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DAPA-HF results transform dapagliflozin from antidiabetic to heart failure drug
PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
REPORTING FROM THE ESC CONGRESS 2019
Key clinical point: Dapagliflozin produced multiple, statistically significant benefits in heart failure patients on top of guideline-directed therapy.
Major finding: The study’s primary endpoint fell by a statistically significant 27% with dapagliflozin compared with placebo in patients without diabetes.
Study details: DAPA-HF, a multinational study with 4,744 patients at 410 sites.
Disclosures: DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF.
Curative intent and palliative care – compatible goals?
The first signs are always vague. Katie (not her real name) was 33 years old and loved to spend her weekends hiking. First, it was fatigue when doing elevation. Then fatigue even while walking across flat ground. One day she just sat in bed and noticed her heart racing.
One blood test, and her primary care doctor called her at home with the results. Go to the emergency room, she said. Katie’s red blood cells were dangerously low. She would need a blood transfusion.
Something was wrong, but the list of possibilities remained broad. Someone in the emergency room tossed out the word “leukemia.” Katie froze. She liked the resident who tossed out “internal bleeding” better.
This was the start of the ups and downs; the good news and bad news; the branch points that opened and closed her future.
The hematologist-oncologist came by. You need to be admitted to the hospital, and we need to do a bone marrow biopsy, she told Katie. It could be – and then the word was said again – this time by a specialist, making it all the more real: leukemia.
Katie had a few days to sit with this. The bone marrow biopsy was done. Now, what type of leukemia? She read on her computer. She knew there were lots of kinds, some better than others. Now, she was praying for a “good” cancer.
It was one of the bad ones. But.
We sent off additional molecular and genetics testing from your bone marrow, the doctor explained. This type of leukemia can be divided into three groups: high risk, standard risk, and low risk. All the signs so far point to low risk. This is good news, Katie thought.
Six days later. The final cytogenetics came back. Actually, Katie had a rare mutation that automatically put her in the high risk category. It meant she would definitely need a bone marrow transplant to be cured. Bad.
And so she underwent induction chemotherapy. The nurse posted a big calendar on her wall and filled it with her daily blood counts. The counts are dropping, Katie noted. This is good, right? It means the leukemia is responding to chemo? Yes. Good news.
Four days later. The blast count in her blood crept up. It could be anything. It could be reactive. It doesn’t necessarily mean refractory leukemia. But. It’s bad news.
In the interim, some more testing came back. You have one sister, right? Sharon? Yes, Katie confirmed. Looks like Sharon is a perfect match for a bone marrow transplant. Katie cried. Such good news.
Two weeks later the next bone marrow biopsy was done. This shows how you responded to the chemotherapy, the doctors explained. Will it be in remission? Will it be refractory? It’s in remission. Wow, good news.
But the window to transplant is small. In the few weeks to get there, another test came back. Even though the cancer is technically in remission, you have something called minimal residual disease. Meaning there are small amounts of leukemia left over. We should bridge with more chemo before transplant.
Was this good news? Bad news? Who knew anymore?
It’s well known in the hematology and oncology world that – even with advanced disease and poor prognoses – patients with blood cancers are less likely to see palliative care than patients with solid tumors. At conferences and in academic journals, leaders in the field expound on why this may be. One reason is the inability for most hospice agencies to offer blood transfusions. That’s certainly a big piece.
Then there’s Katie. When Katie was diagnosed, she asked me what stage her cancer was. It’s a question I hear a lot. With leukemia, I explained, we don’t think about staging the same way we do for conditions like breast cancer or prostate cancer. Since it’s in the blood, it’s stage 4 by definition, I said, but that doesn’t mean anything about prognosis. Our model of thinking is fundamentally different.
With a solid stage 4 cancer, there is generally no chance for cure. The goal is stabilization: We want to keep the cancer where it is for as long as possible. A stable CT scan, in which the disease burden is identical to 3 months before, is a success. The difference between good news and bad news is in lifespan. Receiving bad news is the difference between projecting 2 years and 6 months to live.
With a stage 4 blood cancer like Katie’s leukemia, there is generally a chance for cure. The goal is to make the cancer disappear completely and have someone live a normal lifespan. The outcomes are binary. The difference between good news and bad news is not a difference in lifespan, but a difference in probability of cure. Receiving bad news is the difference between an 80% chance of cure and a 20% chance.
Whenever I order chemotherapy, the electronic record prompts me for my intent: Is this palliative or curative intent? I always type curative intent. The intent is curative until we choose to stop pursuing cure.
Grappling with uncertainty is an enormous challenge for anyone after a diagnosis of cancer. Not knowing whether cure is even possible makes it that much more complex. The outcomes are as diverse as can be. The next branch point can literally be the difference between no more cancer and no more options.
Which raises the question, at what point – if any – should we have asked palliative care to see Katie? I wish we would have done it sooner, not because patients like Katie won’t be cured, but to help them sit with the toughest of uncertainties; prepare for it; live in it as best as possible.
As I write this, Katie is undergoing a bone marrow transplant from her sister, the match. In a few weeks she will face her next branch point – whether the transplant worked. It will move her closer or further from a cure.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz and listen to her each week on the Blood & Cancer podcast.
The first signs are always vague. Katie (not her real name) was 33 years old and loved to spend her weekends hiking. First, it was fatigue when doing elevation. Then fatigue even while walking across flat ground. One day she just sat in bed and noticed her heart racing.
One blood test, and her primary care doctor called her at home with the results. Go to the emergency room, she said. Katie’s red blood cells were dangerously low. She would need a blood transfusion.
Something was wrong, but the list of possibilities remained broad. Someone in the emergency room tossed out the word “leukemia.” Katie froze. She liked the resident who tossed out “internal bleeding” better.
This was the start of the ups and downs; the good news and bad news; the branch points that opened and closed her future.
The hematologist-oncologist came by. You need to be admitted to the hospital, and we need to do a bone marrow biopsy, she told Katie. It could be – and then the word was said again – this time by a specialist, making it all the more real: leukemia.
Katie had a few days to sit with this. The bone marrow biopsy was done. Now, what type of leukemia? She read on her computer. She knew there were lots of kinds, some better than others. Now, she was praying for a “good” cancer.
It was one of the bad ones. But.
We sent off additional molecular and genetics testing from your bone marrow, the doctor explained. This type of leukemia can be divided into three groups: high risk, standard risk, and low risk. All the signs so far point to low risk. This is good news, Katie thought.
Six days later. The final cytogenetics came back. Actually, Katie had a rare mutation that automatically put her in the high risk category. It meant she would definitely need a bone marrow transplant to be cured. Bad.
And so she underwent induction chemotherapy. The nurse posted a big calendar on her wall and filled it with her daily blood counts. The counts are dropping, Katie noted. This is good, right? It means the leukemia is responding to chemo? Yes. Good news.
