Cardiology

A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).

The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.

“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.

“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.

“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
 

Sky high rosuvastatin levels

The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.

The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.

“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.

“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
 

Concern and skepticism

Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.

Catherine Hackett/MDedge News

“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.

“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”

Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.

But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.

Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.

One in a million?

“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.

Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m², respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m² for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m².

“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.

Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.

Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.

[email protected]

SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.

*Correction: This value was missing from the original article.

A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).

The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.

“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.

“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.

“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
 

Sky high rosuvastatin levels

The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.

The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.

“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.

“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
 

Concern and skepticism

Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.

Catherine Hackett/MDedge News

“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.

“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”

Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.

But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.

Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.

One in a million?

“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.

Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m², respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m² for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m².

“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.

Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.

Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.

[email protected]

SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.

*Correction: This value was missing from the original article.

A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).

The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.

“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.

“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.

“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
 

Sky high rosuvastatin levels

The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.

The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.

“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.

“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
 

Concern and skepticism

Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.

Catherine Hackett/MDedge News

“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.

“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”

Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.

But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.

Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.

One in a million?

“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.

Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m², respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m² for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m².

“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.

Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.

Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.

[email protected]

SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.

*Correction: This value was missing from the original article.

Clinical guidelines for cholesterol management may have two blind spots when it comes to heart attack prevention: Most younger adults with premature coronary artery disease who’ve had a myocardial infarction don’t meet guideline criteria for preventative statin therapy, and survivors under age 55 don’t meet the criteria for continuing nonstatin lipid-lowering treatments, a large single-center retrospective study has shown.

“The classic approach we’ve taken to identifying young adults for prevention is inadequate in younger adults,” corresponding author Ann Marie Navar, MD, PhD, of Duke University, Durham, N.C., said in an interview. “While awaiting more definitive research we should at minimum be using all the tools at our disposal, including broader use of coronary artery calcium [CAC] scoring, to identify young people who may benefit from statin therapy.”

The retrospective observational study analyzed records of 6,639 adults who had cardiac catheterization at Duke University Medical Center from 1995 to 2012 for a first myocardial infarction with obstructive coronary artery disease. The study considered those under age 55 years as “younger” patients, comprising 41% of the study group (2,733); 35% were “middle-aged” at 55-65 years (2,324) and 24% were “older,” at 66-75 years (1,582).

The report, published online Aug. 3 in the Journal of the American College of Cardiology, noted that most of the adults with premature CAD did not meet criteria for preventative statin therapy before their first MI based on ACC/American Heart Association clinical guidelines from 2013 and 2018. It also noted that younger MI survivors are also less frequently eligible for secondary prevention with intensive nonstatin lipid-lowering therapies than are older adults despite a much longer potential life span – and opportunity for another MI – for the former.

The researchers sought to evaluate the real-world implications of changes made in the 2018 guideline for adults who develop premature ischemic heart disease, and found that fewer younger patients qualify for preventative statin therapy under the 2018 guidelines.

“Younger individuals with very high-risk criteria are at higher risk of major adverse cardiovascular events, a finding supporting the appropriate implementation of intensive lipid-lowering therapies in these patients,” wrote lead author Michel Zeitouni, MD, MSc, and colleagues.
 

Key findings

The investigators reported that younger adults were significantly less likely to meet a class I recommendation for statins under the 2013 guideline (42.9%), compared with their middle-aged (70%) and older (82.5%) counterparts; and under the 2018 guideline, at 39.4%, 59.5%, and 77.4%, respectively (both P < .001).

Similarly, when both class I and class IIa recommendations were accounted for, younger patients were significantly less likely than were middle-aged and older patients to be eligible for statins before their index MI under both the 2013 (56.7%, 79.5%, and 85.2%, respectively and 2018 guidelines (46.4%, 73.5%, and 88.2%, respectively (both P < .01).

After their first MI, one in four younger patients (28.3%) met the very high-risk criteria compared with 40% of middle-aged and 81.4% of older patients (P trend < .001). In 8 years of follow-up, patients with very high-risk criteria based on the 2018 guideline had twice the rate of death, nonfatal MI, or stroke (hazard ratio [HR]: 2.15; 95% confidence interval, 1.98-2.33; P < .001).

The researchers acknowledged that the 2018 guideline took the important step of implementing risk enhancers – patient characteristics such as obesity and metabolic syndrome – along with the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to better identify high-risk young individuals who need statins. However, they also noted that the ability of the guidelines to identify young adults before their first MI “remains suboptimal.”

How to protect younger patients

“The 2018 guidelines will be most effective if we as providers do our best to identify risk enhancers and if we can use CAC scoring more broadly,” Dr. Navar said, noting that although CAC scoring has been shown to improve risk prediction, insurance coverage can be problematic.

“We also need to be careful to screen for the presence of the risk enhancers, such as inflammatory disease, family history, and women-specific risk factors, to make sure we aren’t missing an important high-risk group,” she added.

Other solutions to better identify at-risk younger adults include considering upgrades to the guidelines’ class IIb recommendation to class IIa to emphasize the importance of recognizing lower-risk younger adults, and recommending statins for patients at higher lifetime risk than age- and sex-matched peers, the researchers noted. “In our cohort, young individuals admitted for a first MI had a higher lifetime ASCVD risk score than did patients in the older age categories,” Dr. Zeitouni and colleagues wrote.

Dr. Navar said that these findings are a reminder that guidelines aren’t mandates. “Guidelines are meant to be a starting point for patients and physicians,” she said. “The absence of a recommendation doesn’t mean something isn’t recommended, but that there is not enough data to say one way or another.” 

The study “provides important evidence” that the 2018 guidelines exempted about half of the younger adults who had a first MI from preventative statin therapy, Ron Blankstein, MD, and Avinainder Singh, MD, MMSc, noted in an editorial (J Am Coll Cardiol. 2020;76:665-8).

Brigham and Women&#039;s Hospital

“Data from both the Duke and Young-MI registries should force us to reexamine how we allocate statin use among young individuals,” they noted. Dr. Blankstein is with Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Singh is with Yale University, New Haven, Conn.

Dr. Zeitouni reported receiving lecture fees from Bristol-Myers Squibb/Pfizer. Dr. Navar reported financial relationships with Amarin, Janssen, Amgen, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Esperion, Novo Nordisk, Novartis, The Medicine Company, New Amsterdam, Cerner and Pfizer. Dr. Blankstein reported receiving research support from Amgen. Dr. Singh has no relevant financial relationships to report.

SOURCE: M. Zeitouni et al. J Am Coll Cardiol 2020 Aug 3;76:653-64.

Clinical guidelines for cholesterol management may have two blind spots when it comes to heart attack prevention: Most younger adults with premature coronary artery disease who’ve had a myocardial infarction don’t meet guideline criteria for preventative statin therapy, and survivors under age 55 don’t meet the criteria for continuing nonstatin lipid-lowering treatments, a large single-center retrospective study has shown.

“The classic approach we’ve taken to identifying young adults for prevention is inadequate in younger adults,” corresponding author Ann Marie Navar, MD, PhD, of Duke University, Durham, N.C., said in an interview. “While awaiting more definitive research we should at minimum be using all the tools at our disposal, including broader use of coronary artery calcium [CAC] scoring, to identify young people who may benefit from statin therapy.”

The retrospective observational study analyzed records of 6,639 adults who had cardiac catheterization at Duke University Medical Center from 1995 to 2012 for a first myocardial infarction with obstructive coronary artery disease. The study considered those under age 55 years as “younger” patients, comprising 41% of the study group (2,733); 35% were “middle-aged” at 55-65 years (2,324) and 24% were “older,” at 66-75 years (1,582).

The report, published online Aug. 3 in the Journal of the American College of Cardiology, noted that most of the adults with premature CAD did not meet criteria for preventative statin therapy before their first MI based on ACC/American Heart Association clinical guidelines from 2013 and 2018. It also noted that younger MI survivors are also less frequently eligible for secondary prevention with intensive nonstatin lipid-lowering therapies than are older adults despite a much longer potential life span – and opportunity for another MI – for the former.

The researchers sought to evaluate the real-world implications of changes made in the 2018 guideline for adults who develop premature ischemic heart disease, and found that fewer younger patients qualify for preventative statin therapy under the 2018 guidelines.

“Younger individuals with very high-risk criteria are at higher risk of major adverse cardiovascular events, a finding supporting the appropriate implementation of intensive lipid-lowering therapies in these patients,” wrote lead author Michel Zeitouni, MD, MSc, and colleagues.
 

Key findings

The investigators reported that younger adults were significantly less likely to meet a class I recommendation for statins under the 2013 guideline (42.9%), compared with their middle-aged (70%) and older (82.5%) counterparts; and under the 2018 guideline, at 39.4%, 59.5%, and 77.4%, respectively (both P < .001).

Similarly, when both class I and class IIa recommendations were accounted for, younger patients were significantly less likely than were middle-aged and older patients to be eligible for statins before their index MI under both the 2013 (56.7%, 79.5%, and 85.2%, respectively and 2018 guidelines (46.4%, 73.5%, and 88.2%, respectively (both P < .01).

After their first MI, one in four younger patients (28.3%) met the very high-risk criteria compared with 40% of middle-aged and 81.4% of older patients (P trend < .001). In 8 years of follow-up, patients with very high-risk criteria based on the 2018 guideline had twice the rate of death, nonfatal MI, or stroke (hazard ratio [HR]: 2.15; 95% confidence interval, 1.98-2.33; P < .001).

The researchers acknowledged that the 2018 guideline took the important step of implementing risk enhancers – patient characteristics such as obesity and metabolic syndrome – along with the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to better identify high-risk young individuals who need statins. However, they also noted that the ability of the guidelines to identify young adults before their first MI “remains suboptimal.”

How to protect younger patients

“The 2018 guidelines will be most effective if we as providers do our best to identify risk enhancers and if we can use CAC scoring more broadly,” Dr. Navar said, noting that although CAC scoring has been shown to improve risk prediction, insurance coverage can be problematic.

“We also need to be careful to screen for the presence of the risk enhancers, such as inflammatory disease, family history, and women-specific risk factors, to make sure we aren’t missing an important high-risk group,” she added.

Other solutions to better identify at-risk younger adults include considering upgrades to the guidelines’ class IIb recommendation to class IIa to emphasize the importance of recognizing lower-risk younger adults, and recommending statins for patients at higher lifetime risk than age- and sex-matched peers, the researchers noted. “In our cohort, young individuals admitted for a first MI had a higher lifetime ASCVD risk score than did patients in the older age categories,” Dr. Zeitouni and colleagues wrote.

Dr. Navar said that these findings are a reminder that guidelines aren’t mandates. “Guidelines are meant to be a starting point for patients and physicians,” she said. “The absence of a recommendation doesn’t mean something isn’t recommended, but that there is not enough data to say one way or another.” 

The study “provides important evidence” that the 2018 guidelines exempted about half of the younger adults who had a first MI from preventative statin therapy, Ron Blankstein, MD, and Avinainder Singh, MD, MMSc, noted in an editorial (J Am Coll Cardiol. 2020;76:665-8).

Brigham and Women&#039;s Hospital

“Data from both the Duke and Young-MI registries should force us to reexamine how we allocate statin use among young individuals,” they noted. Dr. Blankstein is with Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Singh is with Yale University, New Haven, Conn.

Dr. Zeitouni reported receiving lecture fees from Bristol-Myers Squibb/Pfizer. Dr. Navar reported financial relationships with Amarin, Janssen, Amgen, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Esperion, Novo Nordisk, Novartis, The Medicine Company, New Amsterdam, Cerner and Pfizer. Dr. Blankstein reported receiving research support from Amgen. Dr. Singh has no relevant financial relationships to report.

SOURCE: M. Zeitouni et al. J Am Coll Cardiol 2020 Aug 3;76:653-64.

Clinical guidelines for cholesterol management may have two blind spots when it comes to heart attack prevention: Most younger adults with premature coronary artery disease who’ve had a myocardial infarction don’t meet guideline criteria for preventative statin therapy, and survivors under age 55 don’t meet the criteria for continuing nonstatin lipid-lowering treatments, a large single-center retrospective study has shown.

“The classic approach we’ve taken to identifying young adults for prevention is inadequate in younger adults,” corresponding author Ann Marie Navar, MD, PhD, of Duke University, Durham, N.C., said in an interview. “While awaiting more definitive research we should at minimum be using all the tools at our disposal, including broader use of coronary artery calcium [CAC] scoring, to identify young people who may benefit from statin therapy.”

The retrospective observational study analyzed records of 6,639 adults who had cardiac catheterization at Duke University Medical Center from 1995 to 2012 for a first myocardial infarction with obstructive coronary artery disease. The study considered those under age 55 years as “younger” patients, comprising 41% of the study group (2,733); 35% were “middle-aged” at 55-65 years (2,324) and 24% were “older,” at 66-75 years (1,582).

The report, published online Aug. 3 in the Journal of the American College of Cardiology, noted that most of the adults with premature CAD did not meet criteria for preventative statin therapy before their first MI based on ACC/American Heart Association clinical guidelines from 2013 and 2018. It also noted that younger MI survivors are also less frequently eligible for secondary prevention with intensive nonstatin lipid-lowering therapies than are older adults despite a much longer potential life span – and opportunity for another MI – for the former.

The researchers sought to evaluate the real-world implications of changes made in the 2018 guideline for adults who develop premature ischemic heart disease, and found that fewer younger patients qualify for preventative statin therapy under the 2018 guidelines.

“Younger individuals with very high-risk criteria are at higher risk of major adverse cardiovascular events, a finding supporting the appropriate implementation of intensive lipid-lowering therapies in these patients,” wrote lead author Michel Zeitouni, MD, MSc, and colleagues.
 

Key findings

The investigators reported that younger adults were significantly less likely to meet a class I recommendation for statins under the 2013 guideline (42.9%), compared with their middle-aged (70%) and older (82.5%) counterparts; and under the 2018 guideline, at 39.4%, 59.5%, and 77.4%, respectively (both P < .001).

Similarly, when both class I and class IIa recommendations were accounted for, younger patients were significantly less likely than were middle-aged and older patients to be eligible for statins before their index MI under both the 2013 (56.7%, 79.5%, and 85.2%, respectively and 2018 guidelines (46.4%, 73.5%, and 88.2%, respectively (both P < .01).

After their first MI, one in four younger patients (28.3%) met the very high-risk criteria compared with 40% of middle-aged and 81.4% of older patients (P trend < .001). In 8 years of follow-up, patients with very high-risk criteria based on the 2018 guideline had twice the rate of death, nonfatal MI, or stroke (hazard ratio [HR]: 2.15; 95% confidence interval, 1.98-2.33; P < .001).

The researchers acknowledged that the 2018 guideline took the important step of implementing risk enhancers – patient characteristics such as obesity and metabolic syndrome – along with the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to better identify high-risk young individuals who need statins. However, they also noted that the ability of the guidelines to identify young adults before their first MI “remains suboptimal.”

How to protect younger patients

“The 2018 guidelines will be most effective if we as providers do our best to identify risk enhancers and if we can use CAC scoring more broadly,” Dr. Navar said, noting that although CAC scoring has been shown to improve risk prediction, insurance coverage can be problematic.

“We also need to be careful to screen for the presence of the risk enhancers, such as inflammatory disease, family history, and women-specific risk factors, to make sure we aren’t missing an important high-risk group,” she added.

Other solutions to better identify at-risk younger adults include considering upgrades to the guidelines’ class IIb recommendation to class IIa to emphasize the importance of recognizing lower-risk younger adults, and recommending statins for patients at higher lifetime risk than age- and sex-matched peers, the researchers noted. “In our cohort, young individuals admitted for a first MI had a higher lifetime ASCVD risk score than did patients in the older age categories,” Dr. Zeitouni and colleagues wrote.

Dr. Navar said that these findings are a reminder that guidelines aren’t mandates. “Guidelines are meant to be a starting point for patients and physicians,” she said. “The absence of a recommendation doesn’t mean something isn’t recommended, but that there is not enough data to say one way or another.” 

The study “provides important evidence” that the 2018 guidelines exempted about half of the younger adults who had a first MI from preventative statin therapy, Ron Blankstein, MD, and Avinainder Singh, MD, MMSc, noted in an editorial (J Am Coll Cardiol. 2020;76:665-8).

Brigham and Women&#039;s Hospital

“Data from both the Duke and Young-MI registries should force us to reexamine how we allocate statin use among young individuals,” they noted. Dr. Blankstein is with Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Singh is with Yale University, New Haven, Conn.

Dr. Zeitouni reported receiving lecture fees from Bristol-Myers Squibb/Pfizer. Dr. Navar reported financial relationships with Amarin, Janssen, Amgen, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Esperion, Novo Nordisk, Novartis, The Medicine Company, New Amsterdam, Cerner and Pfizer. Dr. Blankstein reported receiving research support from Amgen. Dr. Singh has no relevant financial relationships to report.

SOURCE: M. Zeitouni et al. J Am Coll Cardiol 2020 Aug 3;76:653-64.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

A version of this article originally appeared on Medscape.com.

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

A version of this article originally appeared on Medscape.com.

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

A version of this article originally appeared on Medscape.com.

A 10-year follow-up analysis based on one of cardiology’s most influential trials has shed further light on one of its key issues: how to sharpen selection of patients most likely to benefit from a primary prevention implantable cardioverter-defibrillator (ICD).

In a new report from SCD-HeFT, the survival advantage in patients with heart failure seen 5 years after receiving ICDs, compared with a non-ICD control group, narrowed a bit but remained significant after an additional 5 years. But not all patients with devices shared in that long-term ICD benefit. Patients with either ischemic disease or nonischemic cardiomyopathy (NICM) with devices showed a similar mortality risk reduction in the trial’s previously reported 5-year outcomes. That advantage, compared with non-ICD control patients, persisted throughout the subsequent 5 years for ischemic patients but tapered to nil for those with NICM.

The NICM patients “had what appears to be some accrual of benefit maybe out to about 6 years, and then the curves appear to come together where there’s no apparent further benefit after 6 years,” Jeanne E. Poole, MD, of the University of Washington, Seattle, said in an interview.

In both the 10-year analysis and the earlier results, ICD survival gains went preferentially to patients who enrolled with New York Heart Association (NYHA) functional class II symptoms. Patients who entered in NYHA class III “didn’t appear to have any benefit whatsoever” in either period, Dr. Poole said.

“The simple message is that the same groups of patients that benefited strongly from the ICD in the original SCD-HeFT – the NYHA class 2 patients and those with ischemic cardiomyopathy – were really the ones who benefited the greatest over the long term,” she said.

Dr. Poole is lead author on the SCD-HeFT 10-year analysis, which was published in the July 28 issue of the Journal of the American College of Cardiology.

Why the ICD survival effect disappeared midway in patients with NICM “is hard to sort out,” she said. Many in the control group were offered such devices after the trial concluded. Among those, it’s possible that disproportionately more control patients with NICM, compared with patients with ischemic disease, were fitted with ICDs that were also cardiac resynchronization therapy (CRT) devices, Dr. Poole and her colleagues speculated. That could have shifted their late outcomes to be more in line with patients who had received ICDs when the trial started.

Or “it is possible that the intermediate-term benefit of ICD therapy in NICM is overwhelmed by nonarrhythmic death in extended follow-up” given that ICDs prolong survival only by preventing arrhythmic death, noted an editorial accompanying the new SCD-HeFT publication.

Another possibility: Because NICM is a heterogeneous disorder with many potential causes, perhaps “the absence of long-term mortality benefit among SCD-HeFT participants with NICM was due to an unintended but preferential enrollment of subtypes at relatively lower risk for arrhythmic death in the longer term,” proposed Eric C. Stecker, MD, MPH, Oregon Health & Science University, Portland, and coauthors in their editorial.

“What are the take-away messages from the current analysis by Poole et al?” they asked. “These findings strongly support the clinical efficacy and cost-effectiveness of ICD therapy for the majority of patients with severe but mildly symptomatic ischemic cardiomyopathy who do not have an excessive comorbidity burden.”

But “the implications for patients with NICM are less clear,” they wrote. “Given evidence for intermediate-term benefit and the limitations inherent to assessing longer-term benefit, we do not believe it is appropriate to walk back guideline recommendations regarding ICD implantation for NICM patients.”

The findings in nonischemic patients invite comparison with the randomized DANISH trial, which entered only patients with NICM and, over more than 5 years, saw no primary-prevention ICD advantage for the end point of all-cause mortality.

But patients who received ICDs showed a reduction in arrhythmic death, a secondary end point. And mortality in the trial showed a significant interaction with patient age; survival went up sharply with ICDs for those younger than 60 years.

Also in DANISH, “the ICD treatment effect appears to vary over time, with an earlier phase showing possible survival benefit and a later phase showing attenuation of that benefit,” similar to what was seen long-term in SCD-HeFT, in which the interaction between mortality and time since implantation was significant at P = .0015, observe Dr. Poole and colleagues.

However, Dr. Poole cautioned when interviewed, patient management in DANISH, conducted exclusively in Denmark, may not have been representative of the rest of the world, complicating comparisons with other studies. For example, nearly 60% of all patients in DANISH had defibrillating CRT devices. Virtually everyone was on ACE inhibitors or angiotensin-receptor blockers, and almost 60% were taking aldosterone inhibitors.

“DANISH is an unusually high bar and probably does not reflect all patients with heart failure, and certainly does not reflect patients in the United States in terms of those high levels of guideline-directed medical therapy,” Dr. Poole said. The message from DANISH, she said, seems to be that patients with NICM who are definitely on goal-directed heart failure medications with CRT devices “probably don’t have a meaningful benefit from an ICD, on total mortality, because their sudden death rates are simply so low.”

SCD-HeFT had originally assigned 2,521 patients with heart failure of NYHA class II or III and an left ventricular ejection fraction of less than 35% to receive an ICD, amiodarone without an ICD, or an amiodarone placebo and no ICD; patients in the latter cohorts made up the non-ICD control group.

Those who received an ICD, compared with the non-ICD control patients, showed a 23% drop in all-cause mortality over a median of 45.5 months ending on October 31, 2003, Dr. Poole and colleagues noted in their current report. The trial’s primary results were unveiled 2005.

The current analysis, based on data collected in 2010 and 2011, followed the 1,855 patients alive at the trial’s official conclusion and combined outcomes before and after that time for a median follow-up of 11 years, Dr. Poole and colleagues reported.

In the ICD group, the overall hazard ratio for mortality by intention-to-treat was 0.87 (95% confidence interval, 0.76-0.98; P = .028), compared with the non-ICD control group.

A version of this article originally appeared on Medscape.com.

A 10-year follow-up analysis based on one of cardiology’s most influential trials has shed further light on one of its key issues: how to sharpen selection of patients most likely to benefit from a primary prevention implantable cardioverter-defibrillator (ICD).

In a new report from SCD-HeFT, the survival advantage in patients with heart failure seen 5 years after receiving ICDs, compared with a non-ICD control group, narrowed a bit but remained significant after an additional 5 years. But not all patients with devices shared in that long-term ICD benefit. Patients with either ischemic disease or nonischemic cardiomyopathy (NICM) with devices showed a similar mortality risk reduction in the trial’s previously reported 5-year outcomes. That advantage, compared with non-ICD control patients, persisted throughout the subsequent 5 years for ischemic patients but tapered to nil for those with NICM.

The NICM patients “had what appears to be some accrual of benefit maybe out to about 6 years, and then the curves appear to come together where there’s no apparent further benefit after 6 years,” Jeanne E. Poole, MD, of the University of Washington, Seattle, said in an interview.

In both the 10-year analysis and the earlier results, ICD survival gains went preferentially to patients who enrolled with New York Heart Association (NYHA) functional class II symptoms. Patients who entered in NYHA class III “didn’t appear to have any benefit whatsoever” in either period, Dr. Poole said.

“The simple message is that the same groups of patients that benefited strongly from the ICD in the original SCD-HeFT – the NYHA class 2 patients and those with ischemic cardiomyopathy – were really the ones who benefited the greatest over the long term,” she said.

Dr. Poole is lead author on the SCD-HeFT 10-year analysis, which was published in the July 28 issue of the Journal of the American College of Cardiology.

Why the ICD survival effect disappeared midway in patients with NICM “is hard to sort out,” she said. Many in the control group were offered such devices after the trial concluded. Among those, it’s possible that disproportionately more control patients with NICM, compared with patients with ischemic disease, were fitted with ICDs that were also cardiac resynchronization therapy (CRT) devices, Dr. Poole and her colleagues speculated. That could have shifted their late outcomes to be more in line with patients who had received ICDs when the trial started.

Or “it is possible that the intermediate-term benefit of ICD therapy in NICM is overwhelmed by nonarrhythmic death in extended follow-up” given that ICDs prolong survival only by preventing arrhythmic death, noted an editorial accompanying the new SCD-HeFT publication.

Another possibility: Because NICM is a heterogeneous disorder with many potential causes, perhaps “the absence of long-term mortality benefit among SCD-HeFT participants with NICM was due to an unintended but preferential enrollment of subtypes at relatively lower risk for arrhythmic death in the longer term,” proposed Eric C. Stecker, MD, MPH, Oregon Health & Science University, Portland, and coauthors in their editorial.

“What are the take-away messages from the current analysis by Poole et al?” they asked. “These findings strongly support the clinical efficacy and cost-effectiveness of ICD therapy for the majority of patients with severe but mildly symptomatic ischemic cardiomyopathy who do not have an excessive comorbidity burden.”

But “the implications for patients with NICM are less clear,” they wrote. “Given evidence for intermediate-term benefit and the limitations inherent to assessing longer-term benefit, we do not believe it is appropriate to walk back guideline recommendations regarding ICD implantation for NICM patients.”

The findings in nonischemic patients invite comparison with the randomized DANISH trial, which entered only patients with NICM and, over more than 5 years, saw no primary-prevention ICD advantage for the end point of all-cause mortality.

But patients who received ICDs showed a reduction in arrhythmic death, a secondary end point. And mortality in the trial showed a significant interaction with patient age; survival went up sharply with ICDs for those younger than 60 years.

Also in DANISH, “the ICD treatment effect appears to vary over time, with an earlier phase showing possible survival benefit and a later phase showing attenuation of that benefit,” similar to what was seen long-term in SCD-HeFT, in which the interaction between mortality and time since implantation was significant at P = .0015, observe Dr. Poole and colleagues.

However, Dr. Poole cautioned when interviewed, patient management in DANISH, conducted exclusively in Denmark, may not have been representative of the rest of the world, complicating comparisons with other studies. For example, nearly 60% of all patients in DANISH had defibrillating CRT devices. Virtually everyone was on ACE inhibitors or angiotensin-receptor blockers, and almost 60% were taking aldosterone inhibitors.

“DANISH is an unusually high bar and probably does not reflect all patients with heart failure, and certainly does not reflect patients in the United States in terms of those high levels of guideline-directed medical therapy,” Dr. Poole said. The message from DANISH, she said, seems to be that patients with NICM who are definitely on goal-directed heart failure medications with CRT devices “probably don’t have a meaningful benefit from an ICD, on total mortality, because their sudden death rates are simply so low.”

SCD-HeFT had originally assigned 2,521 patients with heart failure of NYHA class II or III and an left ventricular ejection fraction of less than 35% to receive an ICD, amiodarone without an ICD, or an amiodarone placebo and no ICD; patients in the latter cohorts made up the non-ICD control group.

Those who received an ICD, compared with the non-ICD control patients, showed a 23% drop in all-cause mortality over a median of 45.5 months ending on October 31, 2003, Dr. Poole and colleagues noted in their current report. The trial’s primary results were unveiled 2005.

The current analysis, based on data collected in 2010 and 2011, followed the 1,855 patients alive at the trial’s official conclusion and combined outcomes before and after that time for a median follow-up of 11 years, Dr. Poole and colleagues reported.

In the ICD group, the overall hazard ratio for mortality by intention-to-treat was 0.87 (95% confidence interval, 0.76-0.98; P = .028), compared with the non-ICD control group.

A version of this article originally appeared on Medscape.com.

A 10-year follow-up analysis based on one of cardiology’s most influential trials has shed further light on one of its key issues: how to sharpen selection of patients most likely to benefit from a primary prevention implantable cardioverter-defibrillator (ICD).

In a new report from SCD-HeFT, the survival advantage in patients with heart failure seen 5 years after receiving ICDs, compared with a non-ICD control group, narrowed a bit but remained significant after an additional 5 years. But not all patients with devices shared in that long-term ICD benefit. Patients with either ischemic disease or nonischemic cardiomyopathy (NICM) with devices showed a similar mortality risk reduction in the trial’s previously reported 5-year outcomes. That advantage, compared with non-ICD control patients, persisted throughout the subsequent 5 years for ischemic patients but tapered to nil for those with NICM.

The NICM patients “had what appears to be some accrual of benefit maybe out to about 6 years, and then the curves appear to come together where there’s no apparent further benefit after 6 years,” Jeanne E. Poole, MD, of the University of Washington, Seattle, said in an interview.

In both the 10-year analysis and the earlier results, ICD survival gains went preferentially to patients who enrolled with New York Heart Association (NYHA) functional class II symptoms. Patients who entered in NYHA class III “didn’t appear to have any benefit whatsoever” in either period, Dr. Poole said.

“The simple message is that the same groups of patients that benefited strongly from the ICD in the original SCD-HeFT – the NYHA class 2 patients and those with ischemic cardiomyopathy – were really the ones who benefited the greatest over the long term,” she said.

Dr. Poole is lead author on the SCD-HeFT 10-year analysis, which was published in the July 28 issue of the Journal of the American College of Cardiology.

Why the ICD survival effect disappeared midway in patients with NICM “is hard to sort out,” she said. Many in the control group were offered such devices after the trial concluded. Among those, it’s possible that disproportionately more control patients with NICM, compared with patients with ischemic disease, were fitted with ICDs that were also cardiac resynchronization therapy (CRT) devices, Dr. Poole and her colleagues speculated. That could have shifted their late outcomes to be more in line with patients who had received ICDs when the trial started.

Or “it is possible that the intermediate-term benefit of ICD therapy in NICM is overwhelmed by nonarrhythmic death in extended follow-up” given that ICDs prolong survival only by preventing arrhythmic death, noted an editorial accompanying the new SCD-HeFT publication.

Another possibility: Because NICM is a heterogeneous disorder with many potential causes, perhaps “the absence of long-term mortality benefit among SCD-HeFT participants with NICM was due to an unintended but preferential enrollment of subtypes at relatively lower risk for arrhythmic death in the longer term,” proposed Eric C. Stecker, MD, MPH, Oregon Health & Science University, Portland, and coauthors in their editorial.

“What are the take-away messages from the current analysis by Poole et al?” they asked. “These findings strongly support the clinical efficacy and cost-effectiveness of ICD therapy for the majority of patients with severe but mildly symptomatic ischemic cardiomyopathy who do not have an excessive comorbidity burden.”

But “the implications for patients with NICM are less clear,” they wrote. “Given evidence for intermediate-term benefit and the limitations inherent to assessing longer-term benefit, we do not believe it is appropriate to walk back guideline recommendations regarding ICD implantation for NICM patients.”

The findings in nonischemic patients invite comparison with the randomized DANISH trial, which entered only patients with NICM and, over more than 5 years, saw no primary-prevention ICD advantage for the end point of all-cause mortality.

But patients who received ICDs showed a reduction in arrhythmic death, a secondary end point. And mortality in the trial showed a significant interaction with patient age; survival went up sharply with ICDs for those younger than 60 years.

Also in DANISH, “the ICD treatment effect appears to vary over time, with an earlier phase showing possible survival benefit and a later phase showing attenuation of that benefit,” similar to what was seen long-term in SCD-HeFT, in which the interaction between mortality and time since implantation was significant at P = .0015, observe Dr. Poole and colleagues.

However, Dr. Poole cautioned when interviewed, patient management in DANISH, conducted exclusively in Denmark, may not have been representative of the rest of the world, complicating comparisons with other studies. For example, nearly 60% of all patients in DANISH had defibrillating CRT devices. Virtually everyone was on ACE inhibitors or angiotensin-receptor blockers, and almost 60% were taking aldosterone inhibitors.

“DANISH is an unusually high bar and probably does not reflect all patients with heart failure, and certainly does not reflect patients in the United States in terms of those high levels of guideline-directed medical therapy,” Dr. Poole said. The message from DANISH, she said, seems to be that patients with NICM who are definitely on goal-directed heart failure medications with CRT devices “probably don’t have a meaningful benefit from an ICD, on total mortality, because their sudden death rates are simply so low.”

SCD-HeFT had originally assigned 2,521 patients with heart failure of NYHA class II or III and an left ventricular ejection fraction of less than 35% to receive an ICD, amiodarone without an ICD, or an amiodarone placebo and no ICD; patients in the latter cohorts made up the non-ICD control group.

Those who received an ICD, compared with the non-ICD control patients, showed a 23% drop in all-cause mortality over a median of 45.5 months ending on October 31, 2003, Dr. Poole and colleagues noted in their current report. The trial’s primary results were unveiled 2005.

The current analysis, based on data collected in 2010 and 2011, followed the 1,855 patients alive at the trial’s official conclusion and combined outcomes before and after that time for a median follow-up of 11 years, Dr. Poole and colleagues reported.

In the ICD group, the overall hazard ratio for mortality by intention-to-treat was 0.87 (95% confidence interval, 0.76-0.98; P = .028), compared with the non-ICD control group.

A version of this article originally appeared on Medscape.com.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors used for the treatment of type 2 diabetes, and for heart failure, are associated with a nearly threefold increased risk for diabetic ketoacidosis (DKA), according to a new large database analysis.

Boarding1Now/Thinkstock

The findings, which include data on the use of three different SGLT2 inhibitors in Canada and the United Kingdom and suggest a class effect, were published online July 27 in Annals of Internal Medicine by Antonios Douros, MD, PhD, of McGill University and the Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, and colleagues.

“Our results provide robust evidence that SGLT2 inhibitors are associated with an increased risk for DKA. Of note, increased risks were observed in all molecule-specific analyses, with canagliflozin [Invokana, Janssen] showing the highest effect estimate,” they noted.

And because the beneficial effects of SGLT2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the coming years, “Physicians should be aware of DKA as a potential adverse effect,” Dr. Douros and colleagues wrote.
 

Analysis “generally confirms what has already been published”

Asked for comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, said that the study “generally confirms what has already been published” on the topic. He noted that overall “the risk of SGLT2 inhibitor–induced ketoacidosis is quite low in type 2 diabetes, perhaps on the order of 1 episode per 1000 patient-years.”

However, Dr. Taylor cautioned: “Published evidence suggests that the risk of DKA is increased if patients are unable to eat,” such as when hospitalized patients are not permitted to eat.

“In that setting, it is probably prudent to discontinue an SGLT2 inhibitor. Also, it may be prudent not to prescribe SGLT2 inhibitors to patients with a history of DKA,” he added.

Dr. Taylor also advised: “Although not necessarily supported by this publication, I think that caution should be exercised in prescribing SGLT2 inhibitors to insulin-dependent type 2 diabetes patients. ... Some late-stage type 2 diabetes patients may have severe insulin deficiency, and their physiology may resemble that of a type 1 diabetes patient.”

Dr. Taylor has previously advised against using SGLT2 inhibitors altogether in patients with type 1 diabetes.
 

Increased DKA risk seen across all SGLT2 inhibitors

The study involved electronic health care databases from seven Canadian provinces and the United Kingdom, from which 208,757 new users of SGLT2 inhibitors were propensity-matched 1:1 to new dipeptidyl peptidase-4 (DPP-4) inhibitor users.

Of those taking an SGLT2 inhibitor, 42.3% took canagliflozin, 30.7% dapagliflozin (Farxiga/Forxiga, AstraZeneca), and 27.0% empagliflozin (Jardiance, Boehringer Ingelheim).

Over a mean 0.9-year follow-up, 521 patients were hospitalized with DKA, for an overall incidence rate of 1.41 per 1,000 person-years.

The rate with SGLT2 inhibitors, 2.03 per 1,000 person-years, was nearly three times that seen with DPP-4 inhibitors, at 0.75 per 1,000 person-years, a significant difference (hazard ratio, 2.85).

By individual SGLT2 inhibitor, the hazard ratios compared with DPP-4 inhibitors were 1.86 for dapagliflozin, 2.52 for empagliflozin, and 3.58 for canagliflozin, all statistically significant. Stratification by age, sex, and incident versus prevalent user did not change the association between SGLT2 inhibitors and DKA.

Asked about the higher rate for canagliflozin, Dr. Taylor commented: “It is hard to know whether there are real and reproducible differences in the risks of DKA among the various SGLT2 inhibitors. The differences are not huge and the populations are not well matched.”

But, he noted, “If canagliflozin triggers more glucosuria, it is not surprising that it would also induce more ketosis and possibly ketoacidosis.”

He also noted that the threefold relative increase in DKA with canagliflozin versus comparators is consistent with Janssen’s data, published in 2015. 

“It is, of course, reassuring that both [randomized clinical trials] and epidemiology produce similar estimates of the risk of drug-induced adverse events. Interestingly, the incidence of DKA is approximately threefold higher in the Canadian [data] as compared to Janssen’s clinical trials.”

Dr. Taylor also pointed out that, in the Janssen studies, the risk of canagliflozin-induced DKA appeared to be higher among patients with anti-islet antibodies, which suggests that some may have actually had autoimmune (type 1) diabetes. “So the overall risk of SGLT2 inhibitor-induced DKA may depend at least in part on the mix of patients.”

In the current study, individuals who never used insulin had a greater relative increase in risk of DKA with SGLT2 inhibitors, compared with DPP-4 inhibitors, than did those who did use insulin (hazard ratios, 3.96 vs. 2.24, both compared with DPP-4 inhibitors). However, just among those taking SGLT2 inhibitors, the absolute risk for DKA was higher for those with prior insulin use (3.52 vs. 1.43 per 1,000 person-years). 

The results of sensitivity analyses were consistent with those of the primary analysis.

The study was funded by the Canadian Institutes of Health Research and supported by ICES. Dr. Douros has reported receiving a salary support award from Fonds de recherche du Quebec – sante. Dr. Taylor was previously employed at Bristol-Myers Squibb. He is currently a consultant for Ionis Pharmaceuticals and has reported receiving research support provided to the University of Maryland School of Medicine by Regeneron.

A version of this article originally appeared on Medscape.com.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors used for the treatment of type 2 diabetes, and for heart failure, are associated with a nearly threefold increased risk for diabetic ketoacidosis (DKA), according to a new large database analysis.

Boarding1Now/Thinkstock

The findings, which include data on the use of three different SGLT2 inhibitors in Canada and the United Kingdom and suggest a class effect, were published online July 27 in Annals of Internal Medicine by Antonios Douros, MD, PhD, of McGill University and the Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, and colleagues.

“Our results provide robust evidence that SGLT2 inhibitors are associated with an increased risk for DKA. Of note, increased risks were observed in all molecule-specific analyses, with canagliflozin [Invokana, Janssen] showing the highest effect estimate,” they noted.

And because the beneficial effects of SGLT2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the coming years, “Physicians should be aware of DKA as a potential adverse effect,” Dr. Douros and colleagues wrote.
 

Analysis “generally confirms what has already been published”

Asked for comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, said that the study “generally confirms what has already been published” on the topic. He noted that overall “the risk of SGLT2 inhibitor–induced ketoacidosis is quite low in type 2 diabetes, perhaps on the order of 1 episode per 1000 patient-years.”

However, Dr. Taylor cautioned: “Published evidence suggests that the risk of DKA is increased if patients are unable to eat,” such as when hospitalized patients are not permitted to eat.

“In that setting, it is probably prudent to discontinue an SGLT2 inhibitor. Also, it may be prudent not to prescribe SGLT2 inhibitors to patients with a history of DKA,” he added.

Dr. Taylor also advised: “Although not necessarily supported by this publication, I think that caution should be exercised in prescribing SGLT2 inhibitors to insulin-dependent type 2 diabetes patients. ... Some late-stage type 2 diabetes patients may have severe insulin deficiency, and their physiology may resemble that of a type 1 diabetes patient.”

Dr. Taylor has previously advised against using SGLT2 inhibitors altogether in patients with type 1 diabetes.
 

Increased DKA risk seen across all SGLT2 inhibitors

The study involved electronic health care databases from seven Canadian provinces and the United Kingdom, from which 208,757 new users of SGLT2 inhibitors were propensity-matched 1:1 to new dipeptidyl peptidase-4 (DPP-4) inhibitor users.

Of those taking an SGLT2 inhibitor, 42.3% took canagliflozin, 30.7% dapagliflozin (Farxiga/Forxiga, AstraZeneca), and 27.0% empagliflozin (Jardiance, Boehringer Ingelheim).

Over a mean 0.9-year follow-up, 521 patients were hospitalized with DKA, for an overall incidence rate of 1.41 per 1,000 person-years.

The rate with SGLT2 inhibitors, 2.03 per 1,000 person-years, was nearly three times that seen with DPP-4 inhibitors, at 0.75 per 1,000 person-years, a significant difference (hazard ratio, 2.85).

By individual SGLT2 inhibitor, the hazard ratios compared with DPP-4 inhibitors were 1.86 for dapagliflozin, 2.52 for empagliflozin, and 3.58 for canagliflozin, all statistically significant. Stratification by age, sex, and incident versus prevalent user did not change the association between SGLT2 inhibitors and DKA.

Asked about the higher rate for canagliflozin, Dr. Taylor commented: “It is hard to know whether there are real and reproducible differences in the risks of DKA among the various SGLT2 inhibitors. The differences are not huge and the populations are not well matched.”

But, he noted, “If canagliflozin triggers more glucosuria, it is not surprising that it would also induce more ketosis and possibly ketoacidosis.”

He also noted that the threefold relative increase in DKA with canagliflozin versus comparators is consistent with Janssen’s data, published in 2015. 

“It is, of course, reassuring that both [randomized clinical trials] and epidemiology produce similar estimates of the risk of drug-induced adverse events. Interestingly, the incidence of DKA is approximately threefold higher in the Canadian [data] as compared to Janssen’s clinical trials.”

Dr. Taylor also pointed out that, in the Janssen studies, the risk of canagliflozin-induced DKA appeared to be higher among patients with anti-islet antibodies, which suggests that some may have actually had autoimmune (type 1) diabetes. “So the overall risk of SGLT2 inhibitor-induced DKA may depend at least in part on the mix of patients.”

In the current study, individuals who never used insulin had a greater relative increase in risk of DKA with SGLT2 inhibitors, compared with DPP-4 inhibitors, than did those who did use insulin (hazard ratios, 3.96 vs. 2.24, both compared with DPP-4 inhibitors). However, just among those taking SGLT2 inhibitors, the absolute risk for DKA was higher for those with prior insulin use (3.52 vs. 1.43 per 1,000 person-years). 

The results of sensitivity analyses were consistent with those of the primary analysis.

The study was funded by the Canadian Institutes of Health Research and supported by ICES. Dr. Douros has reported receiving a salary support award from Fonds de recherche du Quebec – sante. Dr. Taylor was previously employed at Bristol-Myers Squibb. He is currently a consultant for Ionis Pharmaceuticals and has reported receiving research support provided to the University of Maryland School of Medicine by Regeneron.

A version of this article originally appeared on Medscape.com.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors used for the treatment of type 2 diabetes, and for heart failure, are associated with a nearly threefold increased risk for diabetic ketoacidosis (DKA), according to a new large database analysis.

Boarding1Now/Thinkstock

The findings, which include data on the use of three different SGLT2 inhibitors in Canada and the United Kingdom and suggest a class effect, were published online July 27 in Annals of Internal Medicine by Antonios Douros, MD, PhD, of McGill University and the Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, and colleagues.

“Our results provide robust evidence that SGLT2 inhibitors are associated with an increased risk for DKA. Of note, increased risks were observed in all molecule-specific analyses, with canagliflozin [Invokana, Janssen] showing the highest effect estimate,” they noted.

And because the beneficial effects of SGLT2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the coming years, “Physicians should be aware of DKA as a potential adverse effect,” Dr. Douros and colleagues wrote.
 

Analysis “generally confirms what has already been published”

Asked for comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, said that the study “generally confirms what has already been published” on the topic. He noted that overall “the risk of SGLT2 inhibitor–induced ketoacidosis is quite low in type 2 diabetes, perhaps on the order of 1 episode per 1000 patient-years.”

However, Dr. Taylor cautioned: “Published evidence suggests that the risk of DKA is increased if patients are unable to eat,” such as when hospitalized patients are not permitted to eat.

“In that setting, it is probably prudent to discontinue an SGLT2 inhibitor. Also, it may be prudent not to prescribe SGLT2 inhibitors to patients with a history of DKA,” he added.

Dr. Taylor also advised: “Although not necessarily supported by this publication, I think that caution should be exercised in prescribing SGLT2 inhibitors to insulin-dependent type 2 diabetes patients. ... Some late-stage type 2 diabetes patients may have severe insulin deficiency, and their physiology may resemble that of a type 1 diabetes patient.”

Dr. Taylor has previously advised against using SGLT2 inhibitors altogether in patients with type 1 diabetes.
 

Increased DKA risk seen across all SGLT2 inhibitors

The study involved electronic health care databases from seven Canadian provinces and the United Kingdom, from which 208,757 new users of SGLT2 inhibitors were propensity-matched 1:1 to new dipeptidyl peptidase-4 (DPP-4) inhibitor users.

Of those taking an SGLT2 inhibitor, 42.3% took canagliflozin, 30.7% dapagliflozin (Farxiga/Forxiga, AstraZeneca), and 27.0% empagliflozin (Jardiance, Boehringer Ingelheim).

Over a mean 0.9-year follow-up, 521 patients were hospitalized with DKA, for an overall incidence rate of 1.41 per 1,000 person-years.

The rate with SGLT2 inhibitors, 2.03 per 1,000 person-years, was nearly three times that seen with DPP-4 inhibitors, at 0.75 per 1,000 person-years, a significant difference (hazard ratio, 2.85).

By individual SGLT2 inhibitor, the hazard ratios compared with DPP-4 inhibitors were 1.86 for dapagliflozin, 2.52 for empagliflozin, and 3.58 for canagliflozin, all statistically significant. Stratification by age, sex, and incident versus prevalent user did not change the association between SGLT2 inhibitors and DKA.

Asked about the higher rate for canagliflozin, Dr. Taylor commented: “It is hard to know whether there are real and reproducible differences in the risks of DKA among the various SGLT2 inhibitors. The differences are not huge and the populations are not well matched.”

But, he noted, “If canagliflozin triggers more glucosuria, it is not surprising that it would also induce more ketosis and possibly ketoacidosis.”

He also noted that the threefold relative increase in DKA with canagliflozin versus comparators is consistent with Janssen’s data, published in 2015. 

“It is, of course, reassuring that both [randomized clinical trials] and epidemiology produce similar estimates of the risk of drug-induced adverse events. Interestingly, the incidence of DKA is approximately threefold higher in the Canadian [data] as compared to Janssen’s clinical trials.”

Dr. Taylor also pointed out that, in the Janssen studies, the risk of canagliflozin-induced DKA appeared to be higher among patients with anti-islet antibodies, which suggests that some may have actually had autoimmune (type 1) diabetes. “So the overall risk of SGLT2 inhibitor-induced DKA may depend at least in part on the mix of patients.”

In the current study, individuals who never used insulin had a greater relative increase in risk of DKA with SGLT2 inhibitors, compared with DPP-4 inhibitors, than did those who did use insulin (hazard ratios, 3.96 vs. 2.24, both compared with DPP-4 inhibitors). However, just among those taking SGLT2 inhibitors, the absolute risk for DKA was higher for those with prior insulin use (3.52 vs. 1.43 per 1,000 person-years). 

The results of sensitivity analyses were consistent with those of the primary analysis.

The study was funded by the Canadian Institutes of Health Research and supported by ICES. Dr. Douros has reported receiving a salary support award from Fonds de recherche du Quebec – sante. Dr. Taylor was previously employed at Bristol-Myers Squibb. He is currently a consultant for Ionis Pharmaceuticals and has reported receiving research support provided to the University of Maryland School of Medicine by Regeneron.

A version of this article originally appeared on Medscape.com.

From the Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL.

Abstract

Objective: To review selected process-of-care interventions that can be applied both during the hospitalization and during the transitional care period to help address the persistent challenge of heart failure readmissions.

Methods: Review of the literature.

Results: Process-of-care interventions that can be implemented to reduce readmissions of heart failure patients include: accurately identifying heart failure patients; providing disease education; titrating guideline-directed medical therapy; ensuring discharge readiness; arranging close discharge follow-up; identifying and addressing social barriers; following up by telephone; using home health; and addressing comorbidities. Importantly, the heart failure hospitalization is an opportunity to set up outpatient success, and setting up feedback loops can aid in post-discharge monitoring.

Conclusion: We encourage teams to consider local capabilities when selecting processes to improve; begin by improving something small to build capacity and team morale, and continually iterate and reexamine processes, as health care systems are continually evolving.

Keywords: heart failure; process improvement; quality improvement; readmission; rehospitalization; transitional care.

The growing population of patients affected by heart failure continues to challenge health systems. The increasing prevalence is paralleled by the rising costs of managing heart failure, which are projected to grow from $30.7 billion in 2012 to $69.8 billion in 2030.¹ A significant portion of these costs relate to readmission after an index heart failure hospitalization. The statistics are staggering: for patients hospitalized with heart failure, approximately 15% to 20% are readmitted within 30 days.^2,3 Though recent temporal trends suggest a modest reduction in readmission rates, there is a concerning correlation with increasing mortality,³ and a recognition that readmission rate decreases may relate to subtle changes in coding-based risk adjustment.⁴ Despite these concerns, efforts to reduce readmissions after heart failure hospitalization command significant attention.

Process improvement methodologies may be helpful in reducing hospital readmissions. Various approaches have been employed, and results have been mixed. An analysis of 70 participating hospitals in the American Heart Association’s Get With the Guidelines initiative found that, while overall readmission rates declined by 1.0% over 3 years, only 1 hospital achieved a 20% reduction in readmission rates.⁵

It is notably difficult to reduce readmissions after heart failure hospitalization. One challenge is that patients with heart failure often have multiple comorbidities, and approximately 50% to 60% of 30-day readmissions after heart failure hospitalization arise from noncardiac causes.¹ Another challenge is that a significant fraction of readmissions in general—perhaps 75%—may not be avoidable.⁶

Recent excellent systematic reviews and meta-analyses provide comprehensive overviews of process improvement strategies that can be used to reduce readmissions after heart failure hospitalizations.^7-9 Yet despite this extensive knowledge, few reports discuss the process of actually implementing these changes: the process of process improvement. Here, we seek to not only highlight some of the most promising potential interventions to reduce heart failure readmissions, but also to discuss a process improvement framework to help engender success, using our experience as a case study. We schematize process improvement efforts as having several distinct phases (Figure 1): processes delivered during the hospitalization and prior to discharge; feedback loops set up to maintain clinical stability at home; and the postdischarge clinic visit as an opportunity to further stabilize the patient and advance the plan of care. The discussion of these interventions follows this organization.

During Hospitalization

The heart failure hospitalization can be used as an opportunity to set up outpatient success, with several goals to target during the index admission. One goal is identifying the root causes of the heart failure syndrome and correcting those root causes, if possible. For example, patients in whom the heart failure syndrome is secondary to valvular heart disease may benefit from transcatheter aortic valve replacement.¹⁰ Another clinical goal is decongesting the patient, which is associated with lower readmission rates.^11,12 These goals focus on the medical aspects of heart failure care. However, beyond these medical aspects, a patient must be equipped to successfully manage the disease at home.

To support medical and nonmedical interventions for hospitalized heart failure patients, a critical first step is identifying patients with heart failure. This accomplishes at least 2 objectives. First, early identification allows early initiation of interventions, such as heart failure education and social work evaluation. Early initiation of these interventions allows sufficient time during the hospitalization to make meaningful progress on these fronts. Second, early identification allows an opportunity for the delivery of cardiology specialty care, which may help with identifying and correcting root causes of the heart failure syndrome. Such access to cardiology has been shown to improve inpatient mortality and readmission rates.¹³

In smaller hospitals, identification of patients with heart failure can be as simple as reviewing overnight admissions. More advanced strategies, such as screeners based on brain natriuretic peptide (BNP) levels and administration of intravenous diuretics, can be employed.^14,15 In the near future, deep learning-based natural language processing will be applied to mine full-text data in the electronic health record to identify heart failure hospitalizations.¹⁶

In the hospital, patients can also receive education about heart failure disease management. This education is a cornerstone of reducing heart failure readmissions. A recent systematic review of nurse education interventions demonstrated reductions in readmissions, hospitalizations, and costs.¹⁷ However, the efficacy of heart failure education hinges on many other variables. For patients to adhere to water restriction and daily weights, for example, there must also be patient understanding, compliance, and accessibility to providers to recommend how to strike the fluid balance. Education is therefore necessary, but not sufficient, for setting up outpatient success.

The hospitalization also represents an important time to start or uptitrate guideline-directed medical therapy (GDMT) for heart failure. Doing so takes advantage of an important opportunity to reduce the risk of readmission and even reverse the disease process.¹⁸ Uptitration of GDMT in patients with heart failure with reduced ejection fraction is associated with a decreased risk of mortality, while discontinuation is associated with an increased risk of mortality.¹⁹ However, recent registry data indicate that intensity of GDMT is just as likely to be decreased as increased during the hospitalization.²⁰ Nevertheless, predischarge initiation of medications may be associated with higher attained doses in follow-up.²¹

Preparing for Discharge

Preparing a patient for discharge after a heart failure hospitalization involves stabilizing the medical condition as well as ensuring that the patient and caregivers have the medication, equipment, and self-care resources at home necessary to manage the condition. Several frameworks have been put forth to help care teams analyze a patient’s readiness for discharge. One is the B-PREPARED score,²² a validated instrument to discriminate among patients with regard to their readiness to discharge from the hospital. This instrument highlights the importance of several key factors that should be addressed during the discharge process, including counseling and written instructions about medications and their side effects; information about equipment needs and community resources; and information on activity levels and restrictions. Nurse education and discharge coordination can improve patients’ perception of discharge readiness,²³ although whether this discharge readiness translates into improved readmission rates appears to depend on the specific follow-up intervention design.⁹

Prior to discharge, it is important to arrange postdischarge follow-up appointments, as emphasized by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines.²⁴ The use of nurse navigators can help with planning follow-up appointments. For example, the ACC Patient Navigator Program was applied in a single-center study of 120 patients randomized to the program versus usual care.²⁵ This study found a significant increase in patient education and follow-up appointments compared to usual care, and a numerical decrease in hospital readmissions, although the finding was not statistically significant.²⁵

A third critical component of preparing for discharge is identifying and addressing social barriers to care. In a study of patients stratified by household income, patients in the lowest income quartile had a higher readmission rate than patients in the highest income quartile.²⁶ Poverty also correlates with heart failure mortality.²⁷ Social factors play an important role in many aspects of patients’ ability to manage their health, including self-care, medication adherence, and ability to follow-up. Identifying these social factors prior to discharge is the first step to addressing them. While few studies specifically address the role of social workers in the management of heart failure care, the general medical literature suggests that social workers embedded in transitional care teams can augment readmission reduction efforts.²⁸

After Discharge

Patients recently discharged from the hospital who have not yet attended their postdischarge appointment are in an incredibly vulnerable phase of care. Patients who are discharged from the hospital may not yet be connected with outpatient care. During this initial transitional care period, feedback loops involving patient communication back to the clinic, and clinic communication back to the patient, are critical to helping patients remain stable. For example, consider monitoring weights daily after hospital discharge. A patient at home can report increasing weights to a provider, who can then recommend an increased dose of diuretic. The patient can complete the feedback loop by taking the extra medication and monitoring the return of weight back to normal.

While daily weight monitoring is a simple process improvement that relies on the principle of establishing feedback loops, many other strategies exist. One commonly employed tool is the postdischarge telephone follow-up call, which is often coupled with other interventions in a comprehensive care bundle.⁸ During the telephone call, several process-of-care defects can be corrected, including missing medications or missing information on appointment times.

Beyond the telephone, newer technologies show promise for helping develop feedback loops for patients at home. One such technology is telemonitoring, whereby physiologic information such as weight, heart rate, and blood pressure is collected and sent back to a monitoring center. While the principle holds promise, several studies have not demonstrated significantly different outcomes as compared to usual care.^13,29 Another promising technology is the CardioMEMS device (Abbott, Inc., Atlanta, GA), which can remotely transmit the pulmonary artery pressure, a physiologic signal which correlates with volume overload. There is now strong evidence supporting the efficacy of pulmonary artery pressure–guided heart failure management.^30,31

Finally, home visits can be an efficient way to communicate symptoms, enable clinical assessment, and provide recommendations. One program that implemented home visits, 24-hour nurses available by call, and telephone follow-up showed a statistically significant reduction in readmissions.³² Furthermore, a meta-analysis of randomized controlled trials comparing home health to usual care showed decreased readmissions and mortality.³³ The efficacy may be in strengthening the feedback loop—home care improves compliance with weight monitoring, fluid restriction, and medications.³⁴ These studies provide a strong rationale for the benefits of home health in stabilizing heart failure patients postdischarge. Indeed, nurse home visits were 1 of the 2 process interventions in a Cochrane review of randomized controlled trials that were shown to statistically significantly decrease readmissions and mortality.⁹ These data underscore the importance of feedback loops for helping ensure patients are clinically stable.

Postdischarge Follow-Up Clinic Visit

The first clinic appointment postdischarge is an important check-in to help advance patient care. Several key tasks can be achieved during the postdischarge visit. First, the patient can be clinically stabilized by adjusting diuretic therapy. If the patient is clinically stable, GDMT can be uptitrated. Second, education around symptoms, medications, diet, and exercise can be reinforced. Finally, clinicians can help connect patients to other members of the multidisciplinary care team, including specialist care, home health, or cardiac rehabilitation.

Achieving 7-day follow-up visits after discharge has been a point of emphasis in national guidelines.²⁴ The ACC promotes a “See You in 7” challenge, advising that all patients discharged with a diagnosis of heart failure have a follow-up appointment within 7 days. Yet based on the latest available data, arrival rates to the postdischarge clinic are dismal, hovering around 30%.³⁵ In a multicenter observational study of hospitals participating in the “See You in 7” collaborative, hospitals were able to increase their 7-day follow-up appointment rates by 2% to 3%, and also noted an absolute decrease in readmission rates by 1% to 2%.³⁶ We have demonstrated, using a mathematical approach called queuing theory, that discharge appointment wait times and clinic access can be significantly improved by providing a modest capacity buffer to clinic availability.³⁷ Those interested in applying this model to their own clinical practice may do so with a free online calculator at http://hfresearch.org.

Another important aspect of postdischarge follow-up is appropriate management of the comorbidity burden, which, as noted, is often significant in patients hospitalized with heart failure.³⁸ For instance, in recent cohorts of hospitalized heart failure patients, the incidence of hypertension was 78%, coronary artery disease was more than 50%, atrial fibrillation was more than 40%, and diabetes was nearly 40%.³⁹ Given this burden of comorbidity, it is not surprising that only 35% of readmissions after an index heart failure hospitalization are for recurrent heart failure.⁴⁰ Coordinating care among primary care physicians and relevant subspecialists is thus essential. Phone calls and secure electronic messages are very helpful in achieving this. There is increasing interest in more nimble care models, such as the patient-centered specialty practice⁴¹ or the dyspnea clinic, to help bring coordinated resources to the patient.⁴²

Process of Process Improvement: Our Experiences

The previous sections outline a series of potential process improvements clinical teams and health systems can implement to impact heart failure readmissions. A plan on paper, however, does not equal a plan in actuality. How does one go about implementing these changes? We offer our local experience starting a heart failure transitional care program as a case study, then draw lessons learned as a set of practical tips for local teams to employ. What we hope to highlight is that there is a large difference between a completed process for transitional care of heart failure patients, and the process of developing that process itself. The former is the hardware, the latter is the software. The latter does not typically get highlighted, but it is absolutely critical to unlocking the capabilities of a team and the institution.

In 2015, Northwestern Memorial Hospital adopted a novel payment arrangement from the Center for Medicare and Medicaid Services for Medicare patients being discharged from the hospital with heart failure. Known as Bundled Payments for Care Improvement,⁴³ this bundled payment model incentivized Northwestern Memorial Hospital charge, principally by reducing hospital readmissions and by collaborating with skilled nursing facilities to control length of stay.

We approached this problem by drawing on the available literature,^44,45 and by first creating a schematic of our high-level approach, which comprised 3 major elements (Figure 2): identification of hospitalized heart failure patients, delivery of a care bundle to hospitalized heart failure patients in hospital, and coordinating postdischarge care, centered on a telephone call and a postdischarge visit.

We then proceeded by building out, in stepwise fashion, each component of our value chain, using Agile techniques as a guiding principle.⁴⁶ Agile, a productivity and process improvement mindset with roots in software development, emphasizes tackling 1 problem at a time, building out new features sequentially and completely, recognizing that the end user does not derive value from a program until new functionality is available for use. Rather than wholesale monolithic change, Agile emphasizes rapid iteration, prototyping, and discarding innovations not found to be helpful. The notion is to stand up new, incremental features rapidly, with each incremental improvement delivering value and helping to accelerate overall change.

Our experience building a robust way to identify heart failure cases is a good example of Agile process improvement in practice. At our hospital, identification of patients with heart failure was a challenge because more than half of heart failure patients are admitted to noncardiology floors. We developed a simple electronic health record query to detect heart failure patients, relying on parameters such as administration of intravenous diuretic or levels of BNP exceeding 100 ng/dL. We deployed this query, finding very high sensitivity for detection of heart failure patients.¹⁴ Patients found to have heart failure were then populated into a list in the electronic health record, which made patients’ heart failure status visible to all members of the health care team. Using this list, we were able to automate several processes necessary for heart failure care. For example, the list made it possible for cardiologists to know if there was a patient who perhaps needed cardiology consultation. Nurse navigators could know which patients needed heart failure education without having to be actively consulted by the admitting team. The same nurse navigators could then know upon discharge which patients needed a follow-up telephone call at 48 hours.

This list of heart failure patients was the end product, which was built through prototyping and iteration. For example, with our initial BNP cutoff of 300 ng/dL, we recognized we were missing several cases, and lowered the cutoff for the screener to 100 ng/dL. When we were satisfied this process was working well, we moved on to the next problem to tackle, avoiding trying to work on too many things at once. By doing so, we were able to focus our process improvement resources on 1 problem at a time, building up a suite of interventions. For our hospital, we settled on a bundle of interventions, captured by the mnemonic HEART:

Heart doctor sees patient in the hospital

Education about heart failure in the hospital

After-visit summary with 7-day appointment printed

Reach out to the patient by telephone within 72 hours

Treat the patient in clinic by the 7-day visit

Conclusion

We would like to emphasize that the elements of our heart failure readmissions interventions were not all put in place at once. This was an iterative process that proceeded in a stepwise fashion, with each step improving the care of our patients. We learned a number of lessons from our experience. First, we would advise that teams not try to do everything. One program simply cannot implement all possible readmission reduction interventions, and certainly not all at once. Trade-offs should be made, and interventions more likely to succeed in the local environment should be prioritized. In addition, interventions that do not fit and do not create synergy with the local practice environment should not be pursued.

Second, we would advise teams to start small, tackling a known problem in heart failure transitions of care first. This initial intuition is often right. An example might be improving 7-day appointments upon discharge. Starting with a problem that can be tackled builds process improvement muscle and improves team morale. Third, we would advise teams to consistently iterate on designs, tweaking and improving performance. Complex organizations always evolve; processes that work 1 year may fail the next because another element of the organization may have changed.

Finally, the framework presented in Figure 1 may be helpful in guiding how to structure interventions. Considering interventions to be delivered in the hospital, interventions to be delivered in the clinic, and how to set up feedback loops to support patients as outpatients help develop a comprehensive heart failure readmissions reduction program.

Corresponding author: R. Kannan Mutharasan, MD, Northwestern University Feinberg School of Medicine, 676 North Saint Clair St., Arkes Pavilion, Suite 7-038, Chicago, IL 60611;[email protected].

Financial disclosures: None.

From the Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL.

Abstract

Objective: To review selected process-of-care interventions that can be applied both during the hospitalization and during the transitional care period to help address the persistent challenge of heart failure readmissions.

Methods: Review of the literature.

Results: Process-of-care interventions that can be implemented to reduce readmissions of heart failure patients include: accurately identifying heart failure patients; providing disease education; titrating guideline-directed medical therapy; ensuring discharge readiness; arranging close discharge follow-up; identifying and addressing social barriers; following up by telephone; using home health; and addressing comorbidities. Importantly, the heart failure hospitalization is an opportunity to set up outpatient success, and setting up feedback loops can aid in post-discharge monitoring.

Conclusion: We encourage teams to consider local capabilities when selecting processes to improve; begin by improving something small to build capacity and team morale, and continually iterate and reexamine processes, as health care systems are continually evolving.

Keywords: heart failure; process improvement; quality improvement; readmission; rehospitalization; transitional care.

The growing population of patients affected by heart failure continues to challenge health systems. The increasing prevalence is paralleled by the rising costs of managing heart failure, which are projected to grow from $30.7 billion in 2012 to $69.8 billion in 2030.¹ A significant portion of these costs relate to readmission after an index heart failure hospitalization. The statistics are staggering: for patients hospitalized with heart failure, approximately 15% to 20% are readmitted within 30 days.^2,3 Though recent temporal trends suggest a modest reduction in readmission rates, there is a concerning correlation with increasing mortality,³ and a recognition that readmission rate decreases may relate to subtle changes in coding-based risk adjustment.⁴ Despite these concerns, efforts to reduce readmissions after heart failure hospitalization command significant attention.

Process improvement methodologies may be helpful in reducing hospital readmissions. Various approaches have been employed, and results have been mixed. An analysis of 70 participating hospitals in the American Heart Association’s Get With the Guidelines initiative found that, while overall readmission rates declined by 1.0% over 3 years, only 1 hospital achieved a 20% reduction in readmission rates.⁵

It is notably difficult to reduce readmissions after heart failure hospitalization. One challenge is that patients with heart failure often have multiple comorbidities, and approximately 50% to 60% of 30-day readmissions after heart failure hospitalization arise from noncardiac causes.¹ Another challenge is that a significant fraction of readmissions in general—perhaps 75%—may not be avoidable.⁶

Recent excellent systematic reviews and meta-analyses provide comprehensive overviews of process improvement strategies that can be used to reduce readmissions after heart failure hospitalizations.^7-9 Yet despite this extensive knowledge, few reports discuss the process of actually implementing these changes: the process of process improvement. Here, we seek to not only highlight some of the most promising potential interventions to reduce heart failure readmissions, but also to discuss a process improvement framework to help engender success, using our experience as a case study. We schematize process improvement efforts as having several distinct phases (Figure 1): processes delivered during the hospitalization and prior to discharge; feedback loops set up to maintain clinical stability at home; and the postdischarge clinic visit as an opportunity to further stabilize the patient and advance the plan of care. The discussion of these interventions follows this organization.

During Hospitalization

The heart failure hospitalization can be used as an opportunity to set up outpatient success, with several goals to target during the index admission. One goal is identifying the root causes of the heart failure syndrome and correcting those root causes, if possible. For example, patients in whom the heart failure syndrome is secondary to valvular heart disease may benefit from transcatheter aortic valve replacement.¹⁰ Another clinical goal is decongesting the patient, which is associated with lower readmission rates.^11,12 These goals focus on the medical aspects of heart failure care. However, beyond these medical aspects, a patient must be equipped to successfully manage the disease at home.

To support medical and nonmedical interventions for hospitalized heart failure patients, a critical first step is identifying patients with heart failure. This accomplishes at least 2 objectives. First, early identification allows early initiation of interventions, such as heart failure education and social work evaluation. Early initiation of these interventions allows sufficient time during the hospitalization to make meaningful progress on these fronts. Second, early identification allows an opportunity for the delivery of cardiology specialty care, which may help with identifying and correcting root causes of the heart failure syndrome. Such access to cardiology has been shown to improve inpatient mortality and readmission rates.¹³

In smaller hospitals, identification of patients with heart failure can be as simple as reviewing overnight admissions. More advanced strategies, such as screeners based on brain natriuretic peptide (BNP) levels and administration of intravenous diuretics, can be employed.^14,15 In the near future, deep learning-based natural language processing will be applied to mine full-text data in the electronic health record to identify heart failure hospitalizations.¹⁶

In the hospital, patients can also receive education about heart failure disease management. This education is a cornerstone of reducing heart failure readmissions. A recent systematic review of nurse education interventions demonstrated reductions in readmissions, hospitalizations, and costs.¹⁷ However, the efficacy of heart failure education hinges on many other variables. For patients to adhere to water restriction and daily weights, for example, there must also be patient understanding, compliance, and accessibility to providers to recommend how to strike the fluid balance. Education is therefore necessary, but not sufficient, for setting up outpatient success.

The hospitalization also represents an important time to start or uptitrate guideline-directed medical therapy (GDMT) for heart failure. Doing so takes advantage of an important opportunity to reduce the risk of readmission and even reverse the disease process.¹⁸ Uptitration of GDMT in patients with heart failure with reduced ejection fraction is associated with a decreased risk of mortality, while discontinuation is associated with an increased risk of mortality.¹⁹ However, recent registry data indicate that intensity of GDMT is just as likely to be decreased as increased during the hospitalization.²⁰ Nevertheless, predischarge initiation of medications may be associated with higher attained doses in follow-up.²¹

Preparing for Discharge

Preparing a patient for discharge after a heart failure hospitalization involves stabilizing the medical condition as well as ensuring that the patient and caregivers have the medication, equipment, and self-care resources at home necessary to manage the condition. Several frameworks have been put forth to help care teams analyze a patient’s readiness for discharge. One is the B-PREPARED score,²² a validated instrument to discriminate among patients with regard to their readiness to discharge from the hospital. This instrument highlights the importance of several key factors that should be addressed during the discharge process, including counseling and written instructions about medications and their side effects; information about equipment needs and community resources; and information on activity levels and restrictions. Nurse education and discharge coordination can improve patients’ perception of discharge readiness,²³ although whether this discharge readiness translates into improved readmission rates appears to depend on the specific follow-up intervention design.⁹

Prior to discharge, it is important to arrange postdischarge follow-up appointments, as emphasized by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines.²⁴ The use of nurse navigators can help with planning follow-up appointments. For example, the ACC Patient Navigator Program was applied in a single-center study of 120 patients randomized to the program versus usual care.²⁵ This study found a significant increase in patient education and follow-up appointments compared to usual care, and a numerical decrease in hospital readmissions, although the finding was not statistically significant.²⁵

A third critical component of preparing for discharge is identifying and addressing social barriers to care. In a study of patients stratified by household income, patients in the lowest income quartile had a higher readmission rate than patients in the highest income quartile.²⁶ Poverty also correlates with heart failure mortality.²⁷ Social factors play an important role in many aspects of patients’ ability to manage their health, including self-care, medication adherence, and ability to follow-up. Identifying these social factors prior to discharge is the first step to addressing them. While few studies specifically address the role of social workers in the management of heart failure care, the general medical literature suggests that social workers embedded in transitional care teams can augment readmission reduction efforts.²⁸

After Discharge

Patients recently discharged from the hospital who have not yet attended their postdischarge appointment are in an incredibly vulnerable phase of care. Patients who are discharged from the hospital may not yet be connected with outpatient care. During this initial transitional care period, feedback loops involving patient communication back to the clinic, and clinic communication back to the patient, are critical to helping patients remain stable. For example, consider monitoring weights daily after hospital discharge. A patient at home can report increasing weights to a provider, who can then recommend an increased dose of diuretic. The patient can complete the feedback loop by taking the extra medication and monitoring the return of weight back to normal.

While daily weight monitoring is a simple process improvement that relies on the principle of establishing feedback loops, many other strategies exist. One commonly employed tool is the postdischarge telephone follow-up call, which is often coupled with other interventions in a comprehensive care bundle.⁸ During the telephone call, several process-of-care defects can be corrected, including missing medications or missing information on appointment times.

Beyond the telephone, newer technologies show promise for helping develop feedback loops for patients at home. One such technology is telemonitoring, whereby physiologic information such as weight, heart rate, and blood pressure is collected and sent back to a monitoring center. While the principle holds promise, several studies have not demonstrated significantly different outcomes as compared to usual care.^13,29 Another promising technology is the CardioMEMS device (Abbott, Inc., Atlanta, GA), which can remotely transmit the pulmonary artery pressure, a physiologic signal which correlates with volume overload. There is now strong evidence supporting the efficacy of pulmonary artery pressure–guided heart failure management.^30,31

Finally, home visits can be an efficient way to communicate symptoms, enable clinical assessment, and provide recommendations. One program that implemented home visits, 24-hour nurses available by call, and telephone follow-up showed a statistically significant reduction in readmissions.³² Furthermore, a meta-analysis of randomized controlled trials comparing home health to usual care showed decreased readmissions and mortality.³³ The efficacy may be in strengthening the feedback loop—home care improves compliance with weight monitoring, fluid restriction, and medications.³⁴ These studies provide a strong rationale for the benefits of home health in stabilizing heart failure patients postdischarge. Indeed, nurse home visits were 1 of the 2 process interventions in a Cochrane review of randomized controlled trials that were shown to statistically significantly decrease readmissions and mortality.⁹ These data underscore the importance of feedback loops for helping ensure patients are clinically stable.

Postdischarge Follow-Up Clinic Visit

The first clinic appointment postdischarge is an important check-in to help advance patient care. Several key tasks can be achieved during the postdischarge visit. First, the patient can be clinically stabilized by adjusting diuretic therapy. If the patient is clinically stable, GDMT can be uptitrated. Second, education around symptoms, medications, diet, and exercise can be reinforced. Finally, clinicians can help connect patients to other members of the multidisciplinary care team, including specialist care, home health, or cardiac rehabilitation.

Achieving 7-day follow-up visits after discharge has been a point of emphasis in national guidelines.²⁴ The ACC promotes a “See You in 7” challenge, advising that all patients discharged with a diagnosis of heart failure have a follow-up appointment within 7 days. Yet based on the latest available data, arrival rates to the postdischarge clinic are dismal, hovering around 30%.³⁵ In a multicenter observational study of hospitals participating in the “See You in 7” collaborative, hospitals were able to increase their 7-day follow-up appointment rates by 2% to 3%, and also noted an absolute decrease in readmission rates by 1% to 2%.³⁶ We have demonstrated, using a mathematical approach called queuing theory, that discharge appointment wait times and clinic access can be significantly improved by providing a modest capacity buffer to clinic availability.³⁷ Those interested in applying this model to their own clinical practice may do so with a free online calculator at http://hfresearch.org.

Another important aspect of postdischarge follow-up is appropriate management of the comorbidity burden, which, as noted, is often significant in patients hospitalized with heart failure.³⁸ For instance, in recent cohorts of hospitalized heart failure patients, the incidence of hypertension was 78%, coronary artery disease was more than 50%, atrial fibrillation was more than 40%, and diabetes was nearly 40%.³⁹ Given this burden of comorbidity, it is not surprising that only 35% of readmissions after an index heart failure hospitalization are for recurrent heart failure.⁴⁰ Coordinating care among primary care physicians and relevant subspecialists is thus essential. Phone calls and secure electronic messages are very helpful in achieving this. There is increasing interest in more nimble care models, such as the patient-centered specialty practice⁴¹ or the dyspnea clinic, to help bring coordinated resources to the patient.⁴²

Process of Process Improvement: Our Experiences

The previous sections outline a series of potential process improvements clinical teams and health systems can implement to impact heart failure readmissions. A plan on paper, however, does not equal a plan in actuality. How does one go about implementing these changes? We offer our local experience starting a heart failure transitional care program as a case study, then draw lessons learned as a set of practical tips for local teams to employ. What we hope to highlight is that there is a large difference between a completed process for transitional care of heart failure patients, and the process of developing that process itself. The former is the hardware, the latter is the software. The latter does not typically get highlighted, but it is absolutely critical to unlocking the capabilities of a team and the institution.

In 2015, Northwestern Memorial Hospital adopted a novel payment arrangement from the Center for Medicare and Medicaid Services for Medicare patients being discharged from the hospital with heart failure. Known as Bundled Payments for Care Improvement,⁴³ this bundled payment model incentivized Northwestern Memorial Hospital charge, principally by reducing hospital readmissions and by collaborating with skilled nursing facilities to control length of stay.

We approached this problem by drawing on the available literature,^44,45 and by first creating a schematic of our high-level approach, which comprised 3 major elements (Figure 2): identification of hospitalized heart failure patients, delivery of a care bundle to hospitalized heart failure patients in hospital, and coordinating postdischarge care, centered on a telephone call and a postdischarge visit.

We then proceeded by building out, in stepwise fashion, each component of our value chain, using Agile techniques as a guiding principle.⁴⁶ Agile, a productivity and process improvement mindset with roots in software development, emphasizes tackling 1 problem at a time, building out new features sequentially and completely, recognizing that the end user does not derive value from a program until new functionality is available for use. Rather than wholesale monolithic change, Agile emphasizes rapid iteration, prototyping, and discarding innovations not found to be helpful. The notion is to stand up new, incremental features rapidly, with each incremental improvement delivering value and helping to accelerate overall change.

Our experience building a robust way to identify heart failure cases is a good example of Agile process improvement in practice. At our hospital, identification of patients with heart failure was a challenge because more than half of heart failure patients are admitted to noncardiology floors. We developed a simple electronic health record query to detect heart failure patients, relying on parameters such as administration of intravenous diuretic or levels of BNP exceeding 100 ng/dL. We deployed this query, finding very high sensitivity for detection of heart failure patients.¹⁴ Patients found to have heart failure were then populated into a list in the electronic health record, which made patients’ heart failure status visible to all members of the health care team. Using this list, we were able to automate several processes necessary for heart failure care. For example, the list made it possible for cardiologists to know if there was a patient who perhaps needed cardiology consultation. Nurse navigators could know which patients needed heart failure education without having to be actively consulted by the admitting team. The same nurse navigators could then know upon discharge which patients needed a follow-up telephone call at 48 hours.

This list of heart failure patients was the end product, which was built through prototyping and iteration. For example, with our initial BNP cutoff of 300 ng/dL, we recognized we were missing several cases, and lowered the cutoff for the screener to 100 ng/dL. When we were satisfied this process was working well, we moved on to the next problem to tackle, avoiding trying to work on too many things at once. By doing so, we were able to focus our process improvement resources on 1 problem at a time, building up a suite of interventions. For our hospital, we settled on a bundle of interventions, captured by the mnemonic HEART:

Heart doctor sees patient in the hospital

Education about heart failure in the hospital

After-visit summary with 7-day appointment printed

Reach out to the patient by telephone within 72 hours

Treat the patient in clinic by the 7-day visit

Conclusion

We would like to emphasize that the elements of our heart failure readmissions interventions were not all put in place at once. This was an iterative process that proceeded in a stepwise fashion, with each step improving the care of our patients. We learned a number of lessons from our experience. First, we would advise that teams not try to do everything. One program simply cannot implement all possible readmission reduction interventions, and certainly not all at once. Trade-offs should be made, and interventions more likely to succeed in the local environment should be prioritized. In addition, interventions that do not fit and do not create synergy with the local practice environment should not be pursued.

Second, we would advise teams to start small, tackling a known problem in heart failure transitions of care first. This initial intuition is often right. An example might be improving 7-day appointments upon discharge. Starting with a problem that can be tackled builds process improvement muscle and improves team morale. Third, we would advise teams to consistently iterate on designs, tweaking and improving performance. Complex organizations always evolve; processes that work 1 year may fail the next because another element of the organization may have changed.

Finally, the framework presented in Figure 1 may be helpful in guiding how to structure interventions. Considering interventions to be delivered in the hospital, interventions to be delivered in the clinic, and how to set up feedback loops to support patients as outpatients help develop a comprehensive heart failure readmissions reduction program.

Corresponding author: R. Kannan Mutharasan, MD, Northwestern University Feinberg School of Medicine, 676 North Saint Clair St., Arkes Pavilion, Suite 7-038, Chicago, IL 60611;[email protected].

Financial disclosures: None.

From the Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL.

Abstract

Objective: To review selected process-of-care interventions that can be applied both during the hospitalization and during the transitional care period to help address the persistent challenge of heart failure readmissions.

Methods: Review of the literature.

Results: Process-of-care interventions that can be implemented to reduce readmissions of heart failure patients include: accurately identifying heart failure patients; providing disease education; titrating guideline-directed medical therapy; ensuring discharge readiness; arranging close discharge follow-up; identifying and addressing social barriers; following up by telephone; using home health; and addressing comorbidities. Importantly, the heart failure hospitalization is an opportunity to set up outpatient success, and setting up feedback loops can aid in post-discharge monitoring.

Conclusion: We encourage teams to consider local capabilities when selecting processes to improve; begin by improving something small to build capacity and team morale, and continually iterate and reexamine processes, as health care systems are continually evolving.

Keywords: heart failure; process improvement; quality improvement; readmission; rehospitalization; transitional care.

The growing population of patients affected by heart failure continues to challenge health systems. The increasing prevalence is paralleled by the rising costs of managing heart failure, which are projected to grow from $30.7 billion in 2012 to $69.8 billion in 2030.¹ A significant portion of these costs relate to readmission after an index heart failure hospitalization. The statistics are staggering: for patients hospitalized with heart failure, approximately 15% to 20% are readmitted within 30 days.^2,3 Though recent temporal trends suggest a modest reduction in readmission rates, there is a concerning correlation with increasing mortality,³ and a recognition that readmission rate decreases may relate to subtle changes in coding-based risk adjustment.⁴ Despite these concerns, efforts to reduce readmissions after heart failure hospitalization command significant attention.

Process improvement methodologies may be helpful in reducing hospital readmissions. Various approaches have been employed, and results have been mixed. An analysis of 70 participating hospitals in the American Heart Association’s Get With the Guidelines initiative found that, while overall readmission rates declined by 1.0% over 3 years, only 1 hospital achieved a 20% reduction in readmission rates.⁵

It is notably difficult to reduce readmissions after heart failure hospitalization. One challenge is that patients with heart failure often have multiple comorbidities, and approximately 50% to 60% of 30-day readmissions after heart failure hospitalization arise from noncardiac causes.¹ Another challenge is that a significant fraction of readmissions in general—perhaps 75%—may not be avoidable.⁶

Recent excellent systematic reviews and meta-analyses provide comprehensive overviews of process improvement strategies that can be used to reduce readmissions after heart failure hospitalizations.^7-9 Yet despite this extensive knowledge, few reports discuss the process of actually implementing these changes: the process of process improvement. Here, we seek to not only highlight some of the most promising potential interventions to reduce heart failure readmissions, but also to discuss a process improvement framework to help engender success, using our experience as a case study. We schematize process improvement efforts as having several distinct phases (Figure 1): processes delivered during the hospitalization and prior to discharge; feedback loops set up to maintain clinical stability at home; and the postdischarge clinic visit as an opportunity to further stabilize the patient and advance the plan of care. The discussion of these interventions follows this organization.

During Hospitalization

The heart failure hospitalization can be used as an opportunity to set up outpatient success, with several goals to target during the index admission. One goal is identifying the root causes of the heart failure syndrome and correcting those root causes, if possible. For example, patients in whom the heart failure syndrome is secondary to valvular heart disease may benefit from transcatheter aortic valve replacement.¹⁰ Another clinical goal is decongesting the patient, which is associated with lower readmission rates.^11,12 These goals focus on the medical aspects of heart failure care. However, beyond these medical aspects, a patient must be equipped to successfully manage the disease at home.

To support medical and nonmedical interventions for hospitalized heart failure patients, a critical first step is identifying patients with heart failure. This accomplishes at least 2 objectives. First, early identification allows early initiation of interventions, such as heart failure education and social work evaluation. Early initiation of these interventions allows sufficient time during the hospitalization to make meaningful progress on these fronts. Second, early identification allows an opportunity for the delivery of cardiology specialty care, which may help with identifying and correcting root causes of the heart failure syndrome. Such access to cardiology has been shown to improve inpatient mortality and readmission rates.¹³

In smaller hospitals, identification of patients with heart failure can be as simple as reviewing overnight admissions. More advanced strategies, such as screeners based on brain natriuretic peptide (BNP) levels and administration of intravenous diuretics, can be employed.^14,15 In the near future, deep learning-based natural language processing will be applied to mine full-text data in the electronic health record to identify heart failure hospitalizations.¹⁶

In the hospital, patients can also receive education about heart failure disease management. This education is a cornerstone of reducing heart failure readmissions. A recent systematic review of nurse education interventions demonstrated reductions in readmissions, hospitalizations, and costs.¹⁷ However, the efficacy of heart failure education hinges on many other variables. For patients to adhere to water restriction and daily weights, for example, there must also be patient understanding, compliance, and accessibility to providers to recommend how to strike the fluid balance. Education is therefore necessary, but not sufficient, for setting up outpatient success.

The hospitalization also represents an important time to start or uptitrate guideline-directed medical therapy (GDMT) for heart failure. Doing so takes advantage of an important opportunity to reduce the risk of readmission and even reverse the disease process.¹⁸ Uptitration of GDMT in patients with heart failure with reduced ejection fraction is associated with a decreased risk of mortality, while discontinuation is associated with an increased risk of mortality.¹⁹ However, recent registry data indicate that intensity of GDMT is just as likely to be decreased as increased during the hospitalization.²⁰ Nevertheless, predischarge initiation of medications may be associated with higher attained doses in follow-up.²¹

Preparing for Discharge

Preparing a patient for discharge after a heart failure hospitalization involves stabilizing the medical condition as well as ensuring that the patient and caregivers have the medication, equipment, and self-care resources at home necessary to manage the condition. Several frameworks have been put forth to help care teams analyze a patient’s readiness for discharge. One is the B-PREPARED score,²² a validated instrument to discriminate among patients with regard to their readiness to discharge from the hospital. This instrument highlights the importance of several key factors that should be addressed during the discharge process, including counseling and written instructions about medications and their side effects; information about equipment needs and community resources; and information on activity levels and restrictions. Nurse education and discharge coordination can improve patients’ perception of discharge readiness,²³ although whether this discharge readiness translates into improved readmission rates appears to depend on the specific follow-up intervention design.⁹

Prior to discharge, it is important to arrange postdischarge follow-up appointments, as emphasized by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines.²⁴ The use of nurse navigators can help with planning follow-up appointments. For example, the ACC Patient Navigator Program was applied in a single-center study of 120 patients randomized to the program versus usual care.²⁵ This study found a significant increase in patient education and follow-up appointments compared to usual care, and a numerical decrease in hospital readmissions, although the finding was not statistically significant.²⁵

A third critical component of preparing for discharge is identifying and addressing social barriers to care. In a study of patients stratified by household income, patients in the lowest income quartile had a higher readmission rate than patients in the highest income quartile.²⁶ Poverty also correlates with heart failure mortality.²⁷ Social factors play an important role in many aspects of patients’ ability to manage their health, including self-care, medication adherence, and ability to follow-up. Identifying these social factors prior to discharge is the first step to addressing them. While few studies specifically address the role of social workers in the management of heart failure care, the general medical literature suggests that social workers embedded in transitional care teams can augment readmission reduction efforts.²⁸

After Discharge

Patients recently discharged from the hospital who have not yet attended their postdischarge appointment are in an incredibly vulnerable phase of care. Patients who are discharged from the hospital may not yet be connected with outpatient care. During this initial transitional care period, feedback loops involving patient communication back to the clinic, and clinic communication back to the patient, are critical to helping patients remain stable. For example, consider monitoring weights daily after hospital discharge. A patient at home can report increasing weights to a provider, who can then recommend an increased dose of diuretic. The patient can complete the feedback loop by taking the extra medication and monitoring the return of weight back to normal.

While daily weight monitoring is a simple process improvement that relies on the principle of establishing feedback loops, many other strategies exist. One commonly employed tool is the postdischarge telephone follow-up call, which is often coupled with other interventions in a comprehensive care bundle.⁸ During the telephone call, several process-of-care defects can be corrected, including missing medications or missing information on appointment times.

Beyond the telephone, newer technologies show promise for helping develop feedback loops for patients at home. One such technology is telemonitoring, whereby physiologic information such as weight, heart rate, and blood pressure is collected and sent back to a monitoring center. While the principle holds promise, several studies have not demonstrated significantly different outcomes as compared to usual care.^13,29 Another promising technology is the CardioMEMS device (Abbott, Inc., Atlanta, GA), which can remotely transmit the pulmonary artery pressure, a physiologic signal which correlates with volume overload. There is now strong evidence supporting the efficacy of pulmonary artery pressure–guided heart failure management.^30,31

Finally, home visits can be an efficient way to communicate symptoms, enable clinical assessment, and provide recommendations. One program that implemented home visits, 24-hour nurses available by call, and telephone follow-up showed a statistically significant reduction in readmissions.³² Furthermore, a meta-analysis of randomized controlled trials comparing home health to usual care showed decreased readmissions and mortality.³³ The efficacy may be in strengthening the feedback loop—home care improves compliance with weight monitoring, fluid restriction, and medications.³⁴ These studies provide a strong rationale for the benefits of home health in stabilizing heart failure patients postdischarge. Indeed, nurse home visits were 1 of the 2 process interventions in a Cochrane review of randomized controlled trials that were shown to statistically significantly decrease readmissions and mortality.⁹ These data underscore the importance of feedback loops for helping ensure patients are clinically stable.

Postdischarge Follow-Up Clinic Visit

The first clinic appointment postdischarge is an important check-in to help advance patient care. Several key tasks can be achieved during the postdischarge visit. First, the patient can be clinically stabilized by adjusting diuretic therapy. If the patient is clinically stable, GDMT can be uptitrated. Second, education around symptoms, medications, diet, and exercise can be reinforced. Finally, clinicians can help connect patients to other members of the multidisciplinary care team, including specialist care, home health, or cardiac rehabilitation.

Achieving 7-day follow-up visits after discharge has been a point of emphasis in national guidelines.²⁴ The ACC promotes a “See You in 7” challenge, advising that all patients discharged with a diagnosis of heart failure have a follow-up appointment within 7 days. Yet based on the latest available data, arrival rates to the postdischarge clinic are dismal, hovering around 30%.³⁵ In a multicenter observational study of hospitals participating in the “See You in 7” collaborative, hospitals were able to increase their 7-day follow-up appointment rates by 2% to 3%, and also noted an absolute decrease in readmission rates by 1% to 2%.³⁶ We have demonstrated, using a mathematical approach called queuing theory, that discharge appointment wait times and clinic access can be significantly improved by providing a modest capacity buffer to clinic availability.³⁷ Those interested in applying this model to their own clinical practice may do so with a free online calculator at http://hfresearch.org.

Another important aspect of postdischarge follow-up is appropriate management of the comorbidity burden, which, as noted, is often significant in patients hospitalized with heart failure.³⁸ For instance, in recent cohorts of hospitalized heart failure patients, the incidence of hypertension was 78%, coronary artery disease was more than 50%, atrial fibrillation was more than 40%, and diabetes was nearly 40%.³⁹ Given this burden of comorbidity, it is not surprising that only 35% of readmissions after an index heart failure hospitalization are for recurrent heart failure.⁴⁰ Coordinating care among primary care physicians and relevant subspecialists is thus essential. Phone calls and secure electronic messages are very helpful in achieving this. There is increasing interest in more nimble care models, such as the patient-centered specialty practice⁴¹ or the dyspnea clinic, to help bring coordinated resources to the patient.⁴²

Process of Process Improvement: Our Experiences

The previous sections outline a series of potential process improvements clinical teams and health systems can implement to impact heart failure readmissions. A plan on paper, however, does not equal a plan in actuality. How does one go about implementing these changes? We offer our local experience starting a heart failure transitional care program as a case study, then draw lessons learned as a set of practical tips for local teams to employ. What we hope to highlight is that there is a large difference between a completed process for transitional care of heart failure patients, and the process of developing that process itself. The former is the hardware, the latter is the software. The latter does not typically get highlighted, but it is absolutely critical to unlocking the capabilities of a team and the institution.

In 2015, Northwestern Memorial Hospital adopted a novel payment arrangement from the Center for Medicare and Medicaid Services for Medicare patients being discharged from the hospital with heart failure. Known as Bundled Payments for Care Improvement,⁴³ this bundled payment model incentivized Northwestern Memorial Hospital charge, principally by reducing hospital readmissions and by collaborating with skilled nursing facilities to control length of stay.

We approached this problem by drawing on the available literature,^44,45 and by first creating a schematic of our high-level approach, which comprised 3 major elements (Figure 2): identification of hospitalized heart failure patients, delivery of a care bundle to hospitalized heart failure patients in hospital, and coordinating postdischarge care, centered on a telephone call and a postdischarge visit.

We then proceeded by building out, in stepwise fashion, each component of our value chain, using Agile techniques as a guiding principle.⁴⁶ Agile, a productivity and process improvement mindset with roots in software development, emphasizes tackling 1 problem at a time, building out new features sequentially and completely, recognizing that the end user does not derive value from a program until new functionality is available for use. Rather than wholesale monolithic change, Agile emphasizes rapid iteration, prototyping, and discarding innovations not found to be helpful. The notion is to stand up new, incremental features rapidly, with each incremental improvement delivering value and helping to accelerate overall change.

Our experience building a robust way to identify heart failure cases is a good example of Agile process improvement in practice. At our hospital, identification of patients with heart failure was a challenge because more than half of heart failure patients are admitted to noncardiology floors. We developed a simple electronic health record query to detect heart failure patients, relying on parameters such as administration of intravenous diuretic or levels of BNP exceeding 100 ng/dL. We deployed this query, finding very high sensitivity for detection of heart failure patients.¹⁴ Patients found to have heart failure were then populated into a list in the electronic health record, which made patients’ heart failure status visible to all members of the health care team. Using this list, we were able to automate several processes necessary for heart failure care. For example, the list made it possible for cardiologists to know if there was a patient who perhaps needed cardiology consultation. Nurse navigators could know which patients needed heart failure education without having to be actively consulted by the admitting team. The same nurse navigators could then know upon discharge which patients needed a follow-up telephone call at 48 hours.

This list of heart failure patients was the end product, which was built through prototyping and iteration. For example, with our initial BNP cutoff of 300 ng/dL, we recognized we were missing several cases, and lowered the cutoff for the screener to 100 ng/dL. When we were satisfied this process was working well, we moved on to the next problem to tackle, avoiding trying to work on too many things at once. By doing so, we were able to focus our process improvement resources on 1 problem at a time, building up a suite of interventions. For our hospital, we settled on a bundle of interventions, captured by the mnemonic HEART:

Heart doctor sees patient in the hospital

Education about heart failure in the hospital

After-visit summary with 7-day appointment printed

Reach out to the patient by telephone within 72 hours

Treat the patient in clinic by the 7-day visit

Conclusion

We would like to emphasize that the elements of our heart failure readmissions interventions were not all put in place at once. This was an iterative process that proceeded in a stepwise fashion, with each step improving the care of our patients. We learned a number of lessons from our experience. First, we would advise that teams not try to do everything. One program simply cannot implement all possible readmission reduction interventions, and certainly not all at once. Trade-offs should be made, and interventions more likely to succeed in the local environment should be prioritized. In addition, interventions that do not fit and do not create synergy with the local practice environment should not be pursued.

Second, we would advise teams to start small, tackling a known problem in heart failure transitions of care first. This initial intuition is often right. An example might be improving 7-day appointments upon discharge. Starting with a problem that can be tackled builds process improvement muscle and improves team morale. Third, we would advise teams to consistently iterate on designs, tweaking and improving performance. Complex organizations always evolve; processes that work 1 year may fail the next because another element of the organization may have changed.

Finally, the framework presented in Figure 1 may be helpful in guiding how to structure interventions. Considering interventions to be delivered in the hospital, interventions to be delivered in the clinic, and how to set up feedback loops to support patients as outpatients help develop a comprehensive heart failure readmissions reduction program.

Corresponding author: R. Kannan Mutharasan, MD, Northwestern University Feinberg School of Medicine, 676 North Saint Clair St., Arkes Pavilion, Suite 7-038, Chicago, IL 60611;[email protected].

Financial disclosures: None.

A new scientific statement from the American Heart Association recommends that genetic testing for inherited cardiovascular disease should be reserved for four specific types of heart diseases – cardiomyopathies, thoracic aortic aneurysms and dissections, arrhythmias, and familial hypercholesterolemia – and should enlist skilled geneticists and genetic counselors in the care team.

The guidance comes in a scientific statement published online in the journal Circulation: Genomic and Precision Medicine.

Kiran Musunuru, MD, PhD, MPH, ML, chair of the writing group for the scientific statement, described in an interview the rationale for publishing the statement at this time. “There was no prior single statement that summarized best practices for the whole gamut of inherited cardiovascular diseases in adults, only statements for individual diseases,” he said in an interview. “With genetic testing seeing explosive growth in the past few years, both in the clinical setting and with direct-to-consumer testing, we felt that cardiovascular practitioners would benefit from having a single document to serve as a general resource on genetic testing.”

The statement describes two types of patients who would be suitable for genetic testing for cardiovascular disease (CVD), Dr. Musunuru noted: “Patients who have been diagnosed with or are strongly suspected to have a cardiovascular disease that is often inherited and family members of patients who have been diagnosed with an inherited cardiovascular disease and found by genetic testing to have a mutation that is felt to be the cause of the disease.”

The statement also spells out two crucial elements for genetic testing: thorough disease-specific phenotyping – that is, using genetic information to identify the individual’s disease characteristics and a comprehensive family history that spans at least three generations. Testing should only proceed after patients has had genetic counseling and made a shared decision with their doctors.

“Genetic counseling is absolutely essential both before genetic testing to educate patients on what genetic testing entails and what potential results to expect, as well as the risks of testing; and after genetic testing, to review the results of the genetic testing and explain the potential consequences for the patient’s health and the health of family members, including children,” Dr. Musunuru said.

The process should involve board-certified geneticists or at least cardiovascular specialists well-versed in genetics and genetic counselors, the statement noted. The latter are “critical” in the care team, Dr. Musunuru said.

After the decision is made to do genetic testing, the next step is to decide the scope of the testing. That can range from targeted sequencing of a single gene or a few genes linked to the disease to large gene panels; the latter “may not increase the likelihood of clinically actionable results in adult patients,” Dr. Musunuru and colleagues wrote.

But genetic testing is no guarantee to identify a cause or confirm a diagnosis of CVD, the statement noted. “The yield for any genetic testing for any inherited cardiovascular disease remains <100%, usually much less than 100%,” the writing committee stated.

Dr. Musunuru explained that the results can sometimes be inconclusive. “In many cases, genetic testing reveals a mutation that is uninterpretable, what we call a variant of uncertain significance,” he said. “It is not clear whether the mutation increases the risk of disease or is entirely benign, which makes it very challenging to counsel patients as to whether anything should be done about the mutation.”

Even in a diagnosed patient the test results can be uncertain. “This makes it challenging to explain why the patient has the disease and whether any of the family members are at risk,” Dr. Musunuru said.

According to the statement, providers should encourage patients with a confirmed or likely pathogenic variant for CVD to share that information with “all of their at-risk relative,” the statement noted, suggesting “family letters” given to patients are a way to navigate HIPAA’s privacy limits.

The statement was written on behalf of the American Heart Association’s Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology.

Dr. Musunuru and writing group members have no relevant financial relationships to disclose.

SOURCE: Musunuru K et al. Circ Genom Precis Med. 2020 Jul 23. doi: 10.1161/HCG.0000000000000067.

A new scientific statement from the American Heart Association recommends that genetic testing for inherited cardiovascular disease should be reserved for four specific types of heart diseases – cardiomyopathies, thoracic aortic aneurysms and dissections, arrhythmias, and familial hypercholesterolemia – and should enlist skilled geneticists and genetic counselors in the care team.

The guidance comes in a scientific statement published online in the journal Circulation: Genomic and Precision Medicine.

Kiran Musunuru, MD, PhD, MPH, ML, chair of the writing group for the scientific statement, described in an interview the rationale for publishing the statement at this time. “There was no prior single statement that summarized best practices for the whole gamut of inherited cardiovascular diseases in adults, only statements for individual diseases,” he said in an interview. “With genetic testing seeing explosive growth in the past few years, both in the clinical setting and with direct-to-consumer testing, we felt that cardiovascular practitioners would benefit from having a single document to serve as a general resource on genetic testing.”

The statement describes two types of patients who would be suitable for genetic testing for cardiovascular disease (CVD), Dr. Musunuru noted: “Patients who have been diagnosed with or are strongly suspected to have a cardiovascular disease that is often inherited and family members of patients who have been diagnosed with an inherited cardiovascular disease and found by genetic testing to have a mutation that is felt to be the cause of the disease.”

The statement also spells out two crucial elements for genetic testing: thorough disease-specific phenotyping – that is, using genetic information to identify the individual’s disease characteristics and a comprehensive family history that spans at least three generations. Testing should only proceed after patients has had genetic counseling and made a shared decision with their doctors.

“Genetic counseling is absolutely essential both before genetic testing to educate patients on what genetic testing entails and what potential results to expect, as well as the risks of testing; and after genetic testing, to review the results of the genetic testing and explain the potential consequences for the patient’s health and the health of family members, including children,” Dr. Musunuru said.

The process should involve board-certified geneticists or at least cardiovascular specialists well-versed in genetics and genetic counselors, the statement noted. The latter are “critical” in the care team, Dr. Musunuru said.

After the decision is made to do genetic testing, the next step is to decide the scope of the testing. That can range from targeted sequencing of a single gene or a few genes linked to the disease to large gene panels; the latter “may not increase the likelihood of clinically actionable results in adult patients,” Dr. Musunuru and colleagues wrote.

But genetic testing is no guarantee to identify a cause or confirm a diagnosis of CVD, the statement noted. “The yield for any genetic testing for any inherited cardiovascular disease remains <100%, usually much less than 100%,” the writing committee stated.

Dr. Musunuru explained that the results can sometimes be inconclusive. “In many cases, genetic testing reveals a mutation that is uninterpretable, what we call a variant of uncertain significance,” he said. “It is not clear whether the mutation increases the risk of disease or is entirely benign, which makes it very challenging to counsel patients as to whether anything should be done about the mutation.”

Even in a diagnosed patient the test results can be uncertain. “This makes it challenging to explain why the patient has the disease and whether any of the family members are at risk,” Dr. Musunuru said.

According to the statement, providers should encourage patients with a confirmed or likely pathogenic variant for CVD to share that information with “all of their at-risk relative,” the statement noted, suggesting “family letters” given to patients are a way to navigate HIPAA’s privacy limits.

The statement was written on behalf of the American Heart Association’s Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology.

Dr. Musunuru and writing group members have no relevant financial relationships to disclose.

SOURCE: Musunuru K et al. Circ Genom Precis Med. 2020 Jul 23. doi: 10.1161/HCG.0000000000000067.

A new scientific statement from the American Heart Association recommends that genetic testing for inherited cardiovascular disease should be reserved for four specific types of heart diseases – cardiomyopathies, thoracic aortic aneurysms and dissections, arrhythmias, and familial hypercholesterolemia – and should enlist skilled geneticists and genetic counselors in the care team.

The guidance comes in a scientific statement published online in the journal Circulation: Genomic and Precision Medicine.

Kiran Musunuru, MD, PhD, MPH, ML, chair of the writing group for the scientific statement, described in an interview the rationale for publishing the statement at this time. “There was no prior single statement that summarized best practices for the whole gamut of inherited cardiovascular diseases in adults, only statements for individual diseases,” he said in an interview. “With genetic testing seeing explosive growth in the past few years, both in the clinical setting and with direct-to-consumer testing, we felt that cardiovascular practitioners would benefit from having a single document to serve as a general resource on genetic testing.”

The statement describes two types of patients who would be suitable for genetic testing for cardiovascular disease (CVD), Dr. Musunuru noted: “Patients who have been diagnosed with or are strongly suspected to have a cardiovascular disease that is often inherited and family members of patients who have been diagnosed with an inherited cardiovascular disease and found by genetic testing to have a mutation that is felt to be the cause of the disease.”

The statement also spells out two crucial elements for genetic testing: thorough disease-specific phenotyping – that is, using genetic information to identify the individual’s disease characteristics and a comprehensive family history that spans at least three generations. Testing should only proceed after patients has had genetic counseling and made a shared decision with their doctors.

“Genetic counseling is absolutely essential both before genetic testing to educate patients on what genetic testing entails and what potential results to expect, as well as the risks of testing; and after genetic testing, to review the results of the genetic testing and explain the potential consequences for the patient’s health and the health of family members, including children,” Dr. Musunuru said.

The process should involve board-certified geneticists or at least cardiovascular specialists well-versed in genetics and genetic counselors, the statement noted. The latter are “critical” in the care team, Dr. Musunuru said.

After the decision is made to do genetic testing, the next step is to decide the scope of the testing. That can range from targeted sequencing of a single gene or a few genes linked to the disease to large gene panels; the latter “may not increase the likelihood of clinically actionable results in adult patients,” Dr. Musunuru and colleagues wrote.

But genetic testing is no guarantee to identify a cause or confirm a diagnosis of CVD, the statement noted. “The yield for any genetic testing for any inherited cardiovascular disease remains <100%, usually much less than 100%,” the writing committee stated.

Dr. Musunuru explained that the results can sometimes be inconclusive. “In many cases, genetic testing reveals a mutation that is uninterpretable, what we call a variant of uncertain significance,” he said. “It is not clear whether the mutation increases the risk of disease or is entirely benign, which makes it very challenging to counsel patients as to whether anything should be done about the mutation.”

Even in a diagnosed patient the test results can be uncertain. “This makes it challenging to explain why the patient has the disease and whether any of the family members are at risk,” Dr. Musunuru said.

According to the statement, providers should encourage patients with a confirmed or likely pathogenic variant for CVD to share that information with “all of their at-risk relative,” the statement noted, suggesting “family letters” given to patients are a way to navigate HIPAA’s privacy limits.

The statement was written on behalf of the American Heart Association’s Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology.

Dr. Musunuru and writing group members have no relevant financial relationships to disclose.

SOURCE: Musunuru K et al. Circ Genom Precis Med. 2020 Jul 23. doi: 10.1161/HCG.0000000000000067.

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

 

 

Commentary

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

 

 

Commentary

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

 

 

Commentary

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

Study Overview

Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.

Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.

Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.

Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.

Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).

The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.

Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.

Commentary

Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.¹ Injection-site reactions remain an issue with this formulation.

Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.² While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.³ Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.⁴ The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.

Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.⁵ Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.³ These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.^6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.

In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.

Clinical Implications

The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.

–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS

Study Overview

Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.

Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.

Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.

Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.

Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).

The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.

Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.

Commentary

Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.¹ Injection-site reactions remain an issue with this formulation.

Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.² While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.³ Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.⁴ The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.

Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.⁵ Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.³ These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.^6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.

In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.

Clinical Implications

The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.

–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS

Study Overview

Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.

Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.

Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.

Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.

Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).

The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.

Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.

Commentary

Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.¹ Injection-site reactions remain an issue with this formulation.

Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.² While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.³ Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.⁴ The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.

Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.⁵ Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.³ These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.^6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.

In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.

Clinical Implications

The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.

–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS