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Five pitfalls in optimizing medical management of HFrEF
SNOWMASS, COLO. – Many of the abundant missed opportunities to optimize pharmacotherapy for heart failure with reduced ejection fraction revolve around not getting fully on board with the guideline-directed medical therapy shown to be highly effective at improving clinical outcomes, Akshay S. Desai, MD, asserted at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“If you take nothing else away from this talk, is really quite profound,” declared Dr. Desai, director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, and a cardiologist at Harvard Medical School, Boston.
He highlighted five common traps or pitfalls for physicians with regard to medical therapy of patients with heart failure with reduced ejection fraction (HFrEF):
Underutilization of guideline-directed medical therapy
The current ACC/American Heart Association/Heart Failure Society of America guidelines on heart failure management (Circulation. 2017 Aug 8;136[6]:e137-61) reflect 20 years of impressive progress in improving heart failure outcomes through the use of increasingly effective guideline-directed medical therapy (GDMT). The magnitude of this improvement was nicely captured in a meta-analysis of 57 randomized controlled trials published during 1987-2015. The meta-analysis showed that, although ACE inhibitor therapy alone had no significant impact on all-cause mortality compared to placebo in patients with HFrEF, the sequential addition of guideline-directed drugs conferred stepwise improvements in survival. This approach culminated in a 56% reduction in all-cause mortality with the combination of an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA), compared with placebo, and a 63% reduction with an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and MRA (Circ Heart Fail. 2017 Jan;10(1). pii: e003529).
Moreover, the benefits of contemporary GDMT extend beyond reductions in all-cause mortality, death due to heart failure, and heart failure–related hospitalizations into areas where one wouldn’t necessarily have expected to see much benefit. For example, an analysis of data on more than 40,000 HFrEF patients in 12 clinical trials showed a sharp decline in the rate of sudden death over the years as new agents were incorporated into GDMT. The cumulative incidence of sudden death within 90 days after randomization plunged from 2.4% in the earliest trial to 1.0% in the most recent one (N Engl J Med. 2017 Jul 6;377[1]:41-51).
“We’re at the point where we now question whether routine use of implantable cardioverter-defibrillators in primary prevention patients with nonischemic heart failure is really worthwhile on the backdrop of effective medical therapy,” Dr. Desai observed.
But there’s a problem: “We don’t do a great job with GDMT, even with this incredible evidence base that we have,” the cardiologist said.
He cited a report from the CHAMP-HF registry that scrutinized the use of GDMT in more than 3,500 ambulatory HFrEF patients in 150 U.S. primary care and cardiology practices. It found that 67% of patients deemed eligible for an MRA weren’t on one. Neither were 33% with no contraindications to beta-blocker therapy and 27% who were eligible for an ACE inhibitor, angiotensin receptor blocker (ARB), or ARNI (J Am Coll Cardiol. 2018 Jul 24;72[4]:351-66).
“This highlights a huge opportunity for further guideline-directed optimization of therapy,” he said.
Underdosing of GDMT
The CHAMP-HF registry contained further disappointing news regarding the state of treatment of patients with HFrEF in ambulatory settings: Among those patients who were on GDMT, very few were receiving the recommended target doses of the medications as established in major clinical trials and specified in the guidelines. Only 14% of patients on an ARNI were on the target dose, as were 28% on a beta-blocker, and 17% of those on an ACE inhibitor or ARB. And among patients who were eligible for all classes of GDMT, just 1% were simultaneously on the target doses of an MRA, beta-blocker, and ARNI, ACE inhibitor, or ARB. This despite solid evidence that, although some benefit is derived from initiating these medications, incremental benefit comes from dose titration.
“Even for those of us who feel like we do this quite well, if we examine our practices systematically – and we’ve done this in our own practices at Brigham and Women’s – you see that a lot of eligible patients aren’t on optimal therapy. And you might argue that many of them have contraindications, but even when you do a deep dive into the literature or the electronic medical record and ask the question – Why is this patient with normal renal function and normal potassium with class II HFrEF not on an MRA? – sometimes it’s hard to establish why that’s the case,” said Dr. Desai.
Interrupting GDMT during hospitalizations
This is common practice. But in fact, continuation of GDMT is generally well tolerated in the setting of acute decompensated heart failure in the absence of severe hypotension and cardiogenic shock. Moreover, in-hospital discontinuation or dose reduction is associated with increased risks of readmission and mortality.
And in treatment-naive HFrEF patients, what better place to introduce a medication and assess its tolerability than the hospital? Plus, medications prescribed at discharge are more likely to be continued in the outpatient setting, he noted.
Being seduced by the illusion of stability
The guidelines state that patients with NYHA class II or III HFrEF who tolerate an ACE inhibitor or ARB should be transitioned to an ARNI to further reduce their risk of morbidity and mortality. Yet many physicians wait to make the switch until clinical decompensation occurs. That’s a mistake, as was demonstrated in the landmark PARADIGM-HF trial. Twenty percent of study participants without a prior hospitalization for heart failure experienced cardiovascular death or heart failure hospitalization during the follow-up period. Patients who were clinically stable as defined by no prior heart failure hospitalization or none within 3 months prior to enrollment were as likely to benefit from ARNI therapy with sacubitril/valsartan (Entresto) as were those with a recent decompensation (JACC Heart Fail. 2016 Oct;4[10]:816-22). “A key message is that stability is an illusion in patients with symptomatic heart failure,”said Dr. Desai. “In PARADIGM-HF, the first event for about half of patients was not heralded by a worsening of symptoms or a heart failure hospitalization, it was an abrupt death at home. This may mean that a missed opportunity to optimize treatment may not come back to you down the road, so waiting until patients get worse in order to optimize their therapy may not be the best strategy.”
Inadequate laboratory monitoring
The MRAs, spironolactone and eplerenone (Inspra), are the GDMT drugs for which laboratory surveillance takes on the greatest importance because of their potential to induce hyperkalemia. The guidelines are clear that a potassium level and measurement of renal function should be obtained within a week of initiating therapy with an MRA, again at 4 weeks, and periodically thereafter.
“In general, this is done in clinical practice almost never,” Dr. Desai stressed.
These agents should be avoided in patients with prior hyperkalemia or advanced chronic kidney disease, and used with care in groups known to be at increased risk for hyperkalemia, including the elderly and patients with diabetes.
He considers spironolactone equivalent to eplerenone so long as the dosing is adequate. He generally reserves eplerenone for patients with poorly tolerated antiandrogenic effects on spironolactone.
Dr. Desai reported serving as a paid consultant to more than half a dozen pharmaceutical or medical device companies.
SNOWMASS, COLO. – Many of the abundant missed opportunities to optimize pharmacotherapy for heart failure with reduced ejection fraction revolve around not getting fully on board with the guideline-directed medical therapy shown to be highly effective at improving clinical outcomes, Akshay S. Desai, MD, asserted at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“If you take nothing else away from this talk, is really quite profound,” declared Dr. Desai, director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, and a cardiologist at Harvard Medical School, Boston.
He highlighted five common traps or pitfalls for physicians with regard to medical therapy of patients with heart failure with reduced ejection fraction (HFrEF):
Underutilization of guideline-directed medical therapy
The current ACC/American Heart Association/Heart Failure Society of America guidelines on heart failure management (Circulation. 2017 Aug 8;136[6]:e137-61) reflect 20 years of impressive progress in improving heart failure outcomes through the use of increasingly effective guideline-directed medical therapy (GDMT). The magnitude of this improvement was nicely captured in a meta-analysis of 57 randomized controlled trials published during 1987-2015. The meta-analysis showed that, although ACE inhibitor therapy alone had no significant impact on all-cause mortality compared to placebo in patients with HFrEF, the sequential addition of guideline-directed drugs conferred stepwise improvements in survival. This approach culminated in a 56% reduction in all-cause mortality with the combination of an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA), compared with placebo, and a 63% reduction with an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and MRA (Circ Heart Fail. 2017 Jan;10(1). pii: e003529).
Moreover, the benefits of contemporary GDMT extend beyond reductions in all-cause mortality, death due to heart failure, and heart failure–related hospitalizations into areas where one wouldn’t necessarily have expected to see much benefit. For example, an analysis of data on more than 40,000 HFrEF patients in 12 clinical trials showed a sharp decline in the rate of sudden death over the years as new agents were incorporated into GDMT. The cumulative incidence of sudden death within 90 days after randomization plunged from 2.4% in the earliest trial to 1.0% in the most recent one (N Engl J Med. 2017 Jul 6;377[1]:41-51).
“We’re at the point where we now question whether routine use of implantable cardioverter-defibrillators in primary prevention patients with nonischemic heart failure is really worthwhile on the backdrop of effective medical therapy,” Dr. Desai observed.
But there’s a problem: “We don’t do a great job with GDMT, even with this incredible evidence base that we have,” the cardiologist said.
He cited a report from the CHAMP-HF registry that scrutinized the use of GDMT in more than 3,500 ambulatory HFrEF patients in 150 U.S. primary care and cardiology practices. It found that 67% of patients deemed eligible for an MRA weren’t on one. Neither were 33% with no contraindications to beta-blocker therapy and 27% who were eligible for an ACE inhibitor, angiotensin receptor blocker (ARB), or ARNI (J Am Coll Cardiol. 2018 Jul 24;72[4]:351-66).
“This highlights a huge opportunity for further guideline-directed optimization of therapy,” he said.
Underdosing of GDMT
The CHAMP-HF registry contained further disappointing news regarding the state of treatment of patients with HFrEF in ambulatory settings: Among those patients who were on GDMT, very few were receiving the recommended target doses of the medications as established in major clinical trials and specified in the guidelines. Only 14% of patients on an ARNI were on the target dose, as were 28% on a beta-blocker, and 17% of those on an ACE inhibitor or ARB. And among patients who were eligible for all classes of GDMT, just 1% were simultaneously on the target doses of an MRA, beta-blocker, and ARNI, ACE inhibitor, or ARB. This despite solid evidence that, although some benefit is derived from initiating these medications, incremental benefit comes from dose titration.
“Even for those of us who feel like we do this quite well, if we examine our practices systematically – and we’ve done this in our own practices at Brigham and Women’s – you see that a lot of eligible patients aren’t on optimal therapy. And you might argue that many of them have contraindications, but even when you do a deep dive into the literature or the electronic medical record and ask the question – Why is this patient with normal renal function and normal potassium with class II HFrEF not on an MRA? – sometimes it’s hard to establish why that’s the case,” said Dr. Desai.
Interrupting GDMT during hospitalizations
This is common practice. But in fact, continuation of GDMT is generally well tolerated in the setting of acute decompensated heart failure in the absence of severe hypotension and cardiogenic shock. Moreover, in-hospital discontinuation or dose reduction is associated with increased risks of readmission and mortality.
And in treatment-naive HFrEF patients, what better place to introduce a medication and assess its tolerability than the hospital? Plus, medications prescribed at discharge are more likely to be continued in the outpatient setting, he noted.
Being seduced by the illusion of stability
The guidelines state that patients with NYHA class II or III HFrEF who tolerate an ACE inhibitor or ARB should be transitioned to an ARNI to further reduce their risk of morbidity and mortality. Yet many physicians wait to make the switch until clinical decompensation occurs. That’s a mistake, as was demonstrated in the landmark PARADIGM-HF trial. Twenty percent of study participants without a prior hospitalization for heart failure experienced cardiovascular death or heart failure hospitalization during the follow-up period. Patients who were clinically stable as defined by no prior heart failure hospitalization or none within 3 months prior to enrollment were as likely to benefit from ARNI therapy with sacubitril/valsartan (Entresto) as were those with a recent decompensation (JACC Heart Fail. 2016 Oct;4[10]:816-22). “A key message is that stability is an illusion in patients with symptomatic heart failure,”said Dr. Desai. “In PARADIGM-HF, the first event for about half of patients was not heralded by a worsening of symptoms or a heart failure hospitalization, it was an abrupt death at home. This may mean that a missed opportunity to optimize treatment may not come back to you down the road, so waiting until patients get worse in order to optimize their therapy may not be the best strategy.”
Inadequate laboratory monitoring
The MRAs, spironolactone and eplerenone (Inspra), are the GDMT drugs for which laboratory surveillance takes on the greatest importance because of their potential to induce hyperkalemia. The guidelines are clear that a potassium level and measurement of renal function should be obtained within a week of initiating therapy with an MRA, again at 4 weeks, and periodically thereafter.
“In general, this is done in clinical practice almost never,” Dr. Desai stressed.
These agents should be avoided in patients with prior hyperkalemia or advanced chronic kidney disease, and used with care in groups known to be at increased risk for hyperkalemia, including the elderly and patients with diabetes.
He considers spironolactone equivalent to eplerenone so long as the dosing is adequate. He generally reserves eplerenone for patients with poorly tolerated antiandrogenic effects on spironolactone.
Dr. Desai reported serving as a paid consultant to more than half a dozen pharmaceutical or medical device companies.
SNOWMASS, COLO. – Many of the abundant missed opportunities to optimize pharmacotherapy for heart failure with reduced ejection fraction revolve around not getting fully on board with the guideline-directed medical therapy shown to be highly effective at improving clinical outcomes, Akshay S. Desai, MD, asserted at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“If you take nothing else away from this talk, is really quite profound,” declared Dr. Desai, director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, and a cardiologist at Harvard Medical School, Boston.
He highlighted five common traps or pitfalls for physicians with regard to medical therapy of patients with heart failure with reduced ejection fraction (HFrEF):
Underutilization of guideline-directed medical therapy
The current ACC/American Heart Association/Heart Failure Society of America guidelines on heart failure management (Circulation. 2017 Aug 8;136[6]:e137-61) reflect 20 years of impressive progress in improving heart failure outcomes through the use of increasingly effective guideline-directed medical therapy (GDMT). The magnitude of this improvement was nicely captured in a meta-analysis of 57 randomized controlled trials published during 1987-2015. The meta-analysis showed that, although ACE inhibitor therapy alone had no significant impact on all-cause mortality compared to placebo in patients with HFrEF, the sequential addition of guideline-directed drugs conferred stepwise improvements in survival. This approach culminated in a 56% reduction in all-cause mortality with the combination of an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA), compared with placebo, and a 63% reduction with an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and MRA (Circ Heart Fail. 2017 Jan;10(1). pii: e003529).
Moreover, the benefits of contemporary GDMT extend beyond reductions in all-cause mortality, death due to heart failure, and heart failure–related hospitalizations into areas where one wouldn’t necessarily have expected to see much benefit. For example, an analysis of data on more than 40,000 HFrEF patients in 12 clinical trials showed a sharp decline in the rate of sudden death over the years as new agents were incorporated into GDMT. The cumulative incidence of sudden death within 90 days after randomization plunged from 2.4% in the earliest trial to 1.0% in the most recent one (N Engl J Med. 2017 Jul 6;377[1]:41-51).
“We’re at the point where we now question whether routine use of implantable cardioverter-defibrillators in primary prevention patients with nonischemic heart failure is really worthwhile on the backdrop of effective medical therapy,” Dr. Desai observed.
But there’s a problem: “We don’t do a great job with GDMT, even with this incredible evidence base that we have,” the cardiologist said.
He cited a report from the CHAMP-HF registry that scrutinized the use of GDMT in more than 3,500 ambulatory HFrEF patients in 150 U.S. primary care and cardiology practices. It found that 67% of patients deemed eligible for an MRA weren’t on one. Neither were 33% with no contraindications to beta-blocker therapy and 27% who were eligible for an ACE inhibitor, angiotensin receptor blocker (ARB), or ARNI (J Am Coll Cardiol. 2018 Jul 24;72[4]:351-66).
“This highlights a huge opportunity for further guideline-directed optimization of therapy,” he said.
Underdosing of GDMT
The CHAMP-HF registry contained further disappointing news regarding the state of treatment of patients with HFrEF in ambulatory settings: Among those patients who were on GDMT, very few were receiving the recommended target doses of the medications as established in major clinical trials and specified in the guidelines. Only 14% of patients on an ARNI were on the target dose, as were 28% on a beta-blocker, and 17% of those on an ACE inhibitor or ARB. And among patients who were eligible for all classes of GDMT, just 1% were simultaneously on the target doses of an MRA, beta-blocker, and ARNI, ACE inhibitor, or ARB. This despite solid evidence that, although some benefit is derived from initiating these medications, incremental benefit comes from dose titration.
“Even for those of us who feel like we do this quite well, if we examine our practices systematically – and we’ve done this in our own practices at Brigham and Women’s – you see that a lot of eligible patients aren’t on optimal therapy. And you might argue that many of them have contraindications, but even when you do a deep dive into the literature or the electronic medical record and ask the question – Why is this patient with normal renal function and normal potassium with class II HFrEF not on an MRA? – sometimes it’s hard to establish why that’s the case,” said Dr. Desai.
Interrupting GDMT during hospitalizations
This is common practice. But in fact, continuation of GDMT is generally well tolerated in the setting of acute decompensated heart failure in the absence of severe hypotension and cardiogenic shock. Moreover, in-hospital discontinuation or dose reduction is associated with increased risks of readmission and mortality.
And in treatment-naive HFrEF patients, what better place to introduce a medication and assess its tolerability than the hospital? Plus, medications prescribed at discharge are more likely to be continued in the outpatient setting, he noted.
Being seduced by the illusion of stability
The guidelines state that patients with NYHA class II or III HFrEF who tolerate an ACE inhibitor or ARB should be transitioned to an ARNI to further reduce their risk of morbidity and mortality. Yet many physicians wait to make the switch until clinical decompensation occurs. That’s a mistake, as was demonstrated in the landmark PARADIGM-HF trial. Twenty percent of study participants without a prior hospitalization for heart failure experienced cardiovascular death or heart failure hospitalization during the follow-up period. Patients who were clinically stable as defined by no prior heart failure hospitalization or none within 3 months prior to enrollment were as likely to benefit from ARNI therapy with sacubitril/valsartan (Entresto) as were those with a recent decompensation (JACC Heart Fail. 2016 Oct;4[10]:816-22). “A key message is that stability is an illusion in patients with symptomatic heart failure,”said Dr. Desai. “In PARADIGM-HF, the first event for about half of patients was not heralded by a worsening of symptoms or a heart failure hospitalization, it was an abrupt death at home. This may mean that a missed opportunity to optimize treatment may not come back to you down the road, so waiting until patients get worse in order to optimize their therapy may not be the best strategy.”
Inadequate laboratory monitoring
The MRAs, spironolactone and eplerenone (Inspra), are the GDMT drugs for which laboratory surveillance takes on the greatest importance because of their potential to induce hyperkalemia. The guidelines are clear that a potassium level and measurement of renal function should be obtained within a week of initiating therapy with an MRA, again at 4 weeks, and periodically thereafter.
“In general, this is done in clinical practice almost never,” Dr. Desai stressed.
These agents should be avoided in patients with prior hyperkalemia or advanced chronic kidney disease, and used with care in groups known to be at increased risk for hyperkalemia, including the elderly and patients with diabetes.
He considers spironolactone equivalent to eplerenone so long as the dosing is adequate. He generally reserves eplerenone for patients with poorly tolerated antiandrogenic effects on spironolactone.
Dr. Desai reported serving as a paid consultant to more than half a dozen pharmaceutical or medical device companies.
REPORTING FROM ACC SNOWMASS 2019
Forget what you learned about infective endocarditis
This week in MDedge Cardiocast: Infective endocarditis isn’t what it used to be, there’s a new, lower goal for Americans’ dietary intake of sodium, a drug to treat multiple myeloma also raises heart failure risk, and Big Pharma says it can’t drop drug list prices alone.
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This week in MDedge Cardiocast: Infective endocarditis isn’t what it used to be, there’s a new, lower goal for Americans’ dietary intake of sodium, a drug to treat multiple myeloma also raises heart failure risk, and Big Pharma says it can’t drop drug list prices alone.
Amazon Alexa
Apple Podcasts
Google Podcasts
TuneIn
This week in MDedge Cardiocast: Infective endocarditis isn’t what it used to be, there’s a new, lower goal for Americans’ dietary intake of sodium, a drug to treat multiple myeloma also raises heart failure risk, and Big Pharma says it can’t drop drug list prices alone.
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Apple Podcasts
Google Podcasts
TuneIn
Poor COPD management might increase MI risk in HIV
SEATTLE – Chronic obstructive pulmonary disease is independently associated with an increased risk of myocardial infarction in people with HIV, according to a report at the Conference on Retroviruses and Opportunistic Infections.
Chronic obstructive pulmonary disease (COPD) is known to increase the risk of myocardial infarction (MI) in the general population, but hadn’t been shown until now to do the same in HIV. The study raises the question of whether COPD is being managed adequately in patients with the virus, according to study lead Kristina Crothers, MD, associate professor in the division of pulmonary, critical care & sleep medicine at the University of Washington, Seattle.
The investigators reviewed 25,509 HIV patients in the Center for AIDS Research Network of Integrated Clinical Systems cohort, a large electronic database of HIV-infected people. They defined COPD by diagnostic codes and inhaler prescriptions. MIs were adjudicated by review.
The team identified 423 subjects with moderate to severe COPD, and 698 who had MIs, including 339 type 1 MIs (T1MI) from a ruptured plaque (54%), and 294 (46%) type 2 heart attacks (T2MI) from a supply-demand mismatch due to sepsis or some other problem. In general, T2MIs are far more common in people with HIV.
COPD was associated with a greater than twofold increased risk of MI after adjustment for age, sex, viral load, nadir CD4 count, hypertension, and other confounders. The risk dropped slightly when smoking – both current smoking and pack years – was added to the model (adjusted hazard ratio 1.88, 95% confidence interval, 1.34-2.63).
The association was particularly strong for T2MI, especially in the setting of bacteremia and sepsis, and unlike T1MI, it remained significant after adjustment for smoking.
The study establishes a link between COPD and MI in HIV, but it could not answer what’s going on. Chronic inflammation from the virus could be at play, but the team also found hints of inadequate COPD management.
“About 60% of patients were on inhalers ... but only about 25% of them were on long-acting inhalers. 75% were only on short-acting.” That’s a problem because long-acting inhalers are needed to control exacerbations, Dr. Crothers said.
The study didn’t capture exacerbation rates, but increased rates could help explain the MI risk. Increased rates of pneumonia could as well, since pneumonia is a common cause of sepsis.
“We need to better manage complications of COPD in this population. I think optimizing long-term COPD management could have many beneficial effects,” Dr. Crothers said.
The National Institutes of Health funded the work. Dr. Crothers had no disclosures.
SOURCE: Crothers K et al. CROI 2019, Abstract 31.
SEATTLE – Chronic obstructive pulmonary disease is independently associated with an increased risk of myocardial infarction in people with HIV, according to a report at the Conference on Retroviruses and Opportunistic Infections.
Chronic obstructive pulmonary disease (COPD) is known to increase the risk of myocardial infarction (MI) in the general population, but hadn’t been shown until now to do the same in HIV. The study raises the question of whether COPD is being managed adequately in patients with the virus, according to study lead Kristina Crothers, MD, associate professor in the division of pulmonary, critical care & sleep medicine at the University of Washington, Seattle.
The investigators reviewed 25,509 HIV patients in the Center for AIDS Research Network of Integrated Clinical Systems cohort, a large electronic database of HIV-infected people. They defined COPD by diagnostic codes and inhaler prescriptions. MIs were adjudicated by review.
The team identified 423 subjects with moderate to severe COPD, and 698 who had MIs, including 339 type 1 MIs (T1MI) from a ruptured plaque (54%), and 294 (46%) type 2 heart attacks (T2MI) from a supply-demand mismatch due to sepsis or some other problem. In general, T2MIs are far more common in people with HIV.
COPD was associated with a greater than twofold increased risk of MI after adjustment for age, sex, viral load, nadir CD4 count, hypertension, and other confounders. The risk dropped slightly when smoking – both current smoking and pack years – was added to the model (adjusted hazard ratio 1.88, 95% confidence interval, 1.34-2.63).
The association was particularly strong for T2MI, especially in the setting of bacteremia and sepsis, and unlike T1MI, it remained significant after adjustment for smoking.
The study establishes a link between COPD and MI in HIV, but it could not answer what’s going on. Chronic inflammation from the virus could be at play, but the team also found hints of inadequate COPD management.
“About 60% of patients were on inhalers ... but only about 25% of them were on long-acting inhalers. 75% were only on short-acting.” That’s a problem because long-acting inhalers are needed to control exacerbations, Dr. Crothers said.
The study didn’t capture exacerbation rates, but increased rates could help explain the MI risk. Increased rates of pneumonia could as well, since pneumonia is a common cause of sepsis.
“We need to better manage complications of COPD in this population. I think optimizing long-term COPD management could have many beneficial effects,” Dr. Crothers said.
The National Institutes of Health funded the work. Dr. Crothers had no disclosures.
SOURCE: Crothers K et al. CROI 2019, Abstract 31.
SEATTLE – Chronic obstructive pulmonary disease is independently associated with an increased risk of myocardial infarction in people with HIV, according to a report at the Conference on Retroviruses and Opportunistic Infections.
Chronic obstructive pulmonary disease (COPD) is known to increase the risk of myocardial infarction (MI) in the general population, but hadn’t been shown until now to do the same in HIV. The study raises the question of whether COPD is being managed adequately in patients with the virus, according to study lead Kristina Crothers, MD, associate professor in the division of pulmonary, critical care & sleep medicine at the University of Washington, Seattle.
The investigators reviewed 25,509 HIV patients in the Center for AIDS Research Network of Integrated Clinical Systems cohort, a large electronic database of HIV-infected people. They defined COPD by diagnostic codes and inhaler prescriptions. MIs were adjudicated by review.
The team identified 423 subjects with moderate to severe COPD, and 698 who had MIs, including 339 type 1 MIs (T1MI) from a ruptured plaque (54%), and 294 (46%) type 2 heart attacks (T2MI) from a supply-demand mismatch due to sepsis or some other problem. In general, T2MIs are far more common in people with HIV.
COPD was associated with a greater than twofold increased risk of MI after adjustment for age, sex, viral load, nadir CD4 count, hypertension, and other confounders. The risk dropped slightly when smoking – both current smoking and pack years – was added to the model (adjusted hazard ratio 1.88, 95% confidence interval, 1.34-2.63).
The association was particularly strong for T2MI, especially in the setting of bacteremia and sepsis, and unlike T1MI, it remained significant after adjustment for smoking.
The study establishes a link between COPD and MI in HIV, but it could not answer what’s going on. Chronic inflammation from the virus could be at play, but the team also found hints of inadequate COPD management.
“About 60% of patients were on inhalers ... but only about 25% of them were on long-acting inhalers. 75% were only on short-acting.” That’s a problem because long-acting inhalers are needed to control exacerbations, Dr. Crothers said.
The study didn’t capture exacerbation rates, but increased rates could help explain the MI risk. Increased rates of pneumonia could as well, since pneumonia is a common cause of sepsis.
“We need to better manage complications of COPD in this population. I think optimizing long-term COPD management could have many beneficial effects,” Dr. Crothers said.
The National Institutes of Health funded the work. Dr. Crothers had no disclosures.
SOURCE: Crothers K et al. CROI 2019, Abstract 31.
REPORTING FROM CROI 2019
Glyceryl trinitrate does not improve outcomes of ischemic stroke
HONOLULU – , according to data presented at the International Stroke Conference sponsored by the American Heart Association. Results suggest that GTN causes adverse effects in patients with intracerebral hemorrhage (ICH), but this observation is not definitive, according to the researchers. Study results were published online ahead of print Feb. 6 in the Lancet.
Nitric oxide is a regulatory molecule that has vasoactive effects and promotes blood pressure reduction. Vascular levels of nitric oxide are low in stroke, which suggests that the molecule may be a target for stroke treatment. GTN, a nitric oxide donor, lowered blood pressure and improved functional outcome among patients with acute stroke in the phase 2 Rapid Intervention with GTN in Hypertensive Stroke Trial (RIGHT).
Philip Bath, MD, Stroke Association Professor of Stroke Medicine at the University of Nottingham (England), and colleagues conducted the RIGHT-2 study to evaluate the safety and efficacy of GTN when administered early after onset of suspected stroke. Paramedics randomized patients in equal groups to a GTN patch or a sham patch in the ambulance. Three more patches were administered in the hospital on the following days. Active and sham patches looked similar and had no writing on them, thus ensuring effective blinding upon administration. Investigators followed up patients by telephone at 90 days to assess the modified Rankin Scale score and markers of disability, mood, cognition, and quality of life.
Eligible participants were adults who had dialed emergency services, independently or with assistance, because of a possible stroke. They had a Face, Arm, Speech, Time (FAST) score of 2 or 3, were within 4 hours of onset, and had a systolic blood pressure greater than 120 mm Hg. Patients from nursing homes, those with hypoglycemia, those who were unconscious, and those with a witnessed seizure were excluded.
Dr. Bath and colleagues planned to enroll 850 patients from five ambulance services in 30 hospitals across the United Kingdom. Data were to be examined through an intention-to-treat analysis. During the trial, however, the investigators observed that the rate of stroke mimics was 26%, rather than the 12% that they had anticipated. To ensure the proper power for the study, the investigators increased the sample size to 1,149 patients. They also changed the planned data analysis from intention-to-treat to hierarchical analysis. Specifically, the researchers planned to perform the primary analysis in patients with stroke or TIA. If the results were positive, then they would perform a standard intention-to-treat analysis.
More than 99% of patients received the first patch. Approximately 57% of the population received the first two patches. One reason for this decrease in adherence was that many patients were discharged from the hospital with a TIA or a stroke mimic. Participants’ average age was 72. The median time from onset to randomization was 71 minutes, and the median time to treatment was 73 minutes. Participants’ mean systolic blood pressure was 162 mm Hg. Approximately 60% of the patients had a FAST score of 3. About 50% of participants had ischemic stroke, 13% had ICH, 10% had TIA, and 26% had stroke mimics.
At 1 hour after treatment initiation, systolic blood pressure decreased by 6.2 mm Hg and diastolic blood pressure decreased by 2.7 mm Hg among patients who received GTN, compared with controls. At one day, the differences were 5.2 mm Hg and 2.5 mm Hg, respectively, in treated patients, compared with controls. Blood pressure became similar between groups thereafter, “in part because of the tachyphylaxis that we know happens with GTN,” said Dr. Bath.
The researchers found no evidence of an effect of GTN on functional outcome at 90 days in participants with stroke or transient ischemic attack. The adjusted common odds ratio of poor outcome was 1.25 in the GTN group, compared with the control group (95 % confidence interval, 0.97-1.60; P = .083). “We were close to getting a negative trial,” said Dr. Bath.
Subgroup analyses revealed differences in outcome according to the time to randomization. GTN had a negative effect in patients treated within 1 hour of onset. Results were neutral, but tended to be negative, in patients treated between 1 and 2 hours of onset. Results were neutral, but tended to be positive, among patients treated at more than 2 hours after onset. There was no difference between groups in the rate of mortality.
One of the study’s limitations was its single-blind design. In addition, the trial was conducted in a single country, and the investigators changed the protocol after it was initiated. “We had a higher-than-expected [stroke] mimic rate, although I’m reassured by most experts that ... this is probably about right,” said Dr. Bath.
A potential reason for the neutral results is the negative effect that GTN had among patients with ICH, said Dr. Bath. “In that very early first hour, we are of course breaking a law that we learned in medical school, which is that the first part of hemostasis is spasm. We gave an antispasmodic: a vasodilator,” he added. “That is speculation.”
The trial was funded by the British Heart Foundation. Dr. Bath declared a modest ownership interest in Platelet Solutions and consultant or advisory board positions with Moleac, DiaMedica, Phagenesis, Nestle, and ReNeuron. The other investigators declared no conflicts of interest.
The RIGHT-2 trial shows the limitations of a prehospital enrollment model, wrote Karen C. Johnston, MD, professor of neurology at the University of Virginia in Charlottesville, and Valerie L. Durkalski-Mauldin, PhD, professor of medicine at Medical University of South Carolina in Charleston, in an editorial accompanying the RIGHT-2 trial results. The rate of nonstroke diagnoses was so high that it would have reduced the study’s power to assess the efficacy of glyceryl trinitrate (GTN), had the investigators not increased the sample size and changed the statistical analysis plan.
“Future prehospital trials need to consider the implications of enrolling, yet excluding, stroke mimics in the primary analysis,” said Dr. Johnston and Dr. Durkalski-Mauldin. Using telemedicine in the ambulance to facilitate direct contact between the stroke provider and the patient and emergency medical services provider could reduce the enrollment of patients with stroke mimics in clinical trials, they added. “Improved tools to exclude stroke mimics in the field have been difficult to develop and validate. The absence of imaging in most ambulances will continue to limit field personnel from definitively determining ischemic stroke from intracerebral hemorrhage, which will limit hyperacute trials to interventions presumed safe in both populations.”
In addition, the blood pressure reduction that GTN provided might not be clinically relevant, said Dr. Johnston and Dr. Durkalski-Mauldin. “The RIGHT-2 investigators report no difference in blood pressure at day 3 or day 4 of treatment, which might have been related to the very low adherence to study protocol by day 4.
“Regardless of these limitations, RIGHT-2 has provided high-level evidence that GTN given within 4 hours of onset does not significantly improve outcome in hyperacute patients presenting with possible stroke,” the authors concluded (Lancet. 2019 Feb 6. doi: 10.1016/
S0140-6736(19)30276-4). Dr. Johnston and Dr. Durkalski-Mauldin declared no conflicts of interest.
The RIGHT-2 trial shows the limitations of a prehospital enrollment model, wrote Karen C. Johnston, MD, professor of neurology at the University of Virginia in Charlottesville, and Valerie L. Durkalski-Mauldin, PhD, professor of medicine at Medical University of South Carolina in Charleston, in an editorial accompanying the RIGHT-2 trial results. The rate of nonstroke diagnoses was so high that it would have reduced the study’s power to assess the efficacy of glyceryl trinitrate (GTN), had the investigators not increased the sample size and changed the statistical analysis plan.
“Future prehospital trials need to consider the implications of enrolling, yet excluding, stroke mimics in the primary analysis,” said Dr. Johnston and Dr. Durkalski-Mauldin. Using telemedicine in the ambulance to facilitate direct contact between the stroke provider and the patient and emergency medical services provider could reduce the enrollment of patients with stroke mimics in clinical trials, they added. “Improved tools to exclude stroke mimics in the field have been difficult to develop and validate. The absence of imaging in most ambulances will continue to limit field personnel from definitively determining ischemic stroke from intracerebral hemorrhage, which will limit hyperacute trials to interventions presumed safe in both populations.”
In addition, the blood pressure reduction that GTN provided might not be clinically relevant, said Dr. Johnston and Dr. Durkalski-Mauldin. “The RIGHT-2 investigators report no difference in blood pressure at day 3 or day 4 of treatment, which might have been related to the very low adherence to study protocol by day 4.
“Regardless of these limitations, RIGHT-2 has provided high-level evidence that GTN given within 4 hours of onset does not significantly improve outcome in hyperacute patients presenting with possible stroke,” the authors concluded (Lancet. 2019 Feb 6. doi: 10.1016/
S0140-6736(19)30276-4). Dr. Johnston and Dr. Durkalski-Mauldin declared no conflicts of interest.
The RIGHT-2 trial shows the limitations of a prehospital enrollment model, wrote Karen C. Johnston, MD, professor of neurology at the University of Virginia in Charlottesville, and Valerie L. Durkalski-Mauldin, PhD, professor of medicine at Medical University of South Carolina in Charleston, in an editorial accompanying the RIGHT-2 trial results. The rate of nonstroke diagnoses was so high that it would have reduced the study’s power to assess the efficacy of glyceryl trinitrate (GTN), had the investigators not increased the sample size and changed the statistical analysis plan.
“Future prehospital trials need to consider the implications of enrolling, yet excluding, stroke mimics in the primary analysis,” said Dr. Johnston and Dr. Durkalski-Mauldin. Using telemedicine in the ambulance to facilitate direct contact between the stroke provider and the patient and emergency medical services provider could reduce the enrollment of patients with stroke mimics in clinical trials, they added. “Improved tools to exclude stroke mimics in the field have been difficult to develop and validate. The absence of imaging in most ambulances will continue to limit field personnel from definitively determining ischemic stroke from intracerebral hemorrhage, which will limit hyperacute trials to interventions presumed safe in both populations.”
In addition, the blood pressure reduction that GTN provided might not be clinically relevant, said Dr. Johnston and Dr. Durkalski-Mauldin. “The RIGHT-2 investigators report no difference in blood pressure at day 3 or day 4 of treatment, which might have been related to the very low adherence to study protocol by day 4.
“Regardless of these limitations, RIGHT-2 has provided high-level evidence that GTN given within 4 hours of onset does not significantly improve outcome in hyperacute patients presenting with possible stroke,” the authors concluded (Lancet. 2019 Feb 6. doi: 10.1016/
S0140-6736(19)30276-4). Dr. Johnston and Dr. Durkalski-Mauldin declared no conflicts of interest.
HONOLULU – , according to data presented at the International Stroke Conference sponsored by the American Heart Association. Results suggest that GTN causes adverse effects in patients with intracerebral hemorrhage (ICH), but this observation is not definitive, according to the researchers. Study results were published online ahead of print Feb. 6 in the Lancet.
Nitric oxide is a regulatory molecule that has vasoactive effects and promotes blood pressure reduction. Vascular levels of nitric oxide are low in stroke, which suggests that the molecule may be a target for stroke treatment. GTN, a nitric oxide donor, lowered blood pressure and improved functional outcome among patients with acute stroke in the phase 2 Rapid Intervention with GTN in Hypertensive Stroke Trial (RIGHT).
Philip Bath, MD, Stroke Association Professor of Stroke Medicine at the University of Nottingham (England), and colleagues conducted the RIGHT-2 study to evaluate the safety and efficacy of GTN when administered early after onset of suspected stroke. Paramedics randomized patients in equal groups to a GTN patch or a sham patch in the ambulance. Three more patches were administered in the hospital on the following days. Active and sham patches looked similar and had no writing on them, thus ensuring effective blinding upon administration. Investigators followed up patients by telephone at 90 days to assess the modified Rankin Scale score and markers of disability, mood, cognition, and quality of life.
Eligible participants were adults who had dialed emergency services, independently or with assistance, because of a possible stroke. They had a Face, Arm, Speech, Time (FAST) score of 2 or 3, were within 4 hours of onset, and had a systolic blood pressure greater than 120 mm Hg. Patients from nursing homes, those with hypoglycemia, those who were unconscious, and those with a witnessed seizure were excluded.
Dr. Bath and colleagues planned to enroll 850 patients from five ambulance services in 30 hospitals across the United Kingdom. Data were to be examined through an intention-to-treat analysis. During the trial, however, the investigators observed that the rate of stroke mimics was 26%, rather than the 12% that they had anticipated. To ensure the proper power for the study, the investigators increased the sample size to 1,149 patients. They also changed the planned data analysis from intention-to-treat to hierarchical analysis. Specifically, the researchers planned to perform the primary analysis in patients with stroke or TIA. If the results were positive, then they would perform a standard intention-to-treat analysis.
More than 99% of patients received the first patch. Approximately 57% of the population received the first two patches. One reason for this decrease in adherence was that many patients were discharged from the hospital with a TIA or a stroke mimic. Participants’ average age was 72. The median time from onset to randomization was 71 minutes, and the median time to treatment was 73 minutes. Participants’ mean systolic blood pressure was 162 mm Hg. Approximately 60% of the patients had a FAST score of 3. About 50% of participants had ischemic stroke, 13% had ICH, 10% had TIA, and 26% had stroke mimics.
At 1 hour after treatment initiation, systolic blood pressure decreased by 6.2 mm Hg and diastolic blood pressure decreased by 2.7 mm Hg among patients who received GTN, compared with controls. At one day, the differences were 5.2 mm Hg and 2.5 mm Hg, respectively, in treated patients, compared with controls. Blood pressure became similar between groups thereafter, “in part because of the tachyphylaxis that we know happens with GTN,” said Dr. Bath.
The researchers found no evidence of an effect of GTN on functional outcome at 90 days in participants with stroke or transient ischemic attack. The adjusted common odds ratio of poor outcome was 1.25 in the GTN group, compared with the control group (95 % confidence interval, 0.97-1.60; P = .083). “We were close to getting a negative trial,” said Dr. Bath.
Subgroup analyses revealed differences in outcome according to the time to randomization. GTN had a negative effect in patients treated within 1 hour of onset. Results were neutral, but tended to be negative, in patients treated between 1 and 2 hours of onset. Results were neutral, but tended to be positive, among patients treated at more than 2 hours after onset. There was no difference between groups in the rate of mortality.
One of the study’s limitations was its single-blind design. In addition, the trial was conducted in a single country, and the investigators changed the protocol after it was initiated. “We had a higher-than-expected [stroke] mimic rate, although I’m reassured by most experts that ... this is probably about right,” said Dr. Bath.
A potential reason for the neutral results is the negative effect that GTN had among patients with ICH, said Dr. Bath. “In that very early first hour, we are of course breaking a law that we learned in medical school, which is that the first part of hemostasis is spasm. We gave an antispasmodic: a vasodilator,” he added. “That is speculation.”
The trial was funded by the British Heart Foundation. Dr. Bath declared a modest ownership interest in Platelet Solutions and consultant or advisory board positions with Moleac, DiaMedica, Phagenesis, Nestle, and ReNeuron. The other investigators declared no conflicts of interest.
HONOLULU – , according to data presented at the International Stroke Conference sponsored by the American Heart Association. Results suggest that GTN causes adverse effects in patients with intracerebral hemorrhage (ICH), but this observation is not definitive, according to the researchers. Study results were published online ahead of print Feb. 6 in the Lancet.
Nitric oxide is a regulatory molecule that has vasoactive effects and promotes blood pressure reduction. Vascular levels of nitric oxide are low in stroke, which suggests that the molecule may be a target for stroke treatment. GTN, a nitric oxide donor, lowered blood pressure and improved functional outcome among patients with acute stroke in the phase 2 Rapid Intervention with GTN in Hypertensive Stroke Trial (RIGHT).
Philip Bath, MD, Stroke Association Professor of Stroke Medicine at the University of Nottingham (England), and colleagues conducted the RIGHT-2 study to evaluate the safety and efficacy of GTN when administered early after onset of suspected stroke. Paramedics randomized patients in equal groups to a GTN patch or a sham patch in the ambulance. Three more patches were administered in the hospital on the following days. Active and sham patches looked similar and had no writing on them, thus ensuring effective blinding upon administration. Investigators followed up patients by telephone at 90 days to assess the modified Rankin Scale score and markers of disability, mood, cognition, and quality of life.
Eligible participants were adults who had dialed emergency services, independently or with assistance, because of a possible stroke. They had a Face, Arm, Speech, Time (FAST) score of 2 or 3, were within 4 hours of onset, and had a systolic blood pressure greater than 120 mm Hg. Patients from nursing homes, those with hypoglycemia, those who were unconscious, and those with a witnessed seizure were excluded.
Dr. Bath and colleagues planned to enroll 850 patients from five ambulance services in 30 hospitals across the United Kingdom. Data were to be examined through an intention-to-treat analysis. During the trial, however, the investigators observed that the rate of stroke mimics was 26%, rather than the 12% that they had anticipated. To ensure the proper power for the study, the investigators increased the sample size to 1,149 patients. They also changed the planned data analysis from intention-to-treat to hierarchical analysis. Specifically, the researchers planned to perform the primary analysis in patients with stroke or TIA. If the results were positive, then they would perform a standard intention-to-treat analysis.
More than 99% of patients received the first patch. Approximately 57% of the population received the first two patches. One reason for this decrease in adherence was that many patients were discharged from the hospital with a TIA or a stroke mimic. Participants’ average age was 72. The median time from onset to randomization was 71 minutes, and the median time to treatment was 73 minutes. Participants’ mean systolic blood pressure was 162 mm Hg. Approximately 60% of the patients had a FAST score of 3. About 50% of participants had ischemic stroke, 13% had ICH, 10% had TIA, and 26% had stroke mimics.
At 1 hour after treatment initiation, systolic blood pressure decreased by 6.2 mm Hg and diastolic blood pressure decreased by 2.7 mm Hg among patients who received GTN, compared with controls. At one day, the differences were 5.2 mm Hg and 2.5 mm Hg, respectively, in treated patients, compared with controls. Blood pressure became similar between groups thereafter, “in part because of the tachyphylaxis that we know happens with GTN,” said Dr. Bath.
The researchers found no evidence of an effect of GTN on functional outcome at 90 days in participants with stroke or transient ischemic attack. The adjusted common odds ratio of poor outcome was 1.25 in the GTN group, compared with the control group (95 % confidence interval, 0.97-1.60; P = .083). “We were close to getting a negative trial,” said Dr. Bath.
Subgroup analyses revealed differences in outcome according to the time to randomization. GTN had a negative effect in patients treated within 1 hour of onset. Results were neutral, but tended to be negative, in patients treated between 1 and 2 hours of onset. Results were neutral, but tended to be positive, among patients treated at more than 2 hours after onset. There was no difference between groups in the rate of mortality.
One of the study’s limitations was its single-blind design. In addition, the trial was conducted in a single country, and the investigators changed the protocol after it was initiated. “We had a higher-than-expected [stroke] mimic rate, although I’m reassured by most experts that ... this is probably about right,” said Dr. Bath.
A potential reason for the neutral results is the negative effect that GTN had among patients with ICH, said Dr. Bath. “In that very early first hour, we are of course breaking a law that we learned in medical school, which is that the first part of hemostasis is spasm. We gave an antispasmodic: a vasodilator,” he added. “That is speculation.”
The trial was funded by the British Heart Foundation. Dr. Bath declared a modest ownership interest in Platelet Solutions and consultant or advisory board positions with Moleac, DiaMedica, Phagenesis, Nestle, and ReNeuron. The other investigators declared no conflicts of interest.
REPORTING FROM ISC 2019
Histoplasmosis Manifests After Decades
Immunocompromised patients can be at risk for complications long after the original health issue was resolved—a problem illustrated by a patient who had a heart transplant in 1986 but developed acute progressive disseminated histoplasmosis decades later.
The patient presented with altered mental status; a Mini-Mental State Exam showed confusion. A computed tomography scan of the patient’s head revealed lesions, raising the suspicion of metastatic malignancy, which was ruled out after biopsy of a medial right temporal brain lesion. MRIs of his chest, abdomen, and pelvis revealed bilateral masses on his adrenal glands. Guided adrenal biopsy showed necrotizing granulomas consistent with a diagnosis of disseminated histoplasmosis.
However, that diagnosis was questioned—the patient had lived in Arizona for years, not, for instance, the Midwest, where histoplasmosis is more common. Nor did he have a history of spelunking, prior exposure to bird or bat droppings. He did report a short visit to North Carolina 30 years earlier. And he had been on immunosuppressive drugs for years.
The patient was started on liposomal amphotericin B, which was discontinued when his renal function deteriorated. He was switched to itraconazole, then restarted on amphotericin B with close monitoring after the diagnosis was confirmed. His doses of immunosuppressive drugs were reduced.
The clinicians note that HIV/AIDS and use of immunosuppressive drugs are among the risk factors for disseminated infection. They cite 1 study that found immunosuppression was the single most common risk factor. In another study, the risk of histoplasmosis increased as CD4+ T cells dropped below 300/µL.
The patient’s case was complicated by the fact that it was > 30 years after his heart transplant, and he had made only a short visit to an endemic area. He also had no history of histoplasmosis—the clinicians say a database search turned up the fact that most reported cases were preceded by symptomatic infection.
When charting patient history, they advise placing emphasis on a history of travel to endemic areas and considering histoplasmosis in immunocompromised patients in nonendemic areas.
Immunocompromised patients can be at risk for complications long after the original health issue was resolved—a problem illustrated by a patient who had a heart transplant in 1986 but developed acute progressive disseminated histoplasmosis decades later.
The patient presented with altered mental status; a Mini-Mental State Exam showed confusion. A computed tomography scan of the patient’s head revealed lesions, raising the suspicion of metastatic malignancy, which was ruled out after biopsy of a medial right temporal brain lesion. MRIs of his chest, abdomen, and pelvis revealed bilateral masses on his adrenal glands. Guided adrenal biopsy showed necrotizing granulomas consistent with a diagnosis of disseminated histoplasmosis.
However, that diagnosis was questioned—the patient had lived in Arizona for years, not, for instance, the Midwest, where histoplasmosis is more common. Nor did he have a history of spelunking, prior exposure to bird or bat droppings. He did report a short visit to North Carolina 30 years earlier. And he had been on immunosuppressive drugs for years.
The patient was started on liposomal amphotericin B, which was discontinued when his renal function deteriorated. He was switched to itraconazole, then restarted on amphotericin B with close monitoring after the diagnosis was confirmed. His doses of immunosuppressive drugs were reduced.
The clinicians note that HIV/AIDS and use of immunosuppressive drugs are among the risk factors for disseminated infection. They cite 1 study that found immunosuppression was the single most common risk factor. In another study, the risk of histoplasmosis increased as CD4+ T cells dropped below 300/µL.
The patient’s case was complicated by the fact that it was > 30 years after his heart transplant, and he had made only a short visit to an endemic area. He also had no history of histoplasmosis—the clinicians say a database search turned up the fact that most reported cases were preceded by symptomatic infection.
When charting patient history, they advise placing emphasis on a history of travel to endemic areas and considering histoplasmosis in immunocompromised patients in nonendemic areas.
Immunocompromised patients can be at risk for complications long after the original health issue was resolved—a problem illustrated by a patient who had a heart transplant in 1986 but developed acute progressive disseminated histoplasmosis decades later.
The patient presented with altered mental status; a Mini-Mental State Exam showed confusion. A computed tomography scan of the patient’s head revealed lesions, raising the suspicion of metastatic malignancy, which was ruled out after biopsy of a medial right temporal brain lesion. MRIs of his chest, abdomen, and pelvis revealed bilateral masses on his adrenal glands. Guided adrenal biopsy showed necrotizing granulomas consistent with a diagnosis of disseminated histoplasmosis.
However, that diagnosis was questioned—the patient had lived in Arizona for years, not, for instance, the Midwest, where histoplasmosis is more common. Nor did he have a history of spelunking, prior exposure to bird or bat droppings. He did report a short visit to North Carolina 30 years earlier. And he had been on immunosuppressive drugs for years.
The patient was started on liposomal amphotericin B, which was discontinued when his renal function deteriorated. He was switched to itraconazole, then restarted on amphotericin B with close monitoring after the diagnosis was confirmed. His doses of immunosuppressive drugs were reduced.
The clinicians note that HIV/AIDS and use of immunosuppressive drugs are among the risk factors for disseminated infection. They cite 1 study that found immunosuppression was the single most common risk factor. In another study, the risk of histoplasmosis increased as CD4+ T cells dropped below 300/µL.
The patient’s case was complicated by the fact that it was > 30 years after his heart transplant, and he had made only a short visit to an endemic area. He also had no history of histoplasmosis—the clinicians say a database search turned up the fact that most reported cases were preceded by symptomatic infection.
When charting patient history, they advise placing emphasis on a history of travel to endemic areas and considering histoplasmosis in immunocompromised patients in nonendemic areas.
Individual pediatric hypertension trials support personalized care
The preferred medication in children with hypertension varied among three common medications in n-of-1 studies with repeated ambulatory blood pressure monitoring that allowed for individualized treatment plans.
“In usual care, the choice of specific antihypertensive regimen is based on physician preference with little or no systematic assessment of treatment benefits and hazards,” wrote Joyce P. Samuel, MD, of the University of Texas Health Science Center, Houston, and her colleagues.
In a study published in Pediatrics, the researchers assessed 32 hypertensive children who participated in n-of-1 studies at a single center. The children underwent repeated ambulatory blood pressure monitoring (APBM) to compare the effects of three medications: lisinopril, amlodipine, and hydrochlorothiazide. The children were at least 9 years old, and their primary referring physician had recommended antihypertensive treatment.
The preferred medication was defined as the one that yielded both a normal ambulatory blood pressure and the greatest reduction in average systolic blood pressure when awake for two treatment periods with no unacceptable side effects. If more than one medication met these criteria, the one with the least side effects was chosen.
Overall, the preferred medication was lisinopril for 16 patients (49%), amlodipine for 8 patients (24%), and hydrochlorothiazide for 4 patients (12%); 4 patients remained uncontrolled on monotherapy.
Each of the three medications was taken for 2 weeks, and patients were assessed with a 24-hour ABPM and a side-effect questionnaire during the final 24 hours of each treatment. A total of 27 patients reported at least one side effect during the study. Unacceptable side effects were most frequent on hydrochlorothiazide (25%), compared with 16% for lisinopril and 13% for amlodipine. None of the patients experienced hypertensive crisis, hypotension, hyperkalemia, or an increase in serum creatinine levels of more than 20% from baseline.
No single medication was preferred for at least 80% of the patients. “Within-patient variation in BP (blood pressure) response was considerable because the best-performing medication decreased the BP by about 12 mm Hg more than the worst-performing medication,” the researchers wrote.
The findings were limited by the possibility that a 2-week trial might be insufficient to evaluate medication effects, and more research is needed to refine the methods of the trials and the generalizability of the n-of-1 approach, the researchers noted. However, “this individualized approach to antihypertensive medication selection holds potential value by involving patients in their own care and facilitating informed treatment decisions,” they said.
“A randomized trial in which researchers compare usual care to routine use of n-of-1 trials with ABPM is needed to assess effects on treatment adherence, patient satisfaction, long-term BP control assessed with ABPM, and hypertensive target organ damage,” Dr. Samuel and her associates advised.
The study was supported in part by the National Center for Advancing Translational Sciences and the National Institutes of Health. The researchers had no financial conflicts to disclose.
SOURCE: Samuel JP et al. Pediatrics. 2019 Mar 6. doi: 10.1542/peds.2018-1818.
The preferred medication in children with hypertension varied among three common medications in n-of-1 studies with repeated ambulatory blood pressure monitoring that allowed for individualized treatment plans.
“In usual care, the choice of specific antihypertensive regimen is based on physician preference with little or no systematic assessment of treatment benefits and hazards,” wrote Joyce P. Samuel, MD, of the University of Texas Health Science Center, Houston, and her colleagues.
In a study published in Pediatrics, the researchers assessed 32 hypertensive children who participated in n-of-1 studies at a single center. The children underwent repeated ambulatory blood pressure monitoring (APBM) to compare the effects of three medications: lisinopril, amlodipine, and hydrochlorothiazide. The children were at least 9 years old, and their primary referring physician had recommended antihypertensive treatment.
The preferred medication was defined as the one that yielded both a normal ambulatory blood pressure and the greatest reduction in average systolic blood pressure when awake for two treatment periods with no unacceptable side effects. If more than one medication met these criteria, the one with the least side effects was chosen.
Overall, the preferred medication was lisinopril for 16 patients (49%), amlodipine for 8 patients (24%), and hydrochlorothiazide for 4 patients (12%); 4 patients remained uncontrolled on monotherapy.
Each of the three medications was taken for 2 weeks, and patients were assessed with a 24-hour ABPM and a side-effect questionnaire during the final 24 hours of each treatment. A total of 27 patients reported at least one side effect during the study. Unacceptable side effects were most frequent on hydrochlorothiazide (25%), compared with 16% for lisinopril and 13% for amlodipine. None of the patients experienced hypertensive crisis, hypotension, hyperkalemia, or an increase in serum creatinine levels of more than 20% from baseline.
No single medication was preferred for at least 80% of the patients. “Within-patient variation in BP (blood pressure) response was considerable because the best-performing medication decreased the BP by about 12 mm Hg more than the worst-performing medication,” the researchers wrote.
The findings were limited by the possibility that a 2-week trial might be insufficient to evaluate medication effects, and more research is needed to refine the methods of the trials and the generalizability of the n-of-1 approach, the researchers noted. However, “this individualized approach to antihypertensive medication selection holds potential value by involving patients in their own care and facilitating informed treatment decisions,” they said.
“A randomized trial in which researchers compare usual care to routine use of n-of-1 trials with ABPM is needed to assess effects on treatment adherence, patient satisfaction, long-term BP control assessed with ABPM, and hypertensive target organ damage,” Dr. Samuel and her associates advised.
The study was supported in part by the National Center for Advancing Translational Sciences and the National Institutes of Health. The researchers had no financial conflicts to disclose.
SOURCE: Samuel JP et al. Pediatrics. 2019 Mar 6. doi: 10.1542/peds.2018-1818.
The preferred medication in children with hypertension varied among three common medications in n-of-1 studies with repeated ambulatory blood pressure monitoring that allowed for individualized treatment plans.
“In usual care, the choice of specific antihypertensive regimen is based on physician preference with little or no systematic assessment of treatment benefits and hazards,” wrote Joyce P. Samuel, MD, of the University of Texas Health Science Center, Houston, and her colleagues.
In a study published in Pediatrics, the researchers assessed 32 hypertensive children who participated in n-of-1 studies at a single center. The children underwent repeated ambulatory blood pressure monitoring (APBM) to compare the effects of three medications: lisinopril, amlodipine, and hydrochlorothiazide. The children were at least 9 years old, and their primary referring physician had recommended antihypertensive treatment.
The preferred medication was defined as the one that yielded both a normal ambulatory blood pressure and the greatest reduction in average systolic blood pressure when awake for two treatment periods with no unacceptable side effects. If more than one medication met these criteria, the one with the least side effects was chosen.
Overall, the preferred medication was lisinopril for 16 patients (49%), amlodipine for 8 patients (24%), and hydrochlorothiazide for 4 patients (12%); 4 patients remained uncontrolled on monotherapy.
Each of the three medications was taken for 2 weeks, and patients were assessed with a 24-hour ABPM and a side-effect questionnaire during the final 24 hours of each treatment. A total of 27 patients reported at least one side effect during the study. Unacceptable side effects were most frequent on hydrochlorothiazide (25%), compared with 16% for lisinopril and 13% for amlodipine. None of the patients experienced hypertensive crisis, hypotension, hyperkalemia, or an increase in serum creatinine levels of more than 20% from baseline.
No single medication was preferred for at least 80% of the patients. “Within-patient variation in BP (blood pressure) response was considerable because the best-performing medication decreased the BP by about 12 mm Hg more than the worst-performing medication,” the researchers wrote.
The findings were limited by the possibility that a 2-week trial might be insufficient to evaluate medication effects, and more research is needed to refine the methods of the trials and the generalizability of the n-of-1 approach, the researchers noted. However, “this individualized approach to antihypertensive medication selection holds potential value by involving patients in their own care and facilitating informed treatment decisions,” they said.
“A randomized trial in which researchers compare usual care to routine use of n-of-1 trials with ABPM is needed to assess effects on treatment adherence, patient satisfaction, long-term BP control assessed with ABPM, and hypertensive target organ damage,” Dr. Samuel and her associates advised.
The study was supported in part by the National Center for Advancing Translational Sciences and the National Institutes of Health. The researchers had no financial conflicts to disclose.
SOURCE: Samuel JP et al. Pediatrics. 2019 Mar 6. doi: 10.1542/peds.2018-1818.
FROM PEDIATRICS
Infective endocarditis isn’t what it used to be
SNOWMASS, COLO. – Infective endocarditis in 2019 is very different from the disease most physicians encountered in training, both in terms of epidemiology and clinical presentation, Patrick T. O’Gara, MD, observed at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
The classic description of infective endocarditis provided by Sir William Osler, MD, was of a subacute bacterial infection characterized by a long latent phase of low-grade fever, back pain, weight loss, and night sweats. It was mainly a right-heart disease of younger individuals with an infected native valve, and the predominant pathogens were streptococci, Dr. O’Gara said.
“I think in the current era endocarditis is more often characterized by an acute illness with toxic features in the context of adults with a high burden of degenerative diseases – for example, patients with rheumatoid arthritis or psoriatic arthritis on immunosuppressive therapy, or diabetes, end-stage renal disease, and risk factors for hospital-acquired infection. Injectable drug use is through the roof, there’s a wider prevalence of cardiac implanted electronic devices, which are a wonderful place for bacteria to hide, and Staphylococcus aureus has certainly become the leading pathogen with regard to endocarditis in the United States, especially MRSA, often multidrug resistant,” said Dr. O’Gara, professor of medicine at Harvard Medical School, Boston.
“Also, no talk about endocarditis is sufficient without paying some attention to the opioid crisis in which we find ourselves. It’s one of the top three causes of death among young men in the United States, along with accidents and gun violence. No region of the country is spared. This has completely inundated our ER and hospitalist services and our inpatient cardiology services with folks who are often repeat offenders when it comes to the difficulty in being able to give up an injectable drug use habit. They have multiple infections and hospitalizations, tricuspid valve involvement, and depending upon the aggressiveness of the Staphylococcus organism, typically they have left-sided disease with multiple complications, including aortic regurgitation and heart failure,” the cardiologist continued.
This description underscored one of Dr. O’Gara’s major points about the challenges posed by infective endocarditis in contemporary practice: “Expect the unexpected,” he advised. “When you’ve seen one case of infective endocarditis, you’ve seen one case of infective endocarditis.”
Outcomes are ‘sobering’
In the current era, outcomes are “sobering,” the cardiologist noted. Infective endocarditis carries a 6-month mortality rate of 20%-25% despite early surgery being performed during the index hospitalization in up to 60% of patients, with a relatively high perioperative mortality rate of about 10%. However, the risk of reinfection occurring in a newly implanted cardiac valve is impressively low at about 2%.
Refer early for multimodality imaging and surgical consultation
Transesophageal echocardiography is valuable in assessment of the infected valve. However, when extravalvular extension of the infection is suspected and the echo assessment is nondiagnostic or indeterminate, it’s time to quickly move on to advanced imaging, such as PET-CT.
The ACC/American Heart Association class I recommendations for early surgery in infected native valves haven’t changed substantially in over a decade. Based largely on observational data, there is an association between early surgery and lower in-hospital mortality (Lancet. 2012 Mar 10;379[9819]:965-975).
Class IIa recommendations for native valve surgery include recurrent emboli and a persistent vegetation despite appropriate antibiotic therapy. A “very controversial” class IIb recommendation for surgery because of weak supporting data is the identification of a mobile vegetation larger than 10 mm, particularly if it’s located on an anterior mitral valve leaflet, he said.
If the decision is made to forgo early surgery, be sure to repeat transesophageal echocardiography on day 7-10 to reassess the size of the patient’s vegetation.
“There is an association between size of vegetation and 1-year mortality, with a cut point of greater than 15 mm. Some would argue this constitutes a reasonable indication for early surgery,” Dr. O’Gara noted.
The embolization rate in patients with infective endocarditis is highest during the day before presentation, the day of presentation, and through the first 2 days afterward. The rate drops precipitously within 2 weeks after initiation of appropriate antibiotic therapy. Thus, to utilize early surgery to maximum effect in order to decrease the risk of embolization, it makes sense to operate within the first several days following presentation, before antibiotics have had sufficient time to catch up with the evolving disease process.
Don’t use half measures when it comes to removal of cardiac implanted electronic devices
The guidelines are clear regarding infected pacemakers, implanted cardioverter-defibrillators, and cardiac resynchronization devices: “It all needs to come out,” Dr. O’Gara emphasized. That includes all leads and the generator in patients with documented infection of only one portion of the device system, as a class I, level of evidence B recommendation. Moreover, complete removal of a pacemaker or defibrillator system is deemed “reasonable” as a class IIa recommendation in all patients with valvular infection caused by S. aureus or fungi even in the absence of evidence of device infection.
“I think we as general cardiologists have become increasingly impressed about how sick and festering these kinds of patients can become, even when we’re not able to prove that the lead is infected. The lead looks okay on transesophageal echo or PET-CT, blood cultures are negative, the valvular heart disease is really not that advanced, but several days go by and the patient is just not responding. We should have a high index of suspicion that there’s an infection we cannot appreciate. But obviously, you make these difficult decisions in consultation with your electrophysiology colleagues,” he added.
Know when the cardiologist should say ‘no’ to early aggressive surgery
While an aggressive early surgical approach often pays off in terms of prevention of embolic sequelae and a reduction in heart failure, the timing of surgery in the 20%-40% of patients with infective endocarditis who present with stroke or other neurologic complications remains controversial. An international group of Canadian and French cardiac surgeons and neurologists developed a useful algorithm regarding the types of neurologic complications for which early cardiac surgery is a poor idea because of the high risk of neurologic exacerbation. For example, a mycotic neuroaneurysm is grounds for postponement of cardiac surgery for at least 4 weeks (Circulation. 2016 Oct 25;134[17]:1280-92).
Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.
SNOWMASS, COLO. – Infective endocarditis in 2019 is very different from the disease most physicians encountered in training, both in terms of epidemiology and clinical presentation, Patrick T. O’Gara, MD, observed at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
The classic description of infective endocarditis provided by Sir William Osler, MD, was of a subacute bacterial infection characterized by a long latent phase of low-grade fever, back pain, weight loss, and night sweats. It was mainly a right-heart disease of younger individuals with an infected native valve, and the predominant pathogens were streptococci, Dr. O’Gara said.
“I think in the current era endocarditis is more often characterized by an acute illness with toxic features in the context of adults with a high burden of degenerative diseases – for example, patients with rheumatoid arthritis or psoriatic arthritis on immunosuppressive therapy, or diabetes, end-stage renal disease, and risk factors for hospital-acquired infection. Injectable drug use is through the roof, there’s a wider prevalence of cardiac implanted electronic devices, which are a wonderful place for bacteria to hide, and Staphylococcus aureus has certainly become the leading pathogen with regard to endocarditis in the United States, especially MRSA, often multidrug resistant,” said Dr. O’Gara, professor of medicine at Harvard Medical School, Boston.
“Also, no talk about endocarditis is sufficient without paying some attention to the opioid crisis in which we find ourselves. It’s one of the top three causes of death among young men in the United States, along with accidents and gun violence. No region of the country is spared. This has completely inundated our ER and hospitalist services and our inpatient cardiology services with folks who are often repeat offenders when it comes to the difficulty in being able to give up an injectable drug use habit. They have multiple infections and hospitalizations, tricuspid valve involvement, and depending upon the aggressiveness of the Staphylococcus organism, typically they have left-sided disease with multiple complications, including aortic regurgitation and heart failure,” the cardiologist continued.
This description underscored one of Dr. O’Gara’s major points about the challenges posed by infective endocarditis in contemporary practice: “Expect the unexpected,” he advised. “When you’ve seen one case of infective endocarditis, you’ve seen one case of infective endocarditis.”
Outcomes are ‘sobering’
In the current era, outcomes are “sobering,” the cardiologist noted. Infective endocarditis carries a 6-month mortality rate of 20%-25% despite early surgery being performed during the index hospitalization in up to 60% of patients, with a relatively high perioperative mortality rate of about 10%. However, the risk of reinfection occurring in a newly implanted cardiac valve is impressively low at about 2%.
Refer early for multimodality imaging and surgical consultation
Transesophageal echocardiography is valuable in assessment of the infected valve. However, when extravalvular extension of the infection is suspected and the echo assessment is nondiagnostic or indeterminate, it’s time to quickly move on to advanced imaging, such as PET-CT.
The ACC/American Heart Association class I recommendations for early surgery in infected native valves haven’t changed substantially in over a decade. Based largely on observational data, there is an association between early surgery and lower in-hospital mortality (Lancet. 2012 Mar 10;379[9819]:965-975).
Class IIa recommendations for native valve surgery include recurrent emboli and a persistent vegetation despite appropriate antibiotic therapy. A “very controversial” class IIb recommendation for surgery because of weak supporting data is the identification of a mobile vegetation larger than 10 mm, particularly if it’s located on an anterior mitral valve leaflet, he said.
If the decision is made to forgo early surgery, be sure to repeat transesophageal echocardiography on day 7-10 to reassess the size of the patient’s vegetation.
“There is an association between size of vegetation and 1-year mortality, with a cut point of greater than 15 mm. Some would argue this constitutes a reasonable indication for early surgery,” Dr. O’Gara noted.
The embolization rate in patients with infective endocarditis is highest during the day before presentation, the day of presentation, and through the first 2 days afterward. The rate drops precipitously within 2 weeks after initiation of appropriate antibiotic therapy. Thus, to utilize early surgery to maximum effect in order to decrease the risk of embolization, it makes sense to operate within the first several days following presentation, before antibiotics have had sufficient time to catch up with the evolving disease process.
Don’t use half measures when it comes to removal of cardiac implanted electronic devices
The guidelines are clear regarding infected pacemakers, implanted cardioverter-defibrillators, and cardiac resynchronization devices: “It all needs to come out,” Dr. O’Gara emphasized. That includes all leads and the generator in patients with documented infection of only one portion of the device system, as a class I, level of evidence B recommendation. Moreover, complete removal of a pacemaker or defibrillator system is deemed “reasonable” as a class IIa recommendation in all patients with valvular infection caused by S. aureus or fungi even in the absence of evidence of device infection.
“I think we as general cardiologists have become increasingly impressed about how sick and festering these kinds of patients can become, even when we’re not able to prove that the lead is infected. The lead looks okay on transesophageal echo or PET-CT, blood cultures are negative, the valvular heart disease is really not that advanced, but several days go by and the patient is just not responding. We should have a high index of suspicion that there’s an infection we cannot appreciate. But obviously, you make these difficult decisions in consultation with your electrophysiology colleagues,” he added.
Know when the cardiologist should say ‘no’ to early aggressive surgery
While an aggressive early surgical approach often pays off in terms of prevention of embolic sequelae and a reduction in heart failure, the timing of surgery in the 20%-40% of patients with infective endocarditis who present with stroke or other neurologic complications remains controversial. An international group of Canadian and French cardiac surgeons and neurologists developed a useful algorithm regarding the types of neurologic complications for which early cardiac surgery is a poor idea because of the high risk of neurologic exacerbation. For example, a mycotic neuroaneurysm is grounds for postponement of cardiac surgery for at least 4 weeks (Circulation. 2016 Oct 25;134[17]:1280-92).
Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.
SNOWMASS, COLO. – Infective endocarditis in 2019 is very different from the disease most physicians encountered in training, both in terms of epidemiology and clinical presentation, Patrick T. O’Gara, MD, observed at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
The classic description of infective endocarditis provided by Sir William Osler, MD, was of a subacute bacterial infection characterized by a long latent phase of low-grade fever, back pain, weight loss, and night sweats. It was mainly a right-heart disease of younger individuals with an infected native valve, and the predominant pathogens were streptococci, Dr. O’Gara said.
“I think in the current era endocarditis is more often characterized by an acute illness with toxic features in the context of adults with a high burden of degenerative diseases – for example, patients with rheumatoid arthritis or psoriatic arthritis on immunosuppressive therapy, or diabetes, end-stage renal disease, and risk factors for hospital-acquired infection. Injectable drug use is through the roof, there’s a wider prevalence of cardiac implanted electronic devices, which are a wonderful place for bacteria to hide, and Staphylococcus aureus has certainly become the leading pathogen with regard to endocarditis in the United States, especially MRSA, often multidrug resistant,” said Dr. O’Gara, professor of medicine at Harvard Medical School, Boston.
“Also, no talk about endocarditis is sufficient without paying some attention to the opioid crisis in which we find ourselves. It’s one of the top three causes of death among young men in the United States, along with accidents and gun violence. No region of the country is spared. This has completely inundated our ER and hospitalist services and our inpatient cardiology services with folks who are often repeat offenders when it comes to the difficulty in being able to give up an injectable drug use habit. They have multiple infections and hospitalizations, tricuspid valve involvement, and depending upon the aggressiveness of the Staphylococcus organism, typically they have left-sided disease with multiple complications, including aortic regurgitation and heart failure,” the cardiologist continued.
This description underscored one of Dr. O’Gara’s major points about the challenges posed by infective endocarditis in contemporary practice: “Expect the unexpected,” he advised. “When you’ve seen one case of infective endocarditis, you’ve seen one case of infective endocarditis.”
Outcomes are ‘sobering’
In the current era, outcomes are “sobering,” the cardiologist noted. Infective endocarditis carries a 6-month mortality rate of 20%-25% despite early surgery being performed during the index hospitalization in up to 60% of patients, with a relatively high perioperative mortality rate of about 10%. However, the risk of reinfection occurring in a newly implanted cardiac valve is impressively low at about 2%.
Refer early for multimodality imaging and surgical consultation
Transesophageal echocardiography is valuable in assessment of the infected valve. However, when extravalvular extension of the infection is suspected and the echo assessment is nondiagnostic or indeterminate, it’s time to quickly move on to advanced imaging, such as PET-CT.
The ACC/American Heart Association class I recommendations for early surgery in infected native valves haven’t changed substantially in over a decade. Based largely on observational data, there is an association between early surgery and lower in-hospital mortality (Lancet. 2012 Mar 10;379[9819]:965-975).
Class IIa recommendations for native valve surgery include recurrent emboli and a persistent vegetation despite appropriate antibiotic therapy. A “very controversial” class IIb recommendation for surgery because of weak supporting data is the identification of a mobile vegetation larger than 10 mm, particularly if it’s located on an anterior mitral valve leaflet, he said.
If the decision is made to forgo early surgery, be sure to repeat transesophageal echocardiography on day 7-10 to reassess the size of the patient’s vegetation.
“There is an association between size of vegetation and 1-year mortality, with a cut point of greater than 15 mm. Some would argue this constitutes a reasonable indication for early surgery,” Dr. O’Gara noted.
The embolization rate in patients with infective endocarditis is highest during the day before presentation, the day of presentation, and through the first 2 days afterward. The rate drops precipitously within 2 weeks after initiation of appropriate antibiotic therapy. Thus, to utilize early surgery to maximum effect in order to decrease the risk of embolization, it makes sense to operate within the first several days following presentation, before antibiotics have had sufficient time to catch up with the evolving disease process.
Don’t use half measures when it comes to removal of cardiac implanted electronic devices
The guidelines are clear regarding infected pacemakers, implanted cardioverter-defibrillators, and cardiac resynchronization devices: “It all needs to come out,” Dr. O’Gara emphasized. That includes all leads and the generator in patients with documented infection of only one portion of the device system, as a class I, level of evidence B recommendation. Moreover, complete removal of a pacemaker or defibrillator system is deemed “reasonable” as a class IIa recommendation in all patients with valvular infection caused by S. aureus or fungi even in the absence of evidence of device infection.
“I think we as general cardiologists have become increasingly impressed about how sick and festering these kinds of patients can become, even when we’re not able to prove that the lead is infected. The lead looks okay on transesophageal echo or PET-CT, blood cultures are negative, the valvular heart disease is really not that advanced, but several days go by and the patient is just not responding. We should have a high index of suspicion that there’s an infection we cannot appreciate. But obviously, you make these difficult decisions in consultation with your electrophysiology colleagues,” he added.
Know when the cardiologist should say ‘no’ to early aggressive surgery
While an aggressive early surgical approach often pays off in terms of prevention of embolic sequelae and a reduction in heart failure, the timing of surgery in the 20%-40% of patients with infective endocarditis who present with stroke or other neurologic complications remains controversial. An international group of Canadian and French cardiac surgeons and neurologists developed a useful algorithm regarding the types of neurologic complications for which early cardiac surgery is a poor idea because of the high risk of neurologic exacerbation. For example, a mycotic neuroaneurysm is grounds for postponement of cardiac surgery for at least 4 weeks (Circulation. 2016 Oct 25;134[17]:1280-92).
Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.
REPORTING FROM ACC SNOWMASS 2019
Report: Cutting sodium consumption recommended
according to a report outlining the first-ever Dietary Reference Intakes (DRIs) recommendation intended to address chronic disease risk.
For individuals aged 14 years and older consuming sodium above that level, cutting back could reduce their risk for hypertension and other chronic diseases, according to the report from the National Academies of Sciences, Engineering, and Medicine.
That cutoff, referred to as a Chronic Disease Risk Reduction Intake (CDRR), represents an expansion of the DRIs model beyond the Recommended Dietary Allowance (RDA) and other measures of adequacy, and the Tolerable Upper Intake Level (UL), which is the maximum intake unlikely to result in adverse health effects, a report author said in a press conference.
“CDRR is a level now that will join all the rest of the alphabet soup and be a part of how we describe recommended dietary intakes,” said Virginia A. Stallings, MD, chair of the committee that reviewed the sodium and potassium DRIs. Most U.S. adults are already consuming sodium above the recommended CDRR, said Dr. Stallings, who is a professor of pediatrics at the University of Pennsylvania, Philadelphia, and the director of the Nutrition Center at Children’s Hospital of Philadelphia.
The recommendation to reduce sodium intakes to below 2,300 mg/day applies to both hypertensive and normotensive individuals, and it could be particularly beneficial in older adults, non-Hispanic blacks, and other groups at higher risk of cardiovascular disease, Dr. Stallings and her coauthors of the new report wrote. The DRIs established in 2005 for both sodium and potassium are also updated based on new methodology in this report
Lower sodium CDRRs were set for younger individuals. Children aged 1-3 years should cut back if sodium intake is above 1,200 mg/day, while the levels for children aged 4-8 years and 9-13 years were set at 1,500 and 1,800 mg/day, respectively, according to the report.
By contrast, authors of this report were unable to establish a CDRR level for potassium based on current evidence. However, that doesn’t rule out the possibility that changing potassium intake could be beneficial, they suggested, adding that the effects of potassium need to be further explored.
Sodium and potassium play important roles in maintaining physiologic homeostasis, and they have also been implicated in risk of cardiovascular disease, mainly through their effects on blood pressure, and other chronic diseases.
“The unique nature of potassium and sodium – that is, the coexistence of their essentiality with a relationship to adverse health effects, including chronic disease risk – necessitated a new approach to the review of intake recommendations for these nutrients within the [DRI] context,” the report reads. The report also affirms, and in some cases revises, levels of sodium and potassium assumed to be adequate in healthy individuals that had been established in 2005. The sodium Adequate Intake (AI) levels for individuals aged 14-50 years is unchanged at 1,500 mg daily, but that for individuals aged 51 years and older has been increased to the 1,500-mg level.
“As we examined the evidence and looked specifically at those age cuts, there was no evidence that older people needed less sodium,” Dr. Stallings said in the press conference.
Potassium AIs were decreased for most age groups. For adults, the new recommended potassium AIs are 3,400 mg/day in men and 2,600 mg/day in women, whereas the AI for potassium was 4,700 mg/day for all adults in the 2005 recommendations.
In 2005, much of the evidence used to establish the potassium AI values was based on research studies that included potassium supplementation, rather than simply potassium intake in the usual diet. “In our process, we did not use supplementation studies, but we used the intake of apparently healthy people,” Dr. Stallings said in the press conference.
Less than half of U.S. and Canadian adults have potassium intakes that meet or exceed the potassium AI, with intakes lowest among non-Hispanic blacks, Dr. Stallings said in the press conference.
Dietary potassium intake is related to fruit and vegetable consumption, which rarely meets the recommended servings per day, Dr. Stallings and her colleagues wrote in a preface to the National Academies report. Milk, white potatoes, and fruit are higher sources of dietary potassium, she said, while coffee is the leading source of potassium for Americans aged 51 years and older.
By contrast, most sodium in the modern diet comes from commercially prepared foods and beverages, instead of consumers adding salt at the time of cooking or eating, Dr. Stallings wrote.
“For the desired public health benefit of reduced sodium intake to be achieved, more attention must be paid by industry to reducing sodium in the food supply and by consumers who have the needed sodium content information and an understanding of how to make health-inspired food choices,” they wrote in the report.
The American Heart Association’s CEO, Nancy Brown, expressed her support for the new recommendation for sodium intake. The recommendation “aligns with what the American Heart Association and other prominent public health organizations have been saying for years: We must eat less salt,” she said.
“Our excessive sodium intake isn’t entirely driven by the salt shaker; it’s largely controlled by the food industry. More than 70 percent of sodium consumed is added to food before it reaches our plates. It is added in restaurants and during the manufacturing of processed and prepackaged foods,” she claimed. “We hope this report encourages the Food and Drug Administration to quickly release its voluntary sodium reduction targets for the food industry. School leaders should also take note and reject the recent U.S. Department of Agriculture decision to weaken sodium standards in school meals and continue their commitment to serve students healthier foods.”
The DRIs report on sodium and potassium was supported by contracts between the National Academy of Sciences and the Centers for Disease Control, Food and Drug Administration, Health Canada, National Institutes of Health, Public Health Agency of Canada, and the Department of Agriculture. Partial support also came from the National Academy of Sciences W. K. Kellogg Foundation Fund and the National Academy of Medicine.
SOURCE: National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for sodium and potassium. Washington: The National Academies Press. doi: 10.17226/25353.
according to a report outlining the first-ever Dietary Reference Intakes (DRIs) recommendation intended to address chronic disease risk.
For individuals aged 14 years and older consuming sodium above that level, cutting back could reduce their risk for hypertension and other chronic diseases, according to the report from the National Academies of Sciences, Engineering, and Medicine.
That cutoff, referred to as a Chronic Disease Risk Reduction Intake (CDRR), represents an expansion of the DRIs model beyond the Recommended Dietary Allowance (RDA) and other measures of adequacy, and the Tolerable Upper Intake Level (UL), which is the maximum intake unlikely to result in adverse health effects, a report author said in a press conference.
“CDRR is a level now that will join all the rest of the alphabet soup and be a part of how we describe recommended dietary intakes,” said Virginia A. Stallings, MD, chair of the committee that reviewed the sodium and potassium DRIs. Most U.S. adults are already consuming sodium above the recommended CDRR, said Dr. Stallings, who is a professor of pediatrics at the University of Pennsylvania, Philadelphia, and the director of the Nutrition Center at Children’s Hospital of Philadelphia.
The recommendation to reduce sodium intakes to below 2,300 mg/day applies to both hypertensive and normotensive individuals, and it could be particularly beneficial in older adults, non-Hispanic blacks, and other groups at higher risk of cardiovascular disease, Dr. Stallings and her coauthors of the new report wrote. The DRIs established in 2005 for both sodium and potassium are also updated based on new methodology in this report
Lower sodium CDRRs were set for younger individuals. Children aged 1-3 years should cut back if sodium intake is above 1,200 mg/day, while the levels for children aged 4-8 years and 9-13 years were set at 1,500 and 1,800 mg/day, respectively, according to the report.
By contrast, authors of this report were unable to establish a CDRR level for potassium based on current evidence. However, that doesn’t rule out the possibility that changing potassium intake could be beneficial, they suggested, adding that the effects of potassium need to be further explored.
Sodium and potassium play important roles in maintaining physiologic homeostasis, and they have also been implicated in risk of cardiovascular disease, mainly through their effects on blood pressure, and other chronic diseases.
“The unique nature of potassium and sodium – that is, the coexistence of their essentiality with a relationship to adverse health effects, including chronic disease risk – necessitated a new approach to the review of intake recommendations for these nutrients within the [DRI] context,” the report reads. The report also affirms, and in some cases revises, levels of sodium and potassium assumed to be adequate in healthy individuals that had been established in 2005. The sodium Adequate Intake (AI) levels for individuals aged 14-50 years is unchanged at 1,500 mg daily, but that for individuals aged 51 years and older has been increased to the 1,500-mg level.
“As we examined the evidence and looked specifically at those age cuts, there was no evidence that older people needed less sodium,” Dr. Stallings said in the press conference.
Potassium AIs were decreased for most age groups. For adults, the new recommended potassium AIs are 3,400 mg/day in men and 2,600 mg/day in women, whereas the AI for potassium was 4,700 mg/day for all adults in the 2005 recommendations.
In 2005, much of the evidence used to establish the potassium AI values was based on research studies that included potassium supplementation, rather than simply potassium intake in the usual diet. “In our process, we did not use supplementation studies, but we used the intake of apparently healthy people,” Dr. Stallings said in the press conference.
Less than half of U.S. and Canadian adults have potassium intakes that meet or exceed the potassium AI, with intakes lowest among non-Hispanic blacks, Dr. Stallings said in the press conference.
Dietary potassium intake is related to fruit and vegetable consumption, which rarely meets the recommended servings per day, Dr. Stallings and her colleagues wrote in a preface to the National Academies report. Milk, white potatoes, and fruit are higher sources of dietary potassium, she said, while coffee is the leading source of potassium for Americans aged 51 years and older.
By contrast, most sodium in the modern diet comes from commercially prepared foods and beverages, instead of consumers adding salt at the time of cooking or eating, Dr. Stallings wrote.
“For the desired public health benefit of reduced sodium intake to be achieved, more attention must be paid by industry to reducing sodium in the food supply and by consumers who have the needed sodium content information and an understanding of how to make health-inspired food choices,” they wrote in the report.
The American Heart Association’s CEO, Nancy Brown, expressed her support for the new recommendation for sodium intake. The recommendation “aligns with what the American Heart Association and other prominent public health organizations have been saying for years: We must eat less salt,” she said.
“Our excessive sodium intake isn’t entirely driven by the salt shaker; it’s largely controlled by the food industry. More than 70 percent of sodium consumed is added to food before it reaches our plates. It is added in restaurants and during the manufacturing of processed and prepackaged foods,” she claimed. “We hope this report encourages the Food and Drug Administration to quickly release its voluntary sodium reduction targets for the food industry. School leaders should also take note and reject the recent U.S. Department of Agriculture decision to weaken sodium standards in school meals and continue their commitment to serve students healthier foods.”
The DRIs report on sodium and potassium was supported by contracts between the National Academy of Sciences and the Centers for Disease Control, Food and Drug Administration, Health Canada, National Institutes of Health, Public Health Agency of Canada, and the Department of Agriculture. Partial support also came from the National Academy of Sciences W. K. Kellogg Foundation Fund and the National Academy of Medicine.
SOURCE: National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for sodium and potassium. Washington: The National Academies Press. doi: 10.17226/25353.
according to a report outlining the first-ever Dietary Reference Intakes (DRIs) recommendation intended to address chronic disease risk.
For individuals aged 14 years and older consuming sodium above that level, cutting back could reduce their risk for hypertension and other chronic diseases, according to the report from the National Academies of Sciences, Engineering, and Medicine.
That cutoff, referred to as a Chronic Disease Risk Reduction Intake (CDRR), represents an expansion of the DRIs model beyond the Recommended Dietary Allowance (RDA) and other measures of adequacy, and the Tolerable Upper Intake Level (UL), which is the maximum intake unlikely to result in adverse health effects, a report author said in a press conference.
“CDRR is a level now that will join all the rest of the alphabet soup and be a part of how we describe recommended dietary intakes,” said Virginia A. Stallings, MD, chair of the committee that reviewed the sodium and potassium DRIs. Most U.S. adults are already consuming sodium above the recommended CDRR, said Dr. Stallings, who is a professor of pediatrics at the University of Pennsylvania, Philadelphia, and the director of the Nutrition Center at Children’s Hospital of Philadelphia.
The recommendation to reduce sodium intakes to below 2,300 mg/day applies to both hypertensive and normotensive individuals, and it could be particularly beneficial in older adults, non-Hispanic blacks, and other groups at higher risk of cardiovascular disease, Dr. Stallings and her coauthors of the new report wrote. The DRIs established in 2005 for both sodium and potassium are also updated based on new methodology in this report
Lower sodium CDRRs were set for younger individuals. Children aged 1-3 years should cut back if sodium intake is above 1,200 mg/day, while the levels for children aged 4-8 years and 9-13 years were set at 1,500 and 1,800 mg/day, respectively, according to the report.
By contrast, authors of this report were unable to establish a CDRR level for potassium based on current evidence. However, that doesn’t rule out the possibility that changing potassium intake could be beneficial, they suggested, adding that the effects of potassium need to be further explored.
Sodium and potassium play important roles in maintaining physiologic homeostasis, and they have also been implicated in risk of cardiovascular disease, mainly through their effects on blood pressure, and other chronic diseases.
“The unique nature of potassium and sodium – that is, the coexistence of their essentiality with a relationship to adverse health effects, including chronic disease risk – necessitated a new approach to the review of intake recommendations for these nutrients within the [DRI] context,” the report reads. The report also affirms, and in some cases revises, levels of sodium and potassium assumed to be adequate in healthy individuals that had been established in 2005. The sodium Adequate Intake (AI) levels for individuals aged 14-50 years is unchanged at 1,500 mg daily, but that for individuals aged 51 years and older has been increased to the 1,500-mg level.
“As we examined the evidence and looked specifically at those age cuts, there was no evidence that older people needed less sodium,” Dr. Stallings said in the press conference.
Potassium AIs were decreased for most age groups. For adults, the new recommended potassium AIs are 3,400 mg/day in men and 2,600 mg/day in women, whereas the AI for potassium was 4,700 mg/day for all adults in the 2005 recommendations.
In 2005, much of the evidence used to establish the potassium AI values was based on research studies that included potassium supplementation, rather than simply potassium intake in the usual diet. “In our process, we did not use supplementation studies, but we used the intake of apparently healthy people,” Dr. Stallings said in the press conference.
Less than half of U.S. and Canadian adults have potassium intakes that meet or exceed the potassium AI, with intakes lowest among non-Hispanic blacks, Dr. Stallings said in the press conference.
Dietary potassium intake is related to fruit and vegetable consumption, which rarely meets the recommended servings per day, Dr. Stallings and her colleagues wrote in a preface to the National Academies report. Milk, white potatoes, and fruit are higher sources of dietary potassium, she said, while coffee is the leading source of potassium for Americans aged 51 years and older.
By contrast, most sodium in the modern diet comes from commercially prepared foods and beverages, instead of consumers adding salt at the time of cooking or eating, Dr. Stallings wrote.
“For the desired public health benefit of reduced sodium intake to be achieved, more attention must be paid by industry to reducing sodium in the food supply and by consumers who have the needed sodium content information and an understanding of how to make health-inspired food choices,” they wrote in the report.
The American Heart Association’s CEO, Nancy Brown, expressed her support for the new recommendation for sodium intake. The recommendation “aligns with what the American Heart Association and other prominent public health organizations have been saying for years: We must eat less salt,” she said.
“Our excessive sodium intake isn’t entirely driven by the salt shaker; it’s largely controlled by the food industry. More than 70 percent of sodium consumed is added to food before it reaches our plates. It is added in restaurants and during the manufacturing of processed and prepackaged foods,” she claimed. “We hope this report encourages the Food and Drug Administration to quickly release its voluntary sodium reduction targets for the food industry. School leaders should also take note and reject the recent U.S. Department of Agriculture decision to weaken sodium standards in school meals and continue their commitment to serve students healthier foods.”
The DRIs report on sodium and potassium was supported by contracts between the National Academy of Sciences and the Centers for Disease Control, Food and Drug Administration, Health Canada, National Institutes of Health, Public Health Agency of Canada, and the Department of Agriculture. Partial support also came from the National Academy of Sciences W. K. Kellogg Foundation Fund and the National Academy of Medicine.
SOURCE: National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for sodium and potassium. Washington: The National Academies Press. doi: 10.17226/25353.
A couple of little known side effects of medications
A 46-year-old woman with diabetes and seizure disorder presents with nausea and fatigue. Her physical exam is unremarkable.
Meds: Glyburide 5 mg daily, metformin 850 mg b.i.d., phenytoin 300 mg daily, topiramate 400 mg daily, pantoprazole 40 mg daily.
Labs: Na 133, K 3.9, Cl 112, HCO3 13, Glu 158, Bun 18, Cr 1.0.
What is the most likely cause of this patient’s acidosis?
A. Phenytoin
B. Topiramate
C. Metformin
D. Pantoprazole
The correct answer to this question is topiramate.
Metformin has had warnings about risk of lactic acidosis occurring in patients with kidney disease, but there is no evidence that metformin is associated with lactic acidosis or raised serum lactate levels in patients with diabetes with normal renal function.1 and its use may decrease CV risk in patients with stage 3 CKD.2 This patient has a non–anion gap acidosis (anion gap is 8).
Topiramate acts as a carbonic anhydrase inhibitor, which causes impairment of both the normal reabsorption of filtered HCO3 by the proximal renal tubule and the excretion of hydrogen ion by the distal tubule.3 Acidosis occurs in most patients who are treated with topiramate. Dr. Ture and colleagues did a cross-sectional study to assess the frequency of metabolic acidosis in patients who were taking topiramate.4 Eighty patients who were on topiramate for seizure prevention prior to elective craniotomy were studied. Metabolic acidosis was present in 71% of the patients. Patients treated with topiramate also have a higher risk for kidney stones and uric acid elevation.
A 60-year-old patient presents with right great toe pain. On exam he has warmth and erythema of the 1st MTP joint. Aspiration of the joint shows uric acid crystals. He has had BP’s of 150-160 mm Hg systolic on his home BP monitoring over the past 6 months. In clinic today BP is 156/90 mm Hg. Labs: Bun 10, Cr 1.0, K 3.8, Uric acid 7.4.
Which blood pressure medication would you recommend?
A. Hydrochlorothiazide
B. Chlorthalidone
C. Lisinopril
D. Losartan
E. Irbesartan
In a patient with gout, diuretics should be avoided if possible, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects and lowers uric acid levels, a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.5-6 The uric acid lowering appears to be a probenecid-like effect. Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Dr. Matsumura et al. looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.7 They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).
Pearls: Topiramate acts as a cerbonic anhydrase inhibitor and can cause a non–anion gap acidosis. Losartan has a modest uricosuric effect and can modestly lower uric acid levels. This is a unique property of losartan and is not shared by other ARBs.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at dpaauw@uw.edu.
References
1. Salpeter SR et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;4:CD002967.
2. Charytan DM et al. Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2019 Jan 22. doi: 10.1111/dom.13642.
3. Mirza N et al. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br J Clin Pharmacol. 2009 Nov;68(5):655-61.
4. Ture H et al. The frequency and severity of metabolic acidosis related to topiramate. J Int Med Res. 2016;44(6):1376-80.
5. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.
6. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.
7. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: the COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.
A 46-year-old woman with diabetes and seizure disorder presents with nausea and fatigue. Her physical exam is unremarkable.
Meds: Glyburide 5 mg daily, metformin 850 mg b.i.d., phenytoin 300 mg daily, topiramate 400 mg daily, pantoprazole 40 mg daily.
Labs: Na 133, K 3.9, Cl 112, HCO3 13, Glu 158, Bun 18, Cr 1.0.
What is the most likely cause of this patient’s acidosis?
A. Phenytoin
B. Topiramate
C. Metformin
D. Pantoprazole
The correct answer to this question is topiramate.
Metformin has had warnings about risk of lactic acidosis occurring in patients with kidney disease, but there is no evidence that metformin is associated with lactic acidosis or raised serum lactate levels in patients with diabetes with normal renal function.1 and its use may decrease CV risk in patients with stage 3 CKD.2 This patient has a non–anion gap acidosis (anion gap is 8).
Topiramate acts as a carbonic anhydrase inhibitor, which causes impairment of both the normal reabsorption of filtered HCO3 by the proximal renal tubule and the excretion of hydrogen ion by the distal tubule.3 Acidosis occurs in most patients who are treated with topiramate. Dr. Ture and colleagues did a cross-sectional study to assess the frequency of metabolic acidosis in patients who were taking topiramate.4 Eighty patients who were on topiramate for seizure prevention prior to elective craniotomy were studied. Metabolic acidosis was present in 71% of the patients. Patients treated with topiramate also have a higher risk for kidney stones and uric acid elevation.
A 60-year-old patient presents with right great toe pain. On exam he has warmth and erythema of the 1st MTP joint. Aspiration of the joint shows uric acid crystals. He has had BP’s of 150-160 mm Hg systolic on his home BP monitoring over the past 6 months. In clinic today BP is 156/90 mm Hg. Labs: Bun 10, Cr 1.0, K 3.8, Uric acid 7.4.
Which blood pressure medication would you recommend?
A. Hydrochlorothiazide
B. Chlorthalidone
C. Lisinopril
D. Losartan
E. Irbesartan
In a patient with gout, diuretics should be avoided if possible, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects and lowers uric acid levels, a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.5-6 The uric acid lowering appears to be a probenecid-like effect. Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Dr. Matsumura et al. looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.7 They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).
Pearls: Topiramate acts as a cerbonic anhydrase inhibitor and can cause a non–anion gap acidosis. Losartan has a modest uricosuric effect and can modestly lower uric acid levels. This is a unique property of losartan and is not shared by other ARBs.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at dpaauw@uw.edu.
References
1. Salpeter SR et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;4:CD002967.
2. Charytan DM et al. Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2019 Jan 22. doi: 10.1111/dom.13642.
3. Mirza N et al. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br J Clin Pharmacol. 2009 Nov;68(5):655-61.
4. Ture H et al. The frequency and severity of metabolic acidosis related to topiramate. J Int Med Res. 2016;44(6):1376-80.
5. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.
6. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.
7. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: the COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.
A 46-year-old woman with diabetes and seizure disorder presents with nausea and fatigue. Her physical exam is unremarkable.
Meds: Glyburide 5 mg daily, metformin 850 mg b.i.d., phenytoin 300 mg daily, topiramate 400 mg daily, pantoprazole 40 mg daily.
Labs: Na 133, K 3.9, Cl 112, HCO3 13, Glu 158, Bun 18, Cr 1.0.
What is the most likely cause of this patient’s acidosis?
A. Phenytoin
B. Topiramate
C. Metformin
D. Pantoprazole
The correct answer to this question is topiramate.
Metformin has had warnings about risk of lactic acidosis occurring in patients with kidney disease, but there is no evidence that metformin is associated with lactic acidosis or raised serum lactate levels in patients with diabetes with normal renal function.1 and its use may decrease CV risk in patients with stage 3 CKD.2 This patient has a non–anion gap acidosis (anion gap is 8).
Topiramate acts as a carbonic anhydrase inhibitor, which causes impairment of both the normal reabsorption of filtered HCO3 by the proximal renal tubule and the excretion of hydrogen ion by the distal tubule.3 Acidosis occurs in most patients who are treated with topiramate. Dr. Ture and colleagues did a cross-sectional study to assess the frequency of metabolic acidosis in patients who were taking topiramate.4 Eighty patients who were on topiramate for seizure prevention prior to elective craniotomy were studied. Metabolic acidosis was present in 71% of the patients. Patients treated with topiramate also have a higher risk for kidney stones and uric acid elevation.
A 60-year-old patient presents with right great toe pain. On exam he has warmth and erythema of the 1st MTP joint. Aspiration of the joint shows uric acid crystals. He has had BP’s of 150-160 mm Hg systolic on his home BP monitoring over the past 6 months. In clinic today BP is 156/90 mm Hg. Labs: Bun 10, Cr 1.0, K 3.8, Uric acid 7.4.
Which blood pressure medication would you recommend?
A. Hydrochlorothiazide
B. Chlorthalidone
C. Lisinopril
D. Losartan
E. Irbesartan
In a patient with gout, diuretics should be avoided if possible, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects and lowers uric acid levels, a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.5-6 The uric acid lowering appears to be a probenecid-like effect. Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Dr. Matsumura et al. looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.7 They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).
Pearls: Topiramate acts as a cerbonic anhydrase inhibitor and can cause a non–anion gap acidosis. Losartan has a modest uricosuric effect and can modestly lower uric acid levels. This is a unique property of losartan and is not shared by other ARBs.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at dpaauw@uw.edu.
References
1. Salpeter SR et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;4:CD002967.
2. Charytan DM et al. Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2019 Jan 22. doi: 10.1111/dom.13642.
3. Mirza N et al. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br J Clin Pharmacol. 2009 Nov;68(5):655-61.
4. Ture H et al. The frequency and severity of metabolic acidosis related to topiramate. J Int Med Res. 2016;44(6):1376-80.
5. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.
6. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.
7. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: the COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.
New SOFA version could streamline outcomes research
SAN DIEGO – The new method replaces some of SOFA’s more subjective criteria with objective measures.
eSOFA relies on electronic health records to reduce reliance on administrative records, which suffer from cross-hospital variability in diagnosis and coding practices, as well as changes in these practices over time. The diagnosis of sepsis itself is also highly subjective. Instead, eSOFA determines dysfunction in six organ systems, indicated by use of vasopressors and mechanical ventilation, and the presence of abnormal laboratory values.
“The SOFA score includes measures like the Glasgow Coma Scale, which undoubtedly at the bedside is a very important clinical sign, but when trying to implement something that is objective for purposes of retrospective case counting and standardization, it can be problematic. The measures we chose [for eSOFA] are concrete, important maneuvers that were initiated by clinicians,” Chanu Rhee, MD, said in an interview.
Dr. Rhee is assistant professor of population medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston. He presented the results of the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine, and the work was simultaneously published online in Critical Care Medicine.
Key elements of SOFA that pose challenges for administrative data include: PaO2/FiO2, which are not routinely measured, and can be difficult to assign to arterial or venous samples; inconsistency in blood pressure and transient increases in vasopressor dose; the subjectivity of the Glasgow Coma Scale, which is also difficult to assess in sedated patients; and inconsistent urine output.
eSOFA introduced new measures for various organ functions, including cardiovascular (vasopressor initiation), pulmonary (mechanical ventilation initiation), renal (doubling of creatinine levels or a 50% or greater decrease in estimated glomerular filtration rate, compared with baseline), hepatic (bilirubin levels greater than or equal to 2.0 mg/dL and at least doubled from baseline), coagulation (platelet count less than 100 cells/mcL and at least a 50% decrease from a baseline of at least 100 cells/mcL), and neurological (lactate greater than or equal to 2.0 mmol/L).
“[eSOFA] opens a window into inter-facility comparisons that has not been possible to do. It’s really critical to ask, ‘How am I doing compared to my peer institutions?’ If you’re doing worse, you can look at the whole spectrum of things to try to drive improvements in care,” said Dr. Rhee.
The new tool isn’t just limited to quality improvement research. Shaeesta Khan, MD, assistant professor of critical care medicine at Geisinger Medical Center,Danville, Pa., has found eSOFA to be useful in her research into how genetic polymorphisms play a role in sepsis outcomes. Geisinger has a large population of patients with completed whole genome sequencing, and Dr. Khan began by trying to glean sepsis outcomes from administrative data.
“I explained SOFA scores to our data broker, and he pulled up 3,000 patients and gave everybody a SOFA score based on the algorithm he created, and it was all over the chart. Once I started doing chart review and phenotype verification, it was just a nightmare,” Dr. Khan said in an interview.
After struggling with the project, one of her mentors put her in touch with one of Dr. Rhee’s colleagues, and she asked the data broker to modify the eSOFA algorithm to fit her specific criteria. “It was a blessing,” she said.
Now, she has data from 5,000 patients with sepsis and sequenced DNA, and can begin comparing outcomes and genetic variants. About 20 candidate genes for sepsis outcomes have been identified to date, but she has a particular interest in PCSK9, which is an innate immune system regulator. She hopes to present results at CCC49 in 2020.
Validating mortality prediction
The researchers compared eSOFA and SOFA in a sample from 111 U.S. acute care hospitals to see if eSOFA had a comparable predictive validity for mortality. The analysis included 942,360 adults seen between 2013 and 2015. A total of 11.1% (104,903) had a presumed serious infection based on a blood culture order and at least 4 consecutive days of antibiotic use.
The analysis showed that 6.1% of those with infections had a sepsis event based on at least a 2-point increase in SOFA score from baseline (Sepsis-3 criteria), compared with 4.4% identified by at least a 1-point increase in eSOFA score. A total of 34,174 patients (3.6%) overlapped between SOFA and eSOFA, which represented good agreement (Cronbach’s alpha, 0.81). Compared with SOFA/Sepsis-3, eSOFA had a sensitivity of 60%, and a positive predictive value of 82%.
Patients identified by eSOFA were slightly more ill, with more requiring ICU admission (41% vs. 35%), and a greater frequency of in-hospital mortality (17% vs. 14%). Those patients who were identified by SOFA/Sepsis-3, but missed by eSOFA, had an overall lower mortality (6%).
There was a similar risk of mortality across deciles between SOFA- and eSOFA-identified sepsis patients. In an independent analysis of four hospitals from the Emory system, the area under the receiver operating characteristics was 0.77 for eSOFA and 0.76 for SOFA (P less than .001).
The Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality funded the study. Dr. Rhee and Dr. Khan have no relevant financial conflicts.
SOURCE: Rhee C et al. Crit Care Med. 2019;47(3):307-14.
SAN DIEGO – The new method replaces some of SOFA’s more subjective criteria with objective measures.
eSOFA relies on electronic health records to reduce reliance on administrative records, which suffer from cross-hospital variability in diagnosis and coding practices, as well as changes in these practices over time. The diagnosis of sepsis itself is also highly subjective. Instead, eSOFA determines dysfunction in six organ systems, indicated by use of vasopressors and mechanical ventilation, and the presence of abnormal laboratory values.
“The SOFA score includes measures like the Glasgow Coma Scale, which undoubtedly at the bedside is a very important clinical sign, but when trying to implement something that is objective for purposes of retrospective case counting and standardization, it can be problematic. The measures we chose [for eSOFA] are concrete, important maneuvers that were initiated by clinicians,” Chanu Rhee, MD, said in an interview.
Dr. Rhee is assistant professor of population medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston. He presented the results of the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine, and the work was simultaneously published online in Critical Care Medicine.
Key elements of SOFA that pose challenges for administrative data include: PaO2/FiO2, which are not routinely measured, and can be difficult to assign to arterial or venous samples; inconsistency in blood pressure and transient increases in vasopressor dose; the subjectivity of the Glasgow Coma Scale, which is also difficult to assess in sedated patients; and inconsistent urine output.
eSOFA introduced new measures for various organ functions, including cardiovascular (vasopressor initiation), pulmonary (mechanical ventilation initiation), renal (doubling of creatinine levels or a 50% or greater decrease in estimated glomerular filtration rate, compared with baseline), hepatic (bilirubin levels greater than or equal to 2.0 mg/dL and at least doubled from baseline), coagulation (platelet count less than 100 cells/mcL and at least a 50% decrease from a baseline of at least 100 cells/mcL), and neurological (lactate greater than or equal to 2.0 mmol/L).
“[eSOFA] opens a window into inter-facility comparisons that has not been possible to do. It’s really critical to ask, ‘How am I doing compared to my peer institutions?’ If you’re doing worse, you can look at the whole spectrum of things to try to drive improvements in care,” said Dr. Rhee.
The new tool isn’t just limited to quality improvement research. Shaeesta Khan, MD, assistant professor of critical care medicine at Geisinger Medical Center,Danville, Pa., has found eSOFA to be useful in her research into how genetic polymorphisms play a role in sepsis outcomes. Geisinger has a large population of patients with completed whole genome sequencing, and Dr. Khan began by trying to glean sepsis outcomes from administrative data.
“I explained SOFA scores to our data broker, and he pulled up 3,000 patients and gave everybody a SOFA score based on the algorithm he created, and it was all over the chart. Once I started doing chart review and phenotype verification, it was just a nightmare,” Dr. Khan said in an interview.
After struggling with the project, one of her mentors put her in touch with one of Dr. Rhee’s colleagues, and she asked the data broker to modify the eSOFA algorithm to fit her specific criteria. “It was a blessing,” she said.
Now, she has data from 5,000 patients with sepsis and sequenced DNA, and can begin comparing outcomes and genetic variants. About 20 candidate genes for sepsis outcomes have been identified to date, but she has a particular interest in PCSK9, which is an innate immune system regulator. She hopes to present results at CCC49 in 2020.
Validating mortality prediction
The researchers compared eSOFA and SOFA in a sample from 111 U.S. acute care hospitals to see if eSOFA had a comparable predictive validity for mortality. The analysis included 942,360 adults seen between 2013 and 2015. A total of 11.1% (104,903) had a presumed serious infection based on a blood culture order and at least 4 consecutive days of antibiotic use.
The analysis showed that 6.1% of those with infections had a sepsis event based on at least a 2-point increase in SOFA score from baseline (Sepsis-3 criteria), compared with 4.4% identified by at least a 1-point increase in eSOFA score. A total of 34,174 patients (3.6%) overlapped between SOFA and eSOFA, which represented good agreement (Cronbach’s alpha, 0.81). Compared with SOFA/Sepsis-3, eSOFA had a sensitivity of 60%, and a positive predictive value of 82%.
Patients identified by eSOFA were slightly more ill, with more requiring ICU admission (41% vs. 35%), and a greater frequency of in-hospital mortality (17% vs. 14%). Those patients who were identified by SOFA/Sepsis-3, but missed by eSOFA, had an overall lower mortality (6%).
There was a similar risk of mortality across deciles between SOFA- and eSOFA-identified sepsis patients. In an independent analysis of four hospitals from the Emory system, the area under the receiver operating characteristics was 0.77 for eSOFA and 0.76 for SOFA (P less than .001).
The Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality funded the study. Dr. Rhee and Dr. Khan have no relevant financial conflicts.
SOURCE: Rhee C et al. Crit Care Med. 2019;47(3):307-14.
SAN DIEGO – The new method replaces some of SOFA’s more subjective criteria with objective measures.
eSOFA relies on electronic health records to reduce reliance on administrative records, which suffer from cross-hospital variability in diagnosis and coding practices, as well as changes in these practices over time. The diagnosis of sepsis itself is also highly subjective. Instead, eSOFA determines dysfunction in six organ systems, indicated by use of vasopressors and mechanical ventilation, and the presence of abnormal laboratory values.
“The SOFA score includes measures like the Glasgow Coma Scale, which undoubtedly at the bedside is a very important clinical sign, but when trying to implement something that is objective for purposes of retrospective case counting and standardization, it can be problematic. The measures we chose [for eSOFA] are concrete, important maneuvers that were initiated by clinicians,” Chanu Rhee, MD, said in an interview.
Dr. Rhee is assistant professor of population medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston. He presented the results of the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine, and the work was simultaneously published online in Critical Care Medicine.
Key elements of SOFA that pose challenges for administrative data include: PaO2/FiO2, which are not routinely measured, and can be difficult to assign to arterial or venous samples; inconsistency in blood pressure and transient increases in vasopressor dose; the subjectivity of the Glasgow Coma Scale, which is also difficult to assess in sedated patients; and inconsistent urine output.
eSOFA introduced new measures for various organ functions, including cardiovascular (vasopressor initiation), pulmonary (mechanical ventilation initiation), renal (doubling of creatinine levels or a 50% or greater decrease in estimated glomerular filtration rate, compared with baseline), hepatic (bilirubin levels greater than or equal to 2.0 mg/dL and at least doubled from baseline), coagulation (platelet count less than 100 cells/mcL and at least a 50% decrease from a baseline of at least 100 cells/mcL), and neurological (lactate greater than or equal to 2.0 mmol/L).
“[eSOFA] opens a window into inter-facility comparisons that has not been possible to do. It’s really critical to ask, ‘How am I doing compared to my peer institutions?’ If you’re doing worse, you can look at the whole spectrum of things to try to drive improvements in care,” said Dr. Rhee.
The new tool isn’t just limited to quality improvement research. Shaeesta Khan, MD, assistant professor of critical care medicine at Geisinger Medical Center,Danville, Pa., has found eSOFA to be useful in her research into how genetic polymorphisms play a role in sepsis outcomes. Geisinger has a large population of patients with completed whole genome sequencing, and Dr. Khan began by trying to glean sepsis outcomes from administrative data.
“I explained SOFA scores to our data broker, and he pulled up 3,000 patients and gave everybody a SOFA score based on the algorithm he created, and it was all over the chart. Once I started doing chart review and phenotype verification, it was just a nightmare,” Dr. Khan said in an interview.
After struggling with the project, one of her mentors put her in touch with one of Dr. Rhee’s colleagues, and she asked the data broker to modify the eSOFA algorithm to fit her specific criteria. “It was a blessing,” she said.
Now, she has data from 5,000 patients with sepsis and sequenced DNA, and can begin comparing outcomes and genetic variants. About 20 candidate genes for sepsis outcomes have been identified to date, but she has a particular interest in PCSK9, which is an innate immune system regulator. She hopes to present results at CCC49 in 2020.
Validating mortality prediction
The researchers compared eSOFA and SOFA in a sample from 111 U.S. acute care hospitals to see if eSOFA had a comparable predictive validity for mortality. The analysis included 942,360 adults seen between 2013 and 2015. A total of 11.1% (104,903) had a presumed serious infection based on a blood culture order and at least 4 consecutive days of antibiotic use.
The analysis showed that 6.1% of those with infections had a sepsis event based on at least a 2-point increase in SOFA score from baseline (Sepsis-3 criteria), compared with 4.4% identified by at least a 1-point increase in eSOFA score. A total of 34,174 patients (3.6%) overlapped between SOFA and eSOFA, which represented good agreement (Cronbach’s alpha, 0.81). Compared with SOFA/Sepsis-3, eSOFA had a sensitivity of 60%, and a positive predictive value of 82%.
Patients identified by eSOFA were slightly more ill, with more requiring ICU admission (41% vs. 35%), and a greater frequency of in-hospital mortality (17% vs. 14%). Those patients who were identified by SOFA/Sepsis-3, but missed by eSOFA, had an overall lower mortality (6%).
There was a similar risk of mortality across deciles between SOFA- and eSOFA-identified sepsis patients. In an independent analysis of four hospitals from the Emory system, the area under the receiver operating characteristics was 0.77 for eSOFA and 0.76 for SOFA (P less than .001).
The Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality funded the study. Dr. Rhee and Dr. Khan have no relevant financial conflicts.
SOURCE: Rhee C et al. Crit Care Med. 2019;47(3):307-14.
REPORTING FROM CCC48