Four days later. The blast count in her blood crept up. It could be anything. It could be reactive. It doesn’t necessarily mean refractory leukemia. But. It’s bad news.
In the interim, some more testing came back. You have one sister, right? Sharon? Yes, Katie confirmed. Looks like Sharon is a perfect match for a bone marrow transplant. Katie cried. Such good news.
Two weeks later the next bone marrow biopsy was done. This shows how you responded to the chemotherapy, the doctors explained. Will it be in remission? Will it be refractory? It’s in remission. Wow, good news.
But the window to transplant is small. In the few weeks to get there, another test came back. Even though the cancer is technically in remission, you have something called minimal residual disease. Meaning there are small amounts of leukemia left over. We should bridge with more chemo before transplant.
Was this good news? Bad news? Who knew anymore?
It’s well known in the hematology and oncology world that – even with advanced disease and poor prognoses – patients with blood cancers are less likely to see palliative care than patients with solid tumors. At conferences and in academic journals, leaders in the field expound on why this may be. One reason is the inability for most hospice agencies to offer blood transfusions. That’s certainly a big piece.
Then there’s Katie. When Katie was diagnosed, she asked me what stage her cancer was. It’s a question I hear a lot. With leukemia, I explained, we don’t think about staging the same way we do for conditions like breast cancer or prostate cancer. Since it’s in the blood, it’s stage 4 by definition, I said, but that doesn’t mean anything about prognosis. Our model of thinking is fundamentally different.
With a solid stage 4 cancer, there is generally no chance for cure. The goal is stabilization: We want to keep the cancer where it is for as long as possible. A stable CT scan, in which the disease burden is identical to 3 months before, is a success. The difference between good news and bad news is in lifespan. Receiving bad news is the difference between projecting 2 years and 6 months to live.
With a stage 4 blood cancer like Katie’s leukemia, there is generally a chance for cure. The goal is to make the cancer disappear completely and have someone live a normal lifespan. The outcomes are binary. The difference between good news and bad news is not a difference in lifespan, but a difference in probability of cure. Receiving bad news is the difference between an 80% chance of cure and a 20% chance.
Whenever I order chemotherapy, the electronic record prompts me for my intent: Is this palliative or curative intent? I always type curative intent. The intent is curative until we choose to stop pursuing cure.
Grappling with uncertainty is an enormous challenge for anyone after a diagnosis of cancer. Not knowing whether cure is even possible makes it that much more complex. The outcomes are as diverse as can be. The next branch point can literally be the difference between no more cancer and no more options.
Which raises the question, at what point – if any – should we have asked palliative care to see Katie? I wish we would have done it sooner, not because patients like Katie won’t be cured, but to help them sit with the toughest of uncertainties; prepare for it; live in it as best as possible.
As I write this, Katie is undergoing a bone marrow transplant from her sister, the match. In a few weeks she will face her next branch point – whether the transplant worked. It will move her closer or further from a cure.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz and listen to her each week on the Blood & Cancer podcast.
The first signs are always vague. Katie (not her real name) was 33 years old and loved to spend her weekends hiking. First, it was fatigue when doing elevation. Then fatigue even while walking across flat ground. One day she just sat in bed and noticed her heart racing.
One blood test, and her primary care doctor called her at home with the results. Go to the emergency room, she said. Katie’s red blood cells were dangerously low. She would need a blood transfusion.
Something was wrong, but the list of possibilities remained broad. Someone in the emergency room tossed out the word “leukemia.” Katie froze. She liked the resident who tossed out “internal bleeding” better.
This was the start of the ups and downs; the good news and bad news; the branch points that opened and closed her future.
The hematologist-oncologist came by. You need to be admitted to the hospital, and we need to do a bone marrow biopsy, she told Katie. It could be – and then the word was said again – this time by a specialist, making it all the more real: leukemia.
Katie had a few days to sit with this. The bone marrow biopsy was done. Now, what type of leukemia? She read on her computer. She knew there were lots of kinds, some better than others. Now, she was praying for a “good” cancer.
It was one of the bad ones. But.
We sent off additional molecular and genetics testing from your bone marrow, the doctor explained. This type of leukemia can be divided into three groups: high risk, standard risk, and low risk. All the signs so far point to low risk. This is good news, Katie thought.
Six days later. The final cytogenetics came back. Actually, Katie had a rare mutation that automatically put her in the high risk category. It meant she would definitely need a bone marrow transplant to be cured. Bad.
And so she underwent induction chemotherapy. The nurse posted a big calendar on her wall and filled it with her daily blood counts. The counts are dropping, Katie noted. This is good, right? It means the leukemia is responding to chemo? Yes. Good news.
Four days later. The blast count in her blood crept up. It could be anything. It could be reactive. It doesn’t necessarily mean refractory leukemia. But. It’s bad news.
In the interim, some more testing came back. You have one sister, right? Sharon? Yes, Katie confirmed. Looks like Sharon is a perfect match for a bone marrow transplant. Katie cried. Such good news.
Two weeks later the next bone marrow biopsy was done. This shows how you responded to the chemotherapy, the doctors explained. Will it be in remission? Will it be refractory? It’s in remission. Wow, good news.
But the window to transplant is small. In the few weeks to get there, another test came back. Even though the cancer is technically in remission, you have something called minimal residual disease. Meaning there are small amounts of leukemia left over. We should bridge with more chemo before transplant.
Was this good news? Bad news? Who knew anymore?
It’s well known in the hematology and oncology world that – even with advanced disease and poor prognoses – patients with blood cancers are less likely to see palliative care than patients with solid tumors. At conferences and in academic journals, leaders in the field expound on why this may be. One reason is the inability for most hospice agencies to offer blood transfusions. That’s certainly a big piece.
Then there’s Katie. When Katie was diagnosed, she asked me what stage her cancer was. It’s a question I hear a lot. With leukemia, I explained, we don’t think about staging the same way we do for conditions like breast cancer or prostate cancer. Since it’s in the blood, it’s stage 4 by definition, I said, but that doesn’t mean anything about prognosis. Our model of thinking is fundamentally different.
With a solid stage 4 cancer, there is generally no chance for cure. The goal is stabilization: We want to keep the cancer where it is for as long as possible. A stable CT scan, in which the disease burden is identical to 3 months before, is a success. The difference between good news and bad news is in lifespan. Receiving bad news is the difference between projecting 2 years and 6 months to live.
With a stage 4 blood cancer like Katie’s leukemia, there is generally a chance for cure. The goal is to make the cancer disappear completely and have someone live a normal lifespan. The outcomes are binary. The difference between good news and bad news is not a difference in lifespan, but a difference in probability of cure. Receiving bad news is the difference between an 80% chance of cure and a 20% chance.
Whenever I order chemotherapy, the electronic record prompts me for my intent: Is this palliative or curative intent? I always type curative intent. The intent is curative until we choose to stop pursuing cure.
Grappling with uncertainty is an enormous challenge for anyone after a diagnosis of cancer. Not knowing whether cure is even possible makes it that much more complex. The outcomes are as diverse as can be. The next branch point can literally be the difference between no more cancer and no more options.
Which raises the question, at what point – if any – should we have asked palliative care to see Katie? I wish we would have done it sooner, not because patients like Katie won’t be cured, but to help them sit with the toughest of uncertainties; prepare for it; live in it as best as possible.
As I write this, Katie is undergoing a bone marrow transplant from her sister, the match. In a few weeks she will face her next branch point – whether the transplant worked. It will move her closer or further from a cure.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz and listen to her each week on the Blood & Cancer podcast.
Community intervention curbs CV disease in hypertensive adults
A community-based care model to control hypertension led by nonphysician health care workers significantly reduced cardiovascular disease risk over 12 months, data from a cluster-controlled randomized study has shown.
Hypertension remains the most common risk factor for cardiovascular disease, but fewer than 20% of individuals with hypertension have their blood pressure controlled, wrote Jon-David Schwalm, MD, of McMaster University in Hamilton, Ont., and colleagues. To help control hypertension in underserved populations, the researchers tested a care model involving nonphysician health workers (NPHWs), primary care physicians, and family members.
The HOPE4 study, presented at the annual congress of the European Society of Cardiology and published simultaneously in the Lancet, included 1,371 adults aged 50 years and older with new or poorly controlled hypertension from 30 communities in Colombia and Malaysia. Sixteen communities were randomized to usual care and 14 to an intervention. The intervention included community screening and treatment of cardiovascular disease risk factors by NPHWs, free medications recommended by NPHWs under physician supervision, and family support for treatment adherence.
After 12 months, the Framingham Risk Scores for 10-year cardiovascular disease risk were significantly lower in the intervention group, compared with the control group (–11.17% vs. –6.40%). In addition, the intervention group showed a significant 11.45 mm Hg greater reduction in systolic blood pressure and a significant 0.41 mmol/L reduction in LDL cholesterol, compared with controls (P less than .0001 for both measures).
Baseline characteristics were similar between the two groups. Approximately 74% of the participants had a history of poorly controlled hypertension, while the remaining patients had new hypertension diagnoses.
“NPHWs were found to be consistently accurate in their ability to identify cardiovascular risk (patient identified by NPHWs as having poorly controlled blood pressure and medication was indicated) and recommend appropriate therapies (antihypertensives and statin as per the study algorithm) when compared with the assessment by local primary care physicians,” the researchers wrote. The study shows how effectively NPHWs can help reduce cardiovascular disease risk at the community level with proper training, effective community outreach, and task sharing with physicians and family members, they noted.
The findings were limited by the inability to assess the safety of specific medications, but no differences in adverse events were reported between the intervention and control groups. Other limitations included the screening of controls for cardiovascular disease risk at baseline, which meant that controls may have modified their behavior as a result, the researchers noted. In addition, the study was not blinded and surrogate outcomes were used because of the short study duration and relatively small sample size, they said.
However, the results support the use of a comprehensive, NPHW-led model, and “the HOPE 4 strategy could help to attain the UN General Assembly Action Plan for a one-third reduction in premature mortality from cardiovascular disease” by 2030, the researchers concluded.
The study was supported by the Canadian Institutes of Health Research; Grand Challenges Canada; Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care; Boehringer Ingelheim; Department of Management of Non-Communicable Diseases, World Health Organization; and the Population Health Research Institute. Lead author Dr. Schwalm and several coauthors disclosed grants to their institutions for this study from the Canadian Institutes of Health Research, Ontario Ministry of Health and Long-Term Care, Boehringer Ingelheim, and the Department of Management of Non-Communicable Diseases, WHO.
SOURCE: Schwalm J-D et al. Lancet. 2019 Sept 2. doi: http://dx.doi.org/10.1016/ S0140-6736(19)31949-X.
A community-based care model to control hypertension led by nonphysician health care workers significantly reduced cardiovascular disease risk over 12 months, data from a cluster-controlled randomized study has shown.
Hypertension remains the most common risk factor for cardiovascular disease, but fewer than 20% of individuals with hypertension have their blood pressure controlled, wrote Jon-David Schwalm, MD, of McMaster University in Hamilton, Ont., and colleagues. To help control hypertension in underserved populations, the researchers tested a care model involving nonphysician health workers (NPHWs), primary care physicians, and family members.
The HOPE4 study, presented at the annual congress of the European Society of Cardiology and published simultaneously in the Lancet, included 1,371 adults aged 50 years and older with new or poorly controlled hypertension from 30 communities in Colombia and Malaysia. Sixteen communities were randomized to usual care and 14 to an intervention. The intervention included community screening and treatment of cardiovascular disease risk factors by NPHWs, free medications recommended by NPHWs under physician supervision, and family support for treatment adherence.
After 12 months, the Framingham Risk Scores for 10-year cardiovascular disease risk were significantly lower in the intervention group, compared with the control group (–11.17% vs. –6.40%). In addition, the intervention group showed a significant 11.45 mm Hg greater reduction in systolic blood pressure and a significant 0.41 mmol/L reduction in LDL cholesterol, compared with controls (P less than .0001 for both measures).
Baseline characteristics were similar between the two groups. Approximately 74% of the participants had a history of poorly controlled hypertension, while the remaining patients had new hypertension diagnoses.
“NPHWs were found to be consistently accurate in their ability to identify cardiovascular risk (patient identified by NPHWs as having poorly controlled blood pressure and medication was indicated) and recommend appropriate therapies (antihypertensives and statin as per the study algorithm) when compared with the assessment by local primary care physicians,” the researchers wrote. The study shows how effectively NPHWs can help reduce cardiovascular disease risk at the community level with proper training, effective community outreach, and task sharing with physicians and family members, they noted.
The findings were limited by the inability to assess the safety of specific medications, but no differences in adverse events were reported between the intervention and control groups. Other limitations included the screening of controls for cardiovascular disease risk at baseline, which meant that controls may have modified their behavior as a result, the researchers noted. In addition, the study was not blinded and surrogate outcomes were used because of the short study duration and relatively small sample size, they said.
However, the results support the use of a comprehensive, NPHW-led model, and “the HOPE 4 strategy could help to attain the UN General Assembly Action Plan for a one-third reduction in premature mortality from cardiovascular disease” by 2030, the researchers concluded.
The study was supported by the Canadian Institutes of Health Research; Grand Challenges Canada; Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care; Boehringer Ingelheim; Department of Management of Non-Communicable Diseases, World Health Organization; and the Population Health Research Institute. Lead author Dr. Schwalm and several coauthors disclosed grants to their institutions for this study from the Canadian Institutes of Health Research, Ontario Ministry of Health and Long-Term Care, Boehringer Ingelheim, and the Department of Management of Non-Communicable Diseases, WHO.
SOURCE: Schwalm J-D et al. Lancet. 2019 Sept 2. doi: http://dx.doi.org/10.1016/ S0140-6736(19)31949-X.
A community-based care model to control hypertension led by nonphysician health care workers significantly reduced cardiovascular disease risk over 12 months, data from a cluster-controlled randomized study has shown.
Hypertension remains the most common risk factor for cardiovascular disease, but fewer than 20% of individuals with hypertension have their blood pressure controlled, wrote Jon-David Schwalm, MD, of McMaster University in Hamilton, Ont., and colleagues. To help control hypertension in underserved populations, the researchers tested a care model involving nonphysician health workers (NPHWs), primary care physicians, and family members.
The HOPE4 study, presented at the annual congress of the European Society of Cardiology and published simultaneously in the Lancet, included 1,371 adults aged 50 years and older with new or poorly controlled hypertension from 30 communities in Colombia and Malaysia. Sixteen communities were randomized to usual care and 14 to an intervention. The intervention included community screening and treatment of cardiovascular disease risk factors by NPHWs, free medications recommended by NPHWs under physician supervision, and family support for treatment adherence.
After 12 months, the Framingham Risk Scores for 10-year cardiovascular disease risk were significantly lower in the intervention group, compared with the control group (–11.17% vs. –6.40%). In addition, the intervention group showed a significant 11.45 mm Hg greater reduction in systolic blood pressure and a significant 0.41 mmol/L reduction in LDL cholesterol, compared with controls (P less than .0001 for both measures).
Baseline characteristics were similar between the two groups. Approximately 74% of the participants had a history of poorly controlled hypertension, while the remaining patients had new hypertension diagnoses.
“NPHWs were found to be consistently accurate in their ability to identify cardiovascular risk (patient identified by NPHWs as having poorly controlled blood pressure and medication was indicated) and recommend appropriate therapies (antihypertensives and statin as per the study algorithm) when compared with the assessment by local primary care physicians,” the researchers wrote. The study shows how effectively NPHWs can help reduce cardiovascular disease risk at the community level with proper training, effective community outreach, and task sharing with physicians and family members, they noted.
The findings were limited by the inability to assess the safety of specific medications, but no differences in adverse events were reported between the intervention and control groups. Other limitations included the screening of controls for cardiovascular disease risk at baseline, which meant that controls may have modified their behavior as a result, the researchers noted. In addition, the study was not blinded and surrogate outcomes were used because of the short study duration and relatively small sample size, they said.
However, the results support the use of a comprehensive, NPHW-led model, and “the HOPE 4 strategy could help to attain the UN General Assembly Action Plan for a one-third reduction in premature mortality from cardiovascular disease” by 2030, the researchers concluded.
The study was supported by the Canadian Institutes of Health Research; Grand Challenges Canada; Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care; Boehringer Ingelheim; Department of Management of Non-Communicable Diseases, World Health Organization; and the Population Health Research Institute. Lead author Dr. Schwalm and several coauthors disclosed grants to their institutions for this study from the Canadian Institutes of Health Research, Ontario Ministry of Health and Long-Term Care, Boehringer Ingelheim, and the Department of Management of Non-Communicable Diseases, WHO.
SOURCE: Schwalm J-D et al. Lancet. 2019 Sept 2. doi: http://dx.doi.org/10.1016/ S0140-6736(19)31949-X.
AT THE ESC CONGRESS 2019
Key clinical point: A community-based model for managing hypertension significantly improved blood pressure and reduced cardiovascular disease risk in adults with hypertension.
Major finding: Framingham Risk Scores decreased by –11.17% in the intervention group vs. –6.40% in the control group (P less than ·0001).
Study details: The data come from a community-based, randomized, controlled trial of 1,371 adults with new or poorly controlled hypertension.
Disclosures: The study was supported by the Canadian Institutes of Health Research: Grand Challenges Canada: Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care; Boehringer Ingelheim; Department of Management of Non-Communicable Diseases, WHO; and Population Health Research Institute. Lead author Dr. Schwalm and several coauthors disclosed grants to their institutions for this study from the Canadian Institutes of Health Research, Ontario Ministry of Health and Long-Term Care, Boehringer Ingelheim, and the Department of Management of Non-Communicable Diseases, WHO.
Source: Schwalm J-D et al. Lancet. 2019 Sept 2. doi: http://dx.doi.org/10.1016/ S0140-6736(19)31949-X.
Sacubitril-valsartan effect on aortic stiffness minimal
PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found , according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.
“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.
The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.
Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm 5 in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm 5 in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm 5 , ranging from -17.6 to 13.2 dyne x s/cm 5 . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.
The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.
Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.
The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.
The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.
SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.
PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found , according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.
“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.
The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.
Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm 5 in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm 5 in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm 5 , ranging from -17.6 to 13.2 dyne x s/cm 5 . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.
The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.
Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.
The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.
The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.
SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.
PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found , according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.
“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.
The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.
Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm 5 in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm 5 in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm 5 , ranging from -17.6 to 13.2 dyne x s/cm 5 . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.
The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.
Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.
The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.
The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.
SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.
AT THE ESC CONGRESS 2019
Key clinical point: Sacubitril-valsartan does not significantly reduce aortic stiffness, compared with enalapril.
Major finding: The difference in aortic characteristic impedance was -2.2 dyne x s/cm5 between treatment groups.
Study details: EVALUATE-HF is a randomized, double-blind clinical trial of 464 participants with heart failure and ejection fraction of less than 40%.
Disclosures: The study was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron.
Source: Desai AS, et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843
Weight loss surgery linked to lower CV event risk in diabetes
, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.
The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.
At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).
The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.
Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).
In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.
In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m2 or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.
The surgery was also associated with significantly greater reductions in HbA1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.
The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.
In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.
“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.
“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.
The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.
“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.
The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.
SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.
Despite a focus on reducing macrovascular events in individuals with type 2 diabetes, none of the major randomized controlled trials of glucose-lowering interventions that support current treatment guidelines have achieved this outcome. This study of bariatric surgery in obese patients with diabetes, however, does show reductions in major adverse cardiovascular events, although these outcomes should be interpreted with caution because of their observational nature and imprecise matching of the study groups.
Despite this, the many known benefits associated with bariatric surgery–induced weight loss suggest that for carefully selected, motivated patients with obesity and type 2 diabetes – who have been unable to lose weight by other means – this could be the preferred treatment option.
Dr. Edward H. Livingston is the deputy editor of JAMA and with the department of surgery at the University of California, Los Angeles. These comments are adapted from an accompanying editorial (JAMA 2019, Sept 2. DOI:10.1001/jama.2019.14577). No conflicts of interest were declared.
Despite a focus on reducing macrovascular events in individuals with type 2 diabetes, none of the major randomized controlled trials of glucose-lowering interventions that support current treatment guidelines have achieved this outcome. This study of bariatric surgery in obese patients with diabetes, however, does show reductions in major adverse cardiovascular events, although these outcomes should be interpreted with caution because of their observational nature and imprecise matching of the study groups.
Despite this, the many known benefits associated with bariatric surgery–induced weight loss suggest that for carefully selected, motivated patients with obesity and type 2 diabetes – who have been unable to lose weight by other means – this could be the preferred treatment option.
Dr. Edward H. Livingston is the deputy editor of JAMA and with the department of surgery at the University of California, Los Angeles. These comments are adapted from an accompanying editorial (JAMA 2019, Sept 2. DOI:10.1001/jama.2019.14577). No conflicts of interest were declared.
Despite a focus on reducing macrovascular events in individuals with type 2 diabetes, none of the major randomized controlled trials of glucose-lowering interventions that support current treatment guidelines have achieved this outcome. This study of bariatric surgery in obese patients with diabetes, however, does show reductions in major adverse cardiovascular events, although these outcomes should be interpreted with caution because of their observational nature and imprecise matching of the study groups.
Despite this, the many known benefits associated with bariatric surgery–induced weight loss suggest that for carefully selected, motivated patients with obesity and type 2 diabetes – who have been unable to lose weight by other means – this could be the preferred treatment option.
Dr. Edward H. Livingston is the deputy editor of JAMA and with the department of surgery at the University of California, Los Angeles. These comments are adapted from an accompanying editorial (JAMA 2019, Sept 2. DOI:10.1001/jama.2019.14577). No conflicts of interest were declared.
, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.
The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.
At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).
The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.
Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).
In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.
In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m2 or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.
The surgery was also associated with significantly greater reductions in HbA1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.
The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.
In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.
“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.
“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.
The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.
“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.
The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.
SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.
, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.
The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.
At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).
The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.
Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).
In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.
In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m2 or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.
The surgery was also associated with significantly greater reductions in HbA1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.
The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.
In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.
“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.
“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.
The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.
“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.
The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.
SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.
AT THE ESC CONGRESS 2019
Key clinical point: Bariatric surgery may reduce the risk of cardiovascular events in people with type 2 diabetes.
Major finding: Bariatric surgery is associated with a 39% reduction in risk of major cardiovascular events.
Study details: Retrospective cohort study in 13,722 individuals with type 2 diabetes and obesity.
Disclosures: The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.
Source: Aminian A et al. JAMA 2019, September 2. DOI: 10.1001/jama.2019.14231.
Periodic repolarization dynamics may predict ICD outcomes
Those with high marker levels more likely to benefit
A novel marker of repolarization may identify patients with cardiomyopathy who would benefit from an implanted cardioverter defibrillator, according to a European research study presented at the annual congress of the European Society of Cardiology and published simultaneously in The Lancet.
High periodic repolarization dynamics were linked to substantial reductions in mortality in a prespecified substudy of the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators).
The degree of periodic repolarization dynamics correlated with reductions in mortality in the 1,371 patients, 968 of whom had ICD implantation and 403 of whom were treated conservatively, in the prospective, nonrandomized controlled cohort study conducted at 44 centers in 15 countries within the European Union. At a median follow-up of 2-7 years, the ICD group had a mortality rate of 14%; at a follow-up of 1-2 years, the control group had a mortality rate of 16%, resulting in a 43% overall reduction in mortality for the ICD group.
Low periodic repolarization dynamics were associated with a low reduction in ICD-related death, whereas high periodic repolarization dynamics were linked to substantial reductions in mortality. In 199 patients with periodic repolarization dynamics of 7.5% or higher, ICD implantation resulted in a 75% reduction in death, compared with controls. Periodic repolarization dynamics also served as reliable predictors of appropriate shocks in patients with ICDs as well as death in controls.
Because of the link between high periodic repolarization dynamics and greater benefits, cardiologists may be able to use the measure as a marker to individualize treatment decisions about the use of ICDs, said Axel Bauer, MD, director of University Hospital for Internal Medicine III, Cardiology and Angiology at Medical University Innsbruck, Austria, and coauthors. “Better patient selection could lead to a reduced number of devices needing to be implanted to save a life.
“Our results should help patients to make decisions about their treatment that take into account individual circumstances and preferences,” the researchers noted.
Their interest in periodic repolarization dynamics arises from increasing evidence that sympathetic mechanisms play a key role in malignant tachyarrhythmias (J Clin Invest. 2005;115:2305-15). They described periodic repolarization dynamics as a “marker of electric instability,” and noted that previous studies have shown a link between increased periodic repolarization dynamics and sudden cardiac death and adequate ICD interventions.
The study noted that more than 100,000 ICDs are implanted in the EU each year at a cost of €2 billion (U.S. $2.2 billion, Europace. 2017;19[suppl 2] ii1-90), but that a 2016 study showed that prophylactic ICD treatment may only benefit select patient subgroups (N Engl J Med. 2016;375:1221-30). While the EU-CERT-ICD supports primary prophylactic ICD therapy as the standard of care for patients with ischemic or nonischemic cardiomyopathy and reduced left ventricular ejection fraction, the invasive nature of ICD implantation carries with it risk of complications.
In an invited commentary, Sana M. Al-Khatib, MD, of Duke University, Durham, N.C., provided some context in interpreting the substudy results, noting, among other considerations, the study’s observational nature, exclusion of almost 40% of potentially eligible patients, and its omission of data for sudden cardiac death (Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736[19]31956-7).
“Periodic repolarization dynamics are not yet ready for prime time,” Dr. Al-Khatib said. The group’s findings need to be validated by other studies, and a reproducible approach to measuring periodic repolarization dynamics should be established, he said. “Until such results are available, periodic repolarization dynamics are unlikely to gain traction as a test that can be consistently used to select patients for primary prevention of sudden cardiac death with ICDs.”
Dr. Bauer and Dr. Al-Khatib had no relevant financial relationships to disclose.
SOURCE: Bauer A et al. Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736(19)31996-8.
Those with high marker levels more likely to benefit
Those with high marker levels more likely to benefit
A novel marker of repolarization may identify patients with cardiomyopathy who would benefit from an implanted cardioverter defibrillator, according to a European research study presented at the annual congress of the European Society of Cardiology and published simultaneously in The Lancet.
High periodic repolarization dynamics were linked to substantial reductions in mortality in a prespecified substudy of the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators).
The degree of periodic repolarization dynamics correlated with reductions in mortality in the 1,371 patients, 968 of whom had ICD implantation and 403 of whom were treated conservatively, in the prospective, nonrandomized controlled cohort study conducted at 44 centers in 15 countries within the European Union. At a median follow-up of 2-7 years, the ICD group had a mortality rate of 14%; at a follow-up of 1-2 years, the control group had a mortality rate of 16%, resulting in a 43% overall reduction in mortality for the ICD group.
Low periodic repolarization dynamics were associated with a low reduction in ICD-related death, whereas high periodic repolarization dynamics were linked to substantial reductions in mortality. In 199 patients with periodic repolarization dynamics of 7.5% or higher, ICD implantation resulted in a 75% reduction in death, compared with controls. Periodic repolarization dynamics also served as reliable predictors of appropriate shocks in patients with ICDs as well as death in controls.
Because of the link between high periodic repolarization dynamics and greater benefits, cardiologists may be able to use the measure as a marker to individualize treatment decisions about the use of ICDs, said Axel Bauer, MD, director of University Hospital for Internal Medicine III, Cardiology and Angiology at Medical University Innsbruck, Austria, and coauthors. “Better patient selection could lead to a reduced number of devices needing to be implanted to save a life.
“Our results should help patients to make decisions about their treatment that take into account individual circumstances and preferences,” the researchers noted.
Their interest in periodic repolarization dynamics arises from increasing evidence that sympathetic mechanisms play a key role in malignant tachyarrhythmias (J Clin Invest. 2005;115:2305-15). They described periodic repolarization dynamics as a “marker of electric instability,” and noted that previous studies have shown a link between increased periodic repolarization dynamics and sudden cardiac death and adequate ICD interventions.
The study noted that more than 100,000 ICDs are implanted in the EU each year at a cost of €2 billion (U.S. $2.2 billion, Europace. 2017;19[suppl 2] ii1-90), but that a 2016 study showed that prophylactic ICD treatment may only benefit select patient subgroups (N Engl J Med. 2016;375:1221-30). While the EU-CERT-ICD supports primary prophylactic ICD therapy as the standard of care for patients with ischemic or nonischemic cardiomyopathy and reduced left ventricular ejection fraction, the invasive nature of ICD implantation carries with it risk of complications.
In an invited commentary, Sana M. Al-Khatib, MD, of Duke University, Durham, N.C., provided some context in interpreting the substudy results, noting, among other considerations, the study’s observational nature, exclusion of almost 40% of potentially eligible patients, and its omission of data for sudden cardiac death (Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736[19]31956-7).
“Periodic repolarization dynamics are not yet ready for prime time,” Dr. Al-Khatib said. The group’s findings need to be validated by other studies, and a reproducible approach to measuring periodic repolarization dynamics should be established, he said. “Until such results are available, periodic repolarization dynamics are unlikely to gain traction as a test that can be consistently used to select patients for primary prevention of sudden cardiac death with ICDs.”
Dr. Bauer and Dr. Al-Khatib had no relevant financial relationships to disclose.
SOURCE: Bauer A et al. Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736(19)31996-8.
A novel marker of repolarization may identify patients with cardiomyopathy who would benefit from an implanted cardioverter defibrillator, according to a European research study presented at the annual congress of the European Society of Cardiology and published simultaneously in The Lancet.
High periodic repolarization dynamics were linked to substantial reductions in mortality in a prespecified substudy of the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators).
The degree of periodic repolarization dynamics correlated with reductions in mortality in the 1,371 patients, 968 of whom had ICD implantation and 403 of whom were treated conservatively, in the prospective, nonrandomized controlled cohort study conducted at 44 centers in 15 countries within the European Union. At a median follow-up of 2-7 years, the ICD group had a mortality rate of 14%; at a follow-up of 1-2 years, the control group had a mortality rate of 16%, resulting in a 43% overall reduction in mortality for the ICD group.
Low periodic repolarization dynamics were associated with a low reduction in ICD-related death, whereas high periodic repolarization dynamics were linked to substantial reductions in mortality. In 199 patients with periodic repolarization dynamics of 7.5% or higher, ICD implantation resulted in a 75% reduction in death, compared with controls. Periodic repolarization dynamics also served as reliable predictors of appropriate shocks in patients with ICDs as well as death in controls.
Because of the link between high periodic repolarization dynamics and greater benefits, cardiologists may be able to use the measure as a marker to individualize treatment decisions about the use of ICDs, said Axel Bauer, MD, director of University Hospital for Internal Medicine III, Cardiology and Angiology at Medical University Innsbruck, Austria, and coauthors. “Better patient selection could lead to a reduced number of devices needing to be implanted to save a life.
“Our results should help patients to make decisions about their treatment that take into account individual circumstances and preferences,” the researchers noted.
Their interest in periodic repolarization dynamics arises from increasing evidence that sympathetic mechanisms play a key role in malignant tachyarrhythmias (J Clin Invest. 2005;115:2305-15). They described periodic repolarization dynamics as a “marker of electric instability,” and noted that previous studies have shown a link between increased periodic repolarization dynamics and sudden cardiac death and adequate ICD interventions.
The study noted that more than 100,000 ICDs are implanted in the EU each year at a cost of €2 billion (U.S. $2.2 billion, Europace. 2017;19[suppl 2] ii1-90), but that a 2016 study showed that prophylactic ICD treatment may only benefit select patient subgroups (N Engl J Med. 2016;375:1221-30). While the EU-CERT-ICD supports primary prophylactic ICD therapy as the standard of care for patients with ischemic or nonischemic cardiomyopathy and reduced left ventricular ejection fraction, the invasive nature of ICD implantation carries with it risk of complications.
In an invited commentary, Sana M. Al-Khatib, MD, of Duke University, Durham, N.C., provided some context in interpreting the substudy results, noting, among other considerations, the study’s observational nature, exclusion of almost 40% of potentially eligible patients, and its omission of data for sudden cardiac death (Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736[19]31956-7).
“Periodic repolarization dynamics are not yet ready for prime time,” Dr. Al-Khatib said. The group’s findings need to be validated by other studies, and a reproducible approach to measuring periodic repolarization dynamics should be established, he said. “Until such results are available, periodic repolarization dynamics are unlikely to gain traction as a test that can be consistently used to select patients for primary prevention of sudden cardiac death with ICDs.”
Dr. Bauer and Dr. Al-Khatib had no relevant financial relationships to disclose.
SOURCE: Bauer A et al. Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736(19)31996-8.
FROM THE ESC CONGRESS 2019
Key clinical point: Periodic repolarization dynamics may guide prophylactic treatment with implantable cardioverter defibrillators.
Major finding: In 199 patients with periodic repolarization dynamics of 7.5% or higher, ICD implantation resulted in a 75% reduction in death, compared with controls.
Study details: Prespecified substudy of 1,371 patients from the European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators (EU-CERT-ICD) study.
Disclosures: The study received funding from the European Community’s 7th Framework Program. Dr. Bauer has no financial relationships to disclose.
Source: Bauer A et al. Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736(19)31996-8.
Click for Credit: Fasting rules for surgery; Biomarkers for PSA vs OA; more
Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. No birth rate gains from levothyroxine in pregnancy
To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020
2. Simple screening for risk of falling in elderly can guide prevention
To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020
3. Time to revisit fasting rules for surgery patients
To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020
4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis
To take the posttest, go to: https://bit.ly/344WPNS
Expires March 28, 2020
5. More chest compression–only CPR leads to increased survival rates
To take the posttest, go to: https://bit.ly/30CahGF
Expires April 1, 2020
Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. No birth rate gains from levothyroxine in pregnancy
To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020
2. Simple screening for risk of falling in elderly can guide prevention
To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020
3. Time to revisit fasting rules for surgery patients
To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020
4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis
To take the posttest, go to: https://bit.ly/344WPNS
Expires March 28, 2020
5. More chest compression–only CPR leads to increased survival rates
To take the posttest, go to: https://bit.ly/30CahGF
Expires April 1, 2020
Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. No birth rate gains from levothyroxine in pregnancy
To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020
2. Simple screening for risk of falling in elderly can guide prevention
To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020
3. Time to revisit fasting rules for surgery patients
To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020
4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis
To take the posttest, go to: https://bit.ly/344WPNS
Expires March 28, 2020
5. More chest compression–only CPR leads to increased survival rates
To take the posttest, go to: https://bit.ly/30CahGF
Expires April 1, 2020
Ticagrelor: Modest benefit, bigger bleed risk in diabetes plus stable CAD
PARIS – , though they also had more major bleeding events than patients receiving placebo plus aspirin.
The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.
Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).
“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.
Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.
Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.
Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.
Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.
Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.
THEMIS was an international multisite double-blind, placebo-controlled study randomizing 19,220 patients 1:1 to receive aspirin, plus placebo (N = 9,601) or ticagrelor (N = 9,619). Patients were followed for a median of 39.9 months; those with previous myocardial infarction or stroke were excluded. Patients had to be at least 50 years old and on anti-hyperglycemic medications for at least 6 months to participate. Patients in the overall study had a baseline age of 66 years, and 31% were female. Most patients were white (71%).
Stable coronary artery disease (CAD) was defined by having any of a previous history of PCI, coronary artery bypass grafting, or angiographically documented stenosis of at least 50% in at least one coronary artery.
During the study period, Dr. Bhatt explained, ticagrelor dosage was reduced from 90 to 60 mg daily as other studies yielded data about improved safety and tolerability without compromise in efficacy at the lower ticagrelor dose.
Permanent treatment discontinuation was common, but more common in patients taking ticagrelor, compared with placebo (34.5% vs. 25.4%). The most frequent reasons for ticagrelor discontinuation were dyspnea and bleeding. All patients who were randomized, save those at a study site that was closed before unblinding, were included in the modified intention-to-treat population for calculation of efficacy outcomes for both THEMIS and THEMIS-PCI.
Given the large number of patients who discontinued the study drug, an estimation was made of the number of events that would have occurred had patients remained in the trial, and outcomes were calculated using these estimations to account for missing data.
Safety outcomes were calculated by including all patients who received at least one dose of a study drug.
An exploratory composite outcome of “net irreversible harm” included all-cause death, myocardial infarction, and stroke, but also fatal bleeding and intracranial hemorrhage. In the full study population, this outcome was seen in 10.1% of the placebo group and 10.8% of the placebo group, for a nonsignificant hazard ratio of 0.93, said Dr. Bhatt.
An additional composite pre-specified exploratory outcome included acute limb ischemia or major amputation; here, the HR of 0.45 favored ticagrelor.
Dr. Bhatt made the point that these pragmatic, patient-centered outcomes are valuable tools when weighing the potential risks and benefits of therapy for a particular patient, and provide a discussion point for individualized, shared decision making.
Results of a pre-specified subgroup analysis of the 58% of THEMIS participants (n = 5,558) with prior PCI were presented by THEMIS’ co-principal investigator, Philippe Gabriel Steg, MD, of the University of Paris and the French National Institute of Health and Medical Research.
“In the history of PCI subgroup, 92% of patients had a history of receiving a stent, and 61% had received at least one drug-eluting stent,” said Dr. Steg.
Patients with PCI saw a slightly greater reduction in relative risk for ischemic events when they received ticagrelor, compared with placebo; the PCI group had a HR of 0.85 for ischemic events (P = .013), compared with a HR of 0.98 for those with no PCI history (P = .76). This meant that ticagrelor DAPT’s efficacy as measured by the primary endpoint of ischemic events lost significance when the non-PCI group was evaluated (P = .76, with P for interaction between the groups of .16).
Some secondary endpoints showed statistical significance for the interaction between PCI status and study drug status. These included the composite outcome of all-cause death, MI, or stroke (P for interaction, .021), and another “mega-composite ischemia” outcome that folded in major amputation of vascular etiology along with all-cause death, MI, and stroke (P = .023).
Looking at bleeding endpoints, there was no significant difference between the groups for TIMI major bleeding, the primary safety endpoint. Patients in the full study cohort as well as the PCI subgroup had significantly more TIMI major bleeding on ticagrelor.
Bleeding measured by Bleeding Academic Research Consortium (BARC) criteria was a secondary endpoint, and the P for interaction just reached statistical significance for the aggregate of all levels of BARC bleeding.
“But the two observations I would draw your attention to are the fact that in patients with a history of PCI, fatal bleeding occurred in the same number of patients in each group – 6 patients in each group,” added Dr. Steg. “And even more importantly, intracranial hemorrhage occurred in 33 patients in the ticagrelor group and 31 patients in the placebo group for patients with a history of PCI, whereas it was 37 and 15 for patients without a history of PCI.” This yielded a significant P value for the interaction of .036.
The exploratory net clinical benefit score favored the PCI group, for a P for interaction of .012. Dr. Steg also shared an analysis showing a net benefit for ticagrelor vs. placebo as a function of the time elapsed between PCI and trial randomization, showing patient benefit to 6 years post drug initiation for the PCI group.
“The subgroup analysis of THEMIS PCI was pre-specified, from a large, clinically meaningful population; it’s plausible and it can be easily explained from the action of dual antiplatelet therapy, and it shows a net benefit,” Dr. Steg said.
The discussant for the presentations was Colin Baigent, , and he wasn’t convinced by the THEMIS-PCI data. He pointed out that looking at the absolute numbers overall for THEMIS yields an absolute benefit of about 8 per 1,000 participants, and an absolute risk of about 12 per 1,000 participants.
“The natural instinct is to then go to the subgroups and try to find people who will see a net benefit,” he said. “Why pick out ‘history of PCI?’” among the 18 pre-specified subgroups, he asked, noting that there was not significant evidence of heterogeneity of hazard ratios among the subgroups.
Overall, “The main results of THEMIS are consistent” with previous investigations into the benefits of ticagrelor DAPT, showing modest efficacy at the expense of a two-fold rise in major bleeding events, said Dr. Baigent, professor of epidemiology at the University of Oxford (England).
The THEMIS study and the subpopulation analysis were funded by AstraZeneca, which markets ticagrelor. Dr. Bhatt reported financial relationships with AstraZeneca and multiple other pharmaceutical companies. In addition to reporting a financial relationship with AstraZeneca, Dr. Steg also reported relationships with multiple pharmaceutical companies. Dr. Baigent reported a financial relationship with Boehringer Engelheim.
Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)
PARIS – , though they also had more major bleeding events than patients receiving placebo plus aspirin.
The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.
Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).
“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.
Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.
Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.
Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.
Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.
Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.
THEMIS was an international multisite double-blind, placebo-controlled study randomizing 19,220 patients 1:1 to receive aspirin, plus placebo (N = 9,601) or ticagrelor (N = 9,619). Patients were followed for a median of 39.9 months; those with previous myocardial infarction or stroke were excluded. Patients had to be at least 50 years old and on anti-hyperglycemic medications for at least 6 months to participate. Patients in the overall study had a baseline age of 66 years, and 31% were female. Most patients were white (71%).
Stable coronary artery disease (CAD) was defined by having any of a previous history of PCI, coronary artery bypass grafting, or angiographically documented stenosis of at least 50% in at least one coronary artery.
During the study period, Dr. Bhatt explained, ticagrelor dosage was reduced from 90 to 60 mg daily as other studies yielded data about improved safety and tolerability without compromise in efficacy at the lower ticagrelor dose.
Permanent treatment discontinuation was common, but more common in patients taking ticagrelor, compared with placebo (34.5% vs. 25.4%). The most frequent reasons for ticagrelor discontinuation were dyspnea and bleeding. All patients who were randomized, save those at a study site that was closed before unblinding, were included in the modified intention-to-treat population for calculation of efficacy outcomes for both THEMIS and THEMIS-PCI.
Given the large number of patients who discontinued the study drug, an estimation was made of the number of events that would have occurred had patients remained in the trial, and outcomes were calculated using these estimations to account for missing data.
Safety outcomes were calculated by including all patients who received at least one dose of a study drug.
An exploratory composite outcome of “net irreversible harm” included all-cause death, myocardial infarction, and stroke, but also fatal bleeding and intracranial hemorrhage. In the full study population, this outcome was seen in 10.1% of the placebo group and 10.8% of the placebo group, for a nonsignificant hazard ratio of 0.93, said Dr. Bhatt.
An additional composite pre-specified exploratory outcome included acute limb ischemia or major amputation; here, the HR of 0.45 favored ticagrelor.
Dr. Bhatt made the point that these pragmatic, patient-centered outcomes are valuable tools when weighing the potential risks and benefits of therapy for a particular patient, and provide a discussion point for individualized, shared decision making.
Results of a pre-specified subgroup analysis of the 58% of THEMIS participants (n = 5,558) with prior PCI were presented by THEMIS’ co-principal investigator, Philippe Gabriel Steg, MD, of the University of Paris and the French National Institute of Health and Medical Research.
“In the history of PCI subgroup, 92% of patients had a history of receiving a stent, and 61% had received at least one drug-eluting stent,” said Dr. Steg.
Patients with PCI saw a slightly greater reduction in relative risk for ischemic events when they received ticagrelor, compared with placebo; the PCI group had a HR of 0.85 for ischemic events (P = .013), compared with a HR of 0.98 for those with no PCI history (P = .76). This meant that ticagrelor DAPT’s efficacy as measured by the primary endpoint of ischemic events lost significance when the non-PCI group was evaluated (P = .76, with P for interaction between the groups of .16).
Some secondary endpoints showed statistical significance for the interaction between PCI status and study drug status. These included the composite outcome of all-cause death, MI, or stroke (P for interaction, .021), and another “mega-composite ischemia” outcome that folded in major amputation of vascular etiology along with all-cause death, MI, and stroke (P = .023).
Looking at bleeding endpoints, there was no significant difference between the groups for TIMI major bleeding, the primary safety endpoint. Patients in the full study cohort as well as the PCI subgroup had significantly more TIMI major bleeding on ticagrelor.
Bleeding measured by Bleeding Academic Research Consortium (BARC) criteria was a secondary endpoint, and the P for interaction just reached statistical significance for the aggregate of all levels of BARC bleeding.
“But the two observations I would draw your attention to are the fact that in patients with a history of PCI, fatal bleeding occurred in the same number of patients in each group – 6 patients in each group,” added Dr. Steg. “And even more importantly, intracranial hemorrhage occurred in 33 patients in the ticagrelor group and 31 patients in the placebo group for patients with a history of PCI, whereas it was 37 and 15 for patients without a history of PCI.” This yielded a significant P value for the interaction of .036.
The exploratory net clinical benefit score favored the PCI group, for a P for interaction of .012. Dr. Steg also shared an analysis showing a net benefit for ticagrelor vs. placebo as a function of the time elapsed between PCI and trial randomization, showing patient benefit to 6 years post drug initiation for the PCI group.
“The subgroup analysis of THEMIS PCI was pre-specified, from a large, clinically meaningful population; it’s plausible and it can be easily explained from the action of dual antiplatelet therapy, and it shows a net benefit,” Dr. Steg said.
The discussant for the presentations was Colin Baigent, , and he wasn’t convinced by the THEMIS-PCI data. He pointed out that looking at the absolute numbers overall for THEMIS yields an absolute benefit of about 8 per 1,000 participants, and an absolute risk of about 12 per 1,000 participants.
“The natural instinct is to then go to the subgroups and try to find people who will see a net benefit,” he said. “Why pick out ‘history of PCI?’” among the 18 pre-specified subgroups, he asked, noting that there was not significant evidence of heterogeneity of hazard ratios among the subgroups.
Overall, “The main results of THEMIS are consistent” with previous investigations into the benefits of ticagrelor DAPT, showing modest efficacy at the expense of a two-fold rise in major bleeding events, said Dr. Baigent, professor of epidemiology at the University of Oxford (England).
The THEMIS study and the subpopulation analysis were funded by AstraZeneca, which markets ticagrelor. Dr. Bhatt reported financial relationships with AstraZeneca and multiple other pharmaceutical companies. In addition to reporting a financial relationship with AstraZeneca, Dr. Steg also reported relationships with multiple pharmaceutical companies. Dr. Baigent reported a financial relationship with Boehringer Engelheim.
Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)
PARIS – , though they also had more major bleeding events than patients receiving placebo plus aspirin.
The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.
Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).
“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.
Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.
Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.
Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.
Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.
Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.
THEMIS was an international multisite double-blind, placebo-controlled study randomizing 19,220 patients 1:1 to receive aspirin, plus placebo (N = 9,601) or ticagrelor (N = 9,619). Patients were followed for a median of 39.9 months; those with previous myocardial infarction or stroke were excluded. Patