked to opioids in both years, and the death rate of cases linked to prescription drugs and heroin remained steady. (Death rates in the report were age adjusted.)
However, the percentage of fatal overdose cases linked to synthetic opioids grew 45% from 2016 to 2017. Overall, 60% of opioid-related fatal overdoses in 2017 involved synthetic opioids.
The report identifies increases in several areas from 2016 to 2017. Opioid-related drug overdose deaths among black people rose by 25%, and an analysis of data from 34 states and the District of Columbia found the highest increases in death rates in North Carolina (29%), Ohio (19%), and Maine (19%).
In regard to deaths linked to synthetic opioids specifically, the highest death rates in 2017 were in West Virginia (37 per 100,000), Ohio (32 per 100,000), and New Hampshire (30 per 100,000).
“Part of what we’re seeing in these increased numbers are individuals who have pain, can’t get prescribed opioids, and turn to street drugs,” Dr. Crystal said, adding that “abruptly cutting patients off is not good, and leaving patients with a lot of untreated pain is not good. If people are going to be discontinued [from opioids] or have their doses reduced, the taper needs to be done very slowly and carefully.”
Synthetic opioids were not the only drugs that are driving up fatal overdoses, as the death rates of cases linked to cocaine and psychostimulants (such as methamphetamine) jumped by more than a third in 2017.
“The most important thing these numbers are telling me is that it’s becoming more and more attractive to drug dealers to put fentanyl in the heroin, cocaine, and other drugs they sell,” Dr. Crystal said. “When that happens, dependence on street drugs becomes much more deadly. It’s almost impossible to get the dose right. Every time you shoot up, you’re taking a chance that you’ll overdose.”
The report had limitations, including the fact that details about drug use were missing from 12% (2016) and 15% (2017) of death certificates in fatal overdose cases. By state, the percentages of those death certificates that included drug information ranged from as little as 55% to 99%.
There’s some possible positive news: The report points to preliminary data from 2018 suggesting that the number of annual drug overdose deaths may be leveling off – although it says more analysis is needed to confirm the trend.
Dr. Crystal, however, is not celebrating. “I don’t see this as a good news story, really,” he said, adding that there’s “a little too much of people patting themselves on the back” because they’re proud of cutbacks in opioid prescriptions.
“This doesn’t have to do with the huge number of people who got started with opioids years ago” and are now at risk of using street drugs, he said. “We haven’t engaged that population at the rate we need to. And flattening out at 70,000 drug overdoses a year is not a good news story.”
Dr. Crystal reported no relevant disclosures.
SOURCE: Scholl L et al. MMWR. 2019 Jan 4;67(5152):1419-27.
FROM MMWR
How can I improve opioid safety at my hospital?
Quality improvement is essential
Case
A 67-year-old opioid-naive male with a history of obstructive sleep apnea and chronic kidney disease became unresponsive 2 days after hip replacement. Physical exam revealed a respiratory rate of 6 breaths/minute and oxygen saturation of 82%. He had received 6 doses of 6-mg IV morphine within the past 7 hours. How can I improve opioid safety at my hospital?
Background
Opioids are the most commonly prescribed class of medication in the hospital and the second–most common class causing adverse drug events (ADEs), the most serious being respiratory depression and death.1
Opioid ADEs and side effects can cause prolonged length of stay and patient suffering. These vary from potentially life-threatening events such as serotonin syndrome and adrenal insufficiency to more manageable problems still requiring intervention such as constipation, urinary retention, cognitive impairment, nausea, and vomiting. Treatment of side effects can lead to complications, including side effects from antiemetics and urinary tract infections from catheters.
A 4-year review found 700 deaths in the United States attributed to patient-controlled analgesia (PCA) use.2 Another study revealed that one out of every 200 patients has postoperative respiratory depression attributable to opioids.3
It is estimated that 2 million patients a year become chronic opioid users. Inpatient opioid prescribing contributes to this problem;4 for instance, 5.9% of patients after minor surgery and 6.5% after major surgery become chronic opioid users if discharged with an opioid.5 Calcaterra et al. found 25% of opioid-naive medical patients received an opioid at discharge from a medical service.6 Those patients had an odds ratio of 4.90 for becoming a chronic opioid user that year.6
Most hospitals have incomplete or outdated policies and procedures for safe opioid prescribing and administration.7 The Joint Commission on Accreditation of Healthcare Organizations has specific pain standards for pain assessment, pain management, and safe opioid prescribing for hospitals. Additions and revisions were developed to go into effect Jan. 1, 2018. (Table 1)8
Quality improvement
Quality improvement (QI) is an effective way to improve opioid safety. The Society of Hospital Medicine has developed a QI guide, “Reducing adverse drug events related to opioids” or “RADEO,” to increase safety and decrease serious ADEs attributable to opioids.7
The steps in the RADEO program are as follows:
1. Assemble your team
It is critical to identify and include stakeholders from multiple disciplines on your project team. This team will be essential to develop a practical project, identify barriers, create solutions, and gain buy-in from medical staff and administrative leadership.
Front-line staff will have invaluable insight and need to be team members. The majority of interventions are performed by nurses; therefore, nursing leadership and input is essential. Representatives from pharmacy, information technology, and the quality department will be extremely valuable team members to guide you through the correct approach to a successful QI project.
A project champion can keep a high profile for the project and build and lead the team.
Identify an “executive sponsor” such as your CEO, CMO, or CNO. This leader will focus the team on issues critical to your organization, such as accreditation from governmental agencies, and help you obtain dedicated time and resources. Aligning with hospital goals will make your project a priority.
Coordinate with existing opioid initiative teams in the hospital to integrate efforts. This will keep the work of different departments aligned and allow you to learn from pitfalls and barriers the other groups experienced.
Patients/families contribute a unique and valuable perspective. Consider including a member of your hospital’s patient and family advisory council on your team.
2. Perform a needs assessment
Determine the current state of your hospital including: opioid prescribers; opioids prescribed; areas with increased ADEs or naloxone use; formulary restrictions, policies, or guidelines for monitoring, prescribing, and administering opioids; order sets; safety alerts; provider education; or patient education.
Your risk management or quality department may be able to a share root cause analysis of ADEs related to opioids. Joint Commission and CMS recommendations as well as other regulatory requirements may shape your QI interventions.8
Most importantly, review all of the concerns and priorities of your diverse team, which will identify areas of most pressing need and provide insight regarding needs you have not considered.
3. Develop SMART aims
Frame your QI project into a series of well-defined, clear SMART aims.9
Specific: Who will carry out the intervention? Who is your target population? What will be improved? In what way will it be improved?
Measurable: What will be measured? How it will be measured? Does it measure the outcome that needs to be improved?
Attainable/achievable: Ensure you have the resources and time to achieve the aim.
Relevant: Ensure each aim moves your team toward the project vision.
Timely: The aim should be achieved within a realistic time frame, long enough to meet goals but not so long that interest is lost.
An example of a poor aim is “Clinicians will improve knowledge of opioids.”
An example of a SMART aim is “75% of inpatient opioid prescribers including MDs, NPs, and PAs will complete and pass the opioid safety training module by July 1, 2018.”
4. Choose metrics
Outcome metrics measure if the intervention has improved patient safety, for example, measuring a decrease in opioid related ADEs. Structure metrics are the physical and organizational properties of the health care delivery setting, for example, the presence of EMR opioid safety. Processes are communication and practice patterns, for example, adherence to policy by examining nursing documentation of pain assessments.
5. Development and implementation 7,10
Use PDSA for development and implementation of the QI intervention.
Plan: Determine the intervention group such as a specific unit, number of units, and if there will be a control group. Determine who will collect the data, if baseline data will be collected, and who will analyze the data. Your information technology department will be essential to determine if the data can be collected via the EMR and how. Input from your multidisciplinary team is critical to anticipate unintended consequences, such as limiting opioid prescribing at discharge inadvertently increasing emergency department visits for pain control.
Do: Start as a small pilot study to make it as easy as possible to implement the project and begin data collection. A small-scale intervention will be more manageable and allow rapid responses to unanticipated problems.
Study: Analyze the data early to determine if the intervention is improving opioid safety and if alterations are needed. At this stage both process metrics (are processes being followed?) and outcome metrics (is the process leading to a desired outcome?) are important.
Act: Based on data analysis, refine the intervention as necessary. You may have to repeat cycles of PDSA to develop the final intervention. Then implement the final intervention to the entire hospital.
The Joint Commission recommendations for opioid QI
The Joint Commission recommends7 the following to reduce opioid-related respiratory depression:
- Effective processes which include processes such as tracking and analyzing ADEs related to opioids.
- Safe technology which includes using technology such as the EMR to monitor opioid prescribing of greater than 90 morphine milligram equivalents.
- Effective tools which include valid and reliable tools to improve opioid safety, such as the Pasero Opioid Induced Sedation Scale (POSS).
- Opioid education and training which includes provider and patient education such as patient discharge education.
Education
Develop educational interventions to ensure medical and hospital staff are aware of new processes, with an emphasis on “why.”7 If possible, use web-based programs that provide CME. Improve education interventions by using multiple live, interactive, and multimedia exposures.
Principles for successful interventions
- Keep it simple for the end user. This makes it more likely that the intervention is performed. Minimize complex tasks such as calculations and if possible design automated processes.
- Build your process into current work flow. If possible simplify or streamline work flow. A project that competes with staff’s other tasks and competing priorities is doomed to fail. It is critical to have input from those performing the intervention to develop a user-friendly and less disruptive intervention.
- Design reliability into the process. Make your intervention the default action. Build prompts into the work flow. Standardize the intervention into the work flow. And, consider having the intervention at scheduled intervals.7
Opioid safety QI interventions
Interventions for improving opioid safety and reducing opioid -elated ADEs may be generalized into areas including risk screening and assessment, pain treatment, opioid administration, pain assessment, post opioid administration monitoring, and patient and provider education (Table 2).7
Back to the case
The patient received naloxone. His respiratory rate and oxygen saturation returned to normal. His dose of morphine was reduced and his interval increased. A multimodal approach was implemented including low-dose scheduled acetaminophen. There were no further ADEs while maintaining good pain control.
A multidisciplinary opioid task force was created and performed a hospital-wide review of opioid ADEs. Opportunities for improvement were identified and new procedures implemented. The Pasero opioid sedation scale (POSS) was added to the nursing work flow to monitor patients who received an opioid for sedation. An algorithm was developed for opioid-naive patients including guidance for opioid selection, dosing, and frequency. Multiple pain control modalities were added to pain control order sets. Annual training was developed for opioid prescribers, pharmacists, and nurses regarding safe and responsible use of opioids.
And, lastly, in-hospital and discharge patient education was developed for patients and families to be well-informed of opioid risk and benefit including how to identify and respond to ADEs.
Bottom line
Quality improvement is an effective method to improve patient safety and reduce serious adverse events related to opioids in the hospital setting.
Dr. Holmes-Maybank, is codirector, Fundamentals of Patient Care Year 1 and Internship 101, and chair, Clinical Competency Examination Committee, division of hospital medicine, Medical University of South Carolina. Dr. Frederickson is medical director, Hospital Medicine and Palliative Care at CHI Health, Omaha, Neb., and assistant professor at Creighton University School of Medicine, Omaha.
References
1. Davies EC et al. Adverse drug reactions in hospital inpatients: a prospective analysis of 3695 patient-episodes. PLoS One. 2009;4(2):e4439. doi: 10.1371/journal.pone.0004439. Epub 2009 Feb 11.
2. Association for the Advancement of Medical Instrumentation. Infusing patients safely: Priority issues from the AAMI/FDA Infusion Device Summit. 2010;1-39.
3. Dahan Aet al. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology. 2010;112:226-238. doi: 10.1097/ALN.0b013e3181c38c25.
4. Estimate about opioid users.
5. Brummett CM et al. New persistent opioid use after minor and major surgical procedures in U.S. adults. JAMA Surg. 2017;152(6):e170504. doi: 10.1001/jamasurg.2017.0504.
6. Calcaterra SL et al. Opioid prescribing at hospital discharge contributes to chronic opioid use. J Gen Intern Med. 2016;31(5):478-85. doi: 10.1007/s11606-015-3539-4.
7. Frederickson TW et al. Reducing adverse drug events related to opioids implementation guide. Philadelphia: Society of Hospital Medicine, 2015.
8. Joint Commission enhances pain assessment and management requirements for accredited hospitals. The Joint Commission Perspectives. 2017;37(7):2-4.
9. Minnesota Department of Health. SMART objectives.
10. Agency for Healthcare Research and Quality. Health Literacy Universal Precautions Toolkit, 2nd Edition.
Plan-Do-Study-Act (PDSA) Directions and Examples.
Recommended reading
Dowell D et al. CDC guideline for prescribing opioids for chronic pain – United States, 2016. Recommendations and Reports. 2016 Mar 18;65(1):1-49.
Frederickson TW et al. Using the 2018 guidelines from the Joint Commission to kickstart your hospital’s program to reduce opioid-induced ventilatory impairment. Anesthesia Patient Safety Foundation Newsletter. 2018;33(1):1-32.
Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: a systematic review of existing guidelines. J Hosp Med. 2018 Apr;13(4):256-62. doi: 10.12788/jhm.2979.
Herzig SJ et al. Improving the safety of opioid use for acute noncancer pain in hospitalized adults: a consensus statement from the society of hospital medicine. J Hosp Med. 2018 Apr;13(4):263-71. doi: 10.12788/jhm.2980.
Joint Commission enhances pain assessment and management requirements for accredited hospitals. The Joint Commission Perspectives. 2017;37(7):2-4.
Key points
- Quality improvement is required by the Joint Commission and is an effective method to improve opioid safety in the hospital setting.
- It is critical to the success of a QI project to develop a multidisciplinary team.
- Input from frontline users of the intervention is essential to produce an effective intervention.
- Executive sponsorship and aligning the goals of your QI project with those of your institution will prioritize your project and increase resource availability.
Quiz
1. Based on a needs assessment at your hospital you assemble a multidisciplinary team to improve education for patients discharged on opioids. You recognize the importance of multidisciplinary input to develop a successful intervention for discharge education. Essential team members include all EXCEPT the following:
a. Executive sponsor
b. Patient representative
c. Nursing
d. Medical student representative ---- CORRECT
Explanation: The assembly of a multidisciplinary team is critical to the success of a QI intervention. An executive sponsor may assist you in aligning your goals with that of the hospital and provide resources for its development and implementation. Patient input would help determine how to best deliver the education. Lastly, the individuals carrying out the intervention are essential to develop an intervention that will easy for the end user and increase the likelihood of being used, in this case nursing.
2. You performed a review of naloxone use at your hospital and find that it is greater than similar hospitals. Prior to starting the QI project, you review SHM’s “Reducing adverse events related to opioids implementation guide” and learn that keys to success for QI implementation include:
a. A team of primarily hospitalists
b. Implementing the intervention hospital wide
c. Information technology input for data collection ---- CORRECT
d. No team – it is more effective to work alone
Explanation: Successful implementation of a QI project involves a multidisciplinary team. It is critical to involve information technology early in the development of the project to determine how and if the data can be collected from the EMR. It is best to pilot the intervention on one or two units to make alterations as needed rapidly and perfect the final intervention prior to rolling it out to the entire hospital.
3. You have assembled a multidisciplinary team to respond to the newly revised JCAHO pain standards. An example of a requirement from the new and revised JCAHO standards for pain assessment and management includes:
a. Programs for physician wellness
b. No opioids for chronic pain
c. No more than 5 days of opioids for acute pain
d. Nonpharmacologic pain management options ---- CORRECT
Explanation: JCAHO released new and revised requirements for pain assessment and management including offering nonpharmacologic pain management options. (See Table 1)
4. Your multidisciplinary QI team decides to develop a project to reduce respiratory depression in patients receiving opioids by monitoring for sedation with the Pasero Opioid Induced Sedation Scale. Principles for successful QI interventions include:
a. Complex tasks
b. Make the intervention a default action ---- CORRECT
c. Avoid EMR prompts
d. Competing with other hospital priorities
Explanation: Principles for successful QI interventions include keeping tasks simple, ensuring the intervention does not compete with other priorities, making the intervention the default action, installing prompts in the EMR, and standardizing the intervention into the work flow.
Quality improvement is essential
Quality improvement is essential
Case
A 67-year-old opioid-naive male with a history of obstructive sleep apnea and chronic kidney disease became unresponsive 2 days after hip replacement. Physical exam revealed a respiratory rate of 6 breaths/minute and oxygen saturation of 82%. He had received 6 doses of 6-mg IV morphine within the past 7 hours. How can I improve opioid safety at my hospital?
Background
Opioids are the most commonly prescribed class of medication in the hospital and the second–most common class causing adverse drug events (ADEs), the most serious being respiratory depression and death.1
Opioid ADEs and side effects can cause prolonged length of stay and patient suffering. These vary from potentially life-threatening events such as serotonin syndrome and adrenal insufficiency to more manageable problems still requiring intervention such as constipation, urinary retention, cognitive impairment, nausea, and vomiting. Treatment of side effects can lead to complications, including side effects from antiemetics and urinary tract infections from catheters.
A 4-year review found 700 deaths in the United States attributed to patient-controlled analgesia (PCA) use.2 Another study revealed that one out of every 200 patients has postoperative respiratory depression attributable to opioids.3
It is estimated that 2 million patients a year become chronic opioid users. Inpatient opioid prescribing contributes to this problem;4 for instance, 5.9% of patients after minor surgery and 6.5% after major surgery become chronic opioid users if discharged with an opioid.5 Calcaterra et al. found 25% of opioid-naive medical patients received an opioid at discharge from a medical service.6 Those patients had an odds ratio of 4.90 for becoming a chronic opioid user that year.6
Most hospitals have incomplete or outdated policies and procedures for safe opioid prescribing and administration.7 The Joint Commission on Accreditation of Healthcare Organizations has specific pain standards for pain assessment, pain management, and safe opioid prescribing for hospitals. Additions and revisions were developed to go into effect Jan. 1, 2018. (Table 1)8
Quality improvement
Quality improvement (QI) is an effective way to improve opioid safety. The Society of Hospital Medicine has developed a QI guide, “Reducing adverse drug events related to opioids” or “RADEO,” to increase safety and decrease serious ADEs attributable to opioids.7
The steps in the RADEO program are as follows:
1. Assemble your team
It is critical to identify and include stakeholders from multiple disciplines on your project team. This team will be essential to develop a practical project, identify barriers, create solutions, and gain buy-in from medical staff and administrative leadership.
Front-line staff will have invaluable insight and need to be team members. The majority of interventions are performed by nurses; therefore, nursing leadership and input is essential. Representatives from pharmacy, information technology, and the quality department will be extremely valuable team members to guide you through the correct approach to a successful QI project.
A project champion can keep a high profile for the project and build and lead the team.
Identify an “executive sponsor” such as your CEO, CMO, or CNO. This leader will focus the team on issues critical to your organization, such as accreditation from governmental agencies, and help you obtain dedicated time and resources. Aligning with hospital goals will make your project a priority.
Coordinate with existing opioid initiative teams in the hospital to integrate efforts. This will keep the work of different departments aligned and allow you to learn from pitfalls and barriers the other groups experienced.
Patients/families contribute a unique and valuable perspective. Consider including a member of your hospital’s patient and family advisory council on your team.
2. Perform a needs assessment
Determine the current state of your hospital including: opioid prescribers; opioids prescribed; areas with increased ADEs or naloxone use; formulary restrictions, policies, or guidelines for monitoring, prescribing, and administering opioids; order sets; safety alerts; provider education; or patient education.
Your risk management or quality department may be able to a share root cause analysis of ADEs related to opioids. Joint Commission and CMS recommendations as well as other regulatory requirements may shape your QI interventions.8
Most importantly, review all of the concerns and priorities of your diverse team, which will identify areas of most pressing need and provide insight regarding needs you have not considered.
3. Develop SMART aims
Frame your QI project into a series of well-defined, clear SMART aims.9
Specific: Who will carry out the intervention? Who is your target population? What will be improved? In what way will it be improved?
Measurable: What will be measured? How it will be measured? Does it measure the outcome that needs to be improved?
Attainable/achievable: Ensure you have the resources and time to achieve the aim.
Relevant: Ensure each aim moves your team toward the project vision.
Timely: The aim should be achieved within a realistic time frame, long enough to meet goals but not so long that interest is lost.
An example of a poor aim is “Clinicians will improve knowledge of opioids.”
An example of a SMART aim is “75% of inpatient opioid prescribers including MDs, NPs, and PAs will complete and pass the opioid safety training module by July 1, 2018.”
4. Choose metrics
Outcome metrics measure if the intervention has improved patient safety, for example, measuring a decrease in opioid related ADEs. Structure metrics are the physical and organizational properties of the health care delivery setting, for example, the presence of EMR opioid safety. Processes are communication and practice patterns, for example, adherence to policy by examining nursing documentation of pain assessments.
5. Development and implementation 7,10
Use PDSA for development and implementation of the QI intervention.
Plan: Determine the intervention group such as a specific unit, number of units, and if there will be a control group. Determine who will collect the data, if baseline data will be collected, and who will analyze the data. Your information technology department will be essential to determine if the data can be collected via the EMR and how. Input from your multidisciplinary team is critical to anticipate unintended consequences, such as limiting opioid prescribing at discharge inadvertently increasing emergency department visits for pain control.
Do: Start as a small pilot study to make it as easy as possible to implement the project and begin data collection. A small-scale intervention will be more manageable and allow rapid responses to unanticipated problems.
Study: Analyze the data early to determine if the intervention is improving opioid safety and if alterations are needed. At this stage both process metrics (are processes being followed?) and outcome metrics (is the process leading to a desired outcome?) are important.
Act: Based on data analysis, refine the intervention as necessary. You may have to repeat cycles of PDSA to develop the final intervention. Then implement the final intervention to the entire hospital.
The Joint Commission recommendations for opioid QI
The Joint Commission recommends7 the following to reduce opioid-related respiratory depression:
- Effective processes which include processes such as tracking and analyzing ADEs related to opioids.
- Safe technology which includes using technology such as the EMR to monitor opioid prescribing of greater than 90 morphine milligram equivalents.
- Effective tools which include valid and reliable tools to improve opioid safety, such as the Pasero Opioid Induced Sedation Scale (POSS).
- Opioid education and training which includes provider and patient education such as patient discharge education.
Education
Develop educational interventions to ensure medical and hospital staff are aware of new processes, with an emphasis on “why.”7 If possible, use web-based programs that provide CME. Improve education interventions by using multiple live, interactive, and multimedia exposures.
Principles for successful interventions
- Keep it simple for the end user. This makes it more likely that the intervention is performed. Minimize complex tasks such as calculations and if possible design automated processes.
- Build your process into current work flow. If possible simplify or streamline work flow. A project that competes with staff’s other tasks and competing priorities is doomed to fail. It is critical to have input from those performing the intervention to develop a user-friendly and less disruptive intervention.
- Design reliability into the process. Make your intervention the default action. Build prompts into the work flow. Standardize the intervention into the work flow. And, consider having the intervention at scheduled intervals.7
Opioid safety QI interventions
Interventions for improving opioid safety and reducing opioid -elated ADEs may be generalized into areas including risk screening and assessment, pain treatment, opioid administration, pain assessment, post opioid administration monitoring, and patient and provider education (Table 2).7
Back to the case
The patient received naloxone. His respiratory rate and oxygen saturation returned to normal. His dose of morphine was reduced and his interval increased. A multimodal approach was implemented including low-dose scheduled acetaminophen. There were no further ADEs while maintaining good pain control.
A multidisciplinary opioid task force was created and performed a hospital-wide review of opioid ADEs. Opportunities for improvement were identified and new procedures implemented. The Pasero opioid sedation scale (POSS) was added to the nursing work flow to monitor patients who received an opioid for sedation. An algorithm was developed for opioid-naive patients including guidance for opioid selection, dosing, and frequency. Multiple pain control modalities were added to pain control order sets. Annual training was developed for opioid prescribers, pharmacists, and nurses regarding safe and responsible use of opioids.
And, lastly, in-hospital and discharge patient education was developed for patients and families to be well-informed of opioid risk and benefit including how to identify and respond to ADEs.
Bottom line
Quality improvement is an effective method to improve patient safety and reduce serious adverse events related to opioids in the hospital setting.
Dr. Holmes-Maybank, is codirector, Fundamentals of Patient Care Year 1 and Internship 101, and chair, Clinical Competency Examination Committee, division of hospital medicine, Medical University of South Carolina. Dr. Frederickson is medical director, Hospital Medicine and Palliative Care at CHI Health, Omaha, Neb., and assistant professor at Creighton University School of Medicine, Omaha.
References
1. Davies EC et al. Adverse drug reactions in hospital inpatients: a prospective analysis of 3695 patient-episodes. PLoS One. 2009;4(2):e4439. doi: 10.1371/journal.pone.0004439. Epub 2009 Feb 11.
2. Association for the Advancement of Medical Instrumentation. Infusing patients safely: Priority issues from the AAMI/FDA Infusion Device Summit. 2010;1-39.
3. Dahan Aet al. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology. 2010;112:226-238. doi: 10.1097/ALN.0b013e3181c38c25.
4. Estimate about opioid users.
5. Brummett CM et al. New persistent opioid use after minor and major surgical procedures in U.S. adults. JAMA Surg. 2017;152(6):e170504. doi: 10.1001/jamasurg.2017.0504.
6. Calcaterra SL et al. Opioid prescribing at hospital discharge contributes to chronic opioid use. J Gen Intern Med. 2016;31(5):478-85. doi: 10.1007/s11606-015-3539-4.
7. Frederickson TW et al. Reducing adverse drug events related to opioids implementation guide. Philadelphia: Society of Hospital Medicine, 2015.
8. Joint Commission enhances pain assessment and management requirements for accredited hospitals. The Joint Commission Perspectives. 2017;37(7):2-4.
9. Minnesota Department of Health. SMART objectives.
10. Agency for Healthcare Research and Quality. Health Literacy Universal Precautions Toolkit, 2nd Edition.
Plan-Do-Study-Act (PDSA) Directions and Examples.
Recommended reading
Dowell D et al. CDC guideline for prescribing opioids for chronic pain – United States, 2016. Recommendations and Reports. 2016 Mar 18;65(1):1-49.
Frederickson TW et al. Using the 2018 guidelines from the Joint Commission to kickstart your hospital’s program to reduce opioid-induced ventilatory impairment. Anesthesia Patient Safety Foundation Newsletter. 2018;33(1):1-32.
Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: a systematic review of existing guidelines. J Hosp Med. 2018 Apr;13(4):256-62. doi: 10.12788/jhm.2979.
Herzig SJ et al. Improving the safety of opioid use for acute noncancer pain in hospitalized adults: a consensus statement from the society of hospital medicine. J Hosp Med. 2018 Apr;13(4):263-71. doi: 10.12788/jhm.2980.
Joint Commission enhances pain assessment and management requirements for accredited hospitals. The Joint Commission Perspectives. 2017;37(7):2-4.
Key points
- Quality improvement is required by the Joint Commission and is an effective method to improve opioid safety in the hospital setting.
- It is critical to the success of a QI project to develop a multidisciplinary team.
- Input from frontline users of the intervention is essential to produce an effective intervention.
- Executive sponsorship and aligning the goals of your QI project with those of your institution will prioritize your project and increase resource availability.
Quiz
1. Based on a needs assessment at your hospital you assemble a multidisciplinary team to improve education for patients discharged on opioids. You recognize the importance of multidisciplinary input to develop a successful intervention for discharge education. Essential team members include all EXCEPT the following:
a. Executive sponsor
b. Patient representative
c. Nursing
d. Medical student representative ---- CORRECT
Explanation: The assembly of a multidisciplinary team is critical to the success of a QI intervention. An executive sponsor may assist you in aligning your goals with that of the hospital and provide resources for its development and implementation. Patient input would help determine how to best deliver the education. Lastly, the individuals carrying out the intervention are essential to develop an intervention that will easy for the end user and increase the likelihood of being used, in this case nursing.
2. You performed a review of naloxone use at your hospital and find that it is greater than similar hospitals. Prior to starting the QI project, you review SHM’s “Reducing adverse events related to opioids implementation guide” and learn that keys to success for QI implementation include:
a. A team of primarily hospitalists
b. Implementing the intervention hospital wide
c. Information technology input for data collection ---- CORRECT
d. No team – it is more effective to work alone
Explanation: Successful implementation of a QI project involves a multidisciplinary team. It is critical to involve information technology early in the development of the project to determine how and if the data can be collected from the EMR. It is best to pilot the intervention on one or two units to make alterations as needed rapidly and perfect the final intervention prior to rolling it out to the entire hospital.
3. You have assembled a multidisciplinary team to respond to the newly revised JCAHO pain standards. An example of a requirement from the new and revised JCAHO standards for pain assessment and management includes:
a. Programs for physician wellness
b. No opioids for chronic pain
c. No more than 5 days of opioids for acute pain
d. Nonpharmacologic pain management options ---- CORRECT
Explanation: JCAHO released new and revised requirements for pain assessment and management including offering nonpharmacologic pain management options. (See Table 1)
4. Your multidisciplinary QI team decides to develop a project to reduce respiratory depression in patients receiving opioids by monitoring for sedation with the Pasero Opioid Induced Sedation Scale. Principles for successful QI interventions include:
a. Complex tasks
b. Make the intervention a default action ---- CORRECT
c. Avoid EMR prompts
d. Competing with other hospital priorities
Explanation: Principles for successful QI interventions include keeping tasks simple, ensuring the intervention does not compete with other priorities, making the intervention the default action, installing prompts in the EMR, and standardizing the intervention into the work flow.
Case
A 67-year-old opioid-naive male with a history of obstructive sleep apnea and chronic kidney disease became unresponsive 2 days after hip replacement. Physical exam revealed a respiratory rate of 6 breaths/minute and oxygen saturation of 82%. He had received 6 doses of 6-mg IV morphine within the past 7 hours. How can I improve opioid safety at my hospital?
Background
Opioids are the most commonly prescribed class of medication in the hospital and the second–most common class causing adverse drug events (ADEs), the most serious being respiratory depression and death.1
Opioid ADEs and side effects can cause prolonged length of stay and patient suffering. These vary from potentially life-threatening events such as serotonin syndrome and adrenal insufficiency to more manageable problems still requiring intervention such as constipation, urinary retention, cognitive impairment, nausea, and vomiting. Treatment of side effects can lead to complications, including side effects from antiemetics and urinary tract infections from catheters.
A 4-year review found 700 deaths in the United States attributed to patient-controlled analgesia (PCA) use.2 Another study revealed that one out of every 200 patients has postoperative respiratory depression attributable to opioids.3
It is estimated that 2 million patients a year become chronic opioid users. Inpatient opioid prescribing contributes to this problem;4 for instance, 5.9% of patients after minor surgery and 6.5% after major surgery become chronic opioid users if discharged with an opioid.5 Calcaterra et al. found 25% of opioid-naive medical patients received an opioid at discharge from a medical service.6 Those patients had an odds ratio of 4.90 for becoming a chronic opioid user that year.6
Most hospitals have incomplete or outdated policies and procedures for safe opioid prescribing and administration.7 The Joint Commission on Accreditation of Healthcare Organizations has specific pain standards for pain assessment, pain management, and safe opioid prescribing for hospitals. Additions and revisions were developed to go into effect Jan. 1, 2018. (Table 1)8
Quality improvement
Quality improvement (QI) is an effective way to improve opioid safety. The Society of Hospital Medicine has developed a QI guide, “Reducing adverse drug events related to opioids” or “RADEO,” to increase safety and decrease serious ADEs attributable to opioids.7
The steps in the RADEO program are as follows:
1. Assemble your team
It is critical to identify and include stakeholders from multiple disciplines on your project team. This team will be essential to develop a practical project, identify barriers, create solutions, and gain buy-in from medical staff and administrative leadership.
Front-line staff will have invaluable insight and need to be team members. The majority of interventions are performed by nurses; therefore, nursing leadership and input is essential. Representatives from pharmacy, information technology, and the quality department will be extremely valuable team members to guide you through the correct approach to a successful QI project.
A project champion can keep a high profile for the project and build and lead the team.
Identify an “executive sponsor” such as your CEO, CMO, or CNO. This leader will focus the team on issues critical to your organization, such as accreditation from governmental agencies, and help you obtain dedicated time and resources. Aligning with hospital goals will make your project a priority.
Coordinate with existing opioid initiative teams in the hospital to integrate efforts. This will keep the work of different departments aligned and allow you to learn from pitfalls and barriers the other groups experienced.
Patients/families contribute a unique and valuable perspective. Consider including a member of your hospital’s patient and family advisory council on your team.
2. Perform a needs assessment
Determine the current state of your hospital including: opioid prescribers; opioids prescribed; areas with increased ADEs or naloxone use; formulary restrictions, policies, or guidelines for monitoring, prescribing, and administering opioids; order sets; safety alerts; provider education; or patient education.
Your risk management or quality department may be able to a share root cause analysis of ADEs related to opioids. Joint Commission and CMS recommendations as well as other regulatory requirements may shape your QI interventions.8
Most importantly, review all of the concerns and priorities of your diverse team, which will identify areas of most pressing need and provide insight regarding needs you have not considered.
3. Develop SMART aims
Frame your QI project into a series of well-defined, clear SMART aims.9
Specific: Who will carry out the intervention? Who is your target population? What will be improved? In what way will it be improved?
Measurable: What will be measured? How it will be measured? Does it measure the outcome that needs to be improved?
Attainable/achievable: Ensure you have the resources and time to achieve the aim.
Relevant: Ensure each aim moves your team toward the project vision.
Timely: The aim should be achieved within a realistic time frame, long enough to meet goals but not so long that interest is lost.
An example of a poor aim is “Clinicians will improve knowledge of opioids.”
An example of a SMART aim is “75% of inpatient opioid prescribers including MDs, NPs, and PAs will complete and pass the opioid safety training module by July 1, 2018.”
4. Choose metrics
Outcome metrics measure if the intervention has improved patient safety, for example, measuring a decrease in opioid related ADEs. Structure metrics are the physical and organizational properties of the health care delivery setting, for example, the presence of EMR opioid safety. Processes are communication and practice patterns, for example, adherence to policy by examining nursing documentation of pain assessments.
5. Development and implementation 7,10
Use PDSA for development and implementation of the QI intervention.
Plan: Determine the intervention group such as a specific unit, number of units, and if there will be a control group. Determine who will collect the data, if baseline data will be collected, and who will analyze the data. Your information technology department will be essential to determine if the data can be collected via the EMR and how. Input from your multidisciplinary team is critical to anticipate unintended consequences, such as limiting opioid prescribing at discharge inadvertently increasing emergency department visits for pain control.
Do: Start as a small pilot study to make it as easy as possible to implement the project and begin data collection. A small-scale intervention will be more manageable and allow rapid responses to unanticipated problems.
Study: Analyze the data early to determine if the intervention is improving opioid safety and if alterations are needed. At this stage both process metrics (are processes being followed?) and outcome metrics (is the process leading to a desired outcome?) are important.
Act: Based on data analysis, refine the intervention as necessary. You may have to repeat cycles of PDSA to develop the final intervention. Then implement the final intervention to the entire hospital.
The Joint Commission recommendations for opioid QI
The Joint Commission recommends7 the following to reduce opioid-related respiratory depression:
- Effective processes which include processes such as tracking and analyzing ADEs related to opioids.
- Safe technology which includes using technology such as the EMR to monitor opioid prescribing of greater than 90 morphine milligram equivalents.
- Effective tools which include valid and reliable tools to improve opioid safety, such as the Pasero Opioid Induced Sedation Scale (POSS).
- Opioid education and training which includes provider and patient education such as patient discharge education.
Education
Develop educational interventions to ensure medical and hospital staff are aware of new processes, with an emphasis on “why.”7 If possible, use web-based programs that provide CME. Improve education interventions by using multiple live, interactive, and multimedia exposures.
Principles for successful interventions
- Keep it simple for the end user. This makes it more likely that the intervention is performed. Minimize complex tasks such as calculations and if possible design automated processes.
- Build your process into current work flow. If possible simplify or streamline work flow. A project that competes with staff’s other tasks and competing priorities is doomed to fail. It is critical to have input from those performing the intervention to develop a user-friendly and less disruptive intervention.
- Design reliability into the process. Make your intervention the default action. Build prompts into the work flow. Standardize the intervention into the work flow. And, consider having the intervention at scheduled intervals.7
Opioid safety QI interventions
Interventions for improving opioid safety and reducing opioid -elated ADEs may be generalized into areas including risk screening and assessment, pain treatment, opioid administration, pain assessment, post opioid administration monitoring, and patient and provider education (Table 2).7
Back to the case
The patient received naloxone. His respiratory rate and oxygen saturation returned to normal. His dose of morphine was reduced and his interval increased. A multimodal approach was implemented including low-dose scheduled acetaminophen. There were no further ADEs while maintaining good pain control.
A multidisciplinary opioid task force was created and performed a hospital-wide review of opioid ADEs. Opportunities for improvement were identified and new procedures implemented. The Pasero opioid sedation scale (POSS) was added to the nursing work flow to monitor patients who received an opioid for sedation. An algorithm was developed for opioid-naive patients including guidance for opioid selection, dosing, and frequency. Multiple pain control modalities were added to pain control order sets. Annual training was developed for opioid prescribers, pharmacists, and nurses regarding safe and responsible use of opioids.
And, lastly, in-hospital and discharge patient education was developed for patients and families to be well-informed of opioid risk and benefit including how to identify and respond to ADEs.
Bottom line
Quality improvement is an effective method to improve patient safety and reduce serious adverse events related to opioids in the hospital setting.
Dr. Holmes-Maybank, is codirector, Fundamentals of Patient Care Year 1 and Internship 101, and chair, Clinical Competency Examination Committee, division of hospital medicine, Medical University of South Carolina. Dr. Frederickson is medical director, Hospital Medicine and Palliative Care at CHI Health, Omaha, Neb., and assistant professor at Creighton University School of Medicine, Omaha.
References
1. Davies EC et al. Adverse drug reactions in hospital inpatients: a prospective analysis of 3695 patient-episodes. PLoS One. 2009;4(2):e4439. doi: 10.1371/journal.pone.0004439. Epub 2009 Feb 11.
2. Association for the Advancement of Medical Instrumentation. Infusing patients safely: Priority issues from the AAMI/FDA Infusion Device Summit. 2010;1-39.
3. Dahan Aet al. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology. 2010;112:226-238. doi: 10.1097/ALN.0b013e3181c38c25.
4. Estimate about opioid users.
5. Brummett CM et al. New persistent opioid use after minor and major surgical procedures in U.S. adults. JAMA Surg. 2017;152(6):e170504. doi: 10.1001/jamasurg.2017.0504.
6. Calcaterra SL et al. Opioid prescribing at hospital discharge contributes to chronic opioid use. J Gen Intern Med. 2016;31(5):478-85. doi: 10.1007/s11606-015-3539-4.
7. Frederickson TW et al. Reducing adverse drug events related to opioids implementation guide. Philadelphia: Society of Hospital Medicine, 2015.
8. Joint Commission enhances pain assessment and management requirements for accredited hospitals. The Joint Commission Perspectives. 2017;37(7):2-4.
9. Minnesota Department of Health. SMART objectives.
10. Agency for Healthcare Research and Quality. Health Literacy Universal Precautions Toolkit, 2nd Edition.
Plan-Do-Study-Act (PDSA) Directions and Examples.
Recommended reading
Dowell D et al. CDC guideline for prescribing opioids for chronic pain – United States, 2016. Recommendations and Reports. 2016 Mar 18;65(1):1-49.
Frederickson TW et al. Using the 2018 guidelines from the Joint Commission to kickstart your hospital’s program to reduce opioid-induced ventilatory impairment. Anesthesia Patient Safety Foundation Newsletter. 2018;33(1):1-32.
Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: a systematic review of existing guidelines. J Hosp Med. 2018 Apr;13(4):256-62. doi: 10.12788/jhm.2979.
Herzig SJ et al. Improving the safety of opioid use for acute noncancer pain in hospitalized adults: a consensus statement from the society of hospital medicine. J Hosp Med. 2018 Apr;13(4):263-71. doi: 10.12788/jhm.2980.
Joint Commission enhances pain assessment and management requirements for accredited hospitals. The Joint Commission Perspectives. 2017;37(7):2-4.
Key points
- Quality improvement is required by the Joint Commission and is an effective method to improve opioid safety in the hospital setting.
- It is critical to the success of a QI project to develop a multidisciplinary team.
- Input from frontline users of the intervention is essential to produce an effective intervention.
- Executive sponsorship and aligning the goals of your QI project with those of your institution will prioritize your project and increase resource availability.
Quiz
1. Based on a needs assessment at your hospital you assemble a multidisciplinary team to improve education for patients discharged on opioids. You recognize the importance of multidisciplinary input to develop a successful intervention for discharge education. Essential team members include all EXCEPT the following:
a. Executive sponsor
b. Patient representative
c. Nursing
d. Medical student representative ---- CORRECT
Explanation: The assembly of a multidisciplinary team is critical to the success of a QI intervention. An executive sponsor may assist you in aligning your goals with that of the hospital and provide resources for its development and implementation. Patient input would help determine how to best deliver the education. Lastly, the individuals carrying out the intervention are essential to develop an intervention that will easy for the end user and increase the likelihood of being used, in this case nursing.
2. You performed a review of naloxone use at your hospital and find that it is greater than similar hospitals. Prior to starting the QI project, you review SHM’s “Reducing adverse events related to opioids implementation guide” and learn that keys to success for QI implementation include:
a. A team of primarily hospitalists
b. Implementing the intervention hospital wide
c. Information technology input for data collection ---- CORRECT
d. No team – it is more effective to work alone
Explanation: Successful implementation of a QI project involves a multidisciplinary team. It is critical to involve information technology early in the development of the project to determine how and if the data can be collected from the EMR. It is best to pilot the intervention on one or two units to make alterations as needed rapidly and perfect the final intervention prior to rolling it out to the entire hospital.
3. You have assembled a multidisciplinary team to respond to the newly revised JCAHO pain standards. An example of a requirement from the new and revised JCAHO standards for pain assessment and management includes:
a. Programs for physician wellness
b. No opioids for chronic pain
c. No more than 5 days of opioids for acute pain
d. Nonpharmacologic pain management options ---- CORRECT
Explanation: JCAHO released new and revised requirements for pain assessment and management including offering nonpharmacologic pain management options. (See Table 1)
4. Your multidisciplinary QI team decides to develop a project to reduce respiratory depression in patients receiving opioids by monitoring for sedation with the Pasero Opioid Induced Sedation Scale. Principles for successful QI interventions include:
a. Complex tasks
b. Make the intervention a default action ---- CORRECT
c. Avoid EMR prompts
d. Competing with other hospital priorities
Explanation: Principles for successful QI interventions include keeping tasks simple, ensuring the intervention does not compete with other priorities, making the intervention the default action, installing prompts in the EMR, and standardizing the intervention into the work flow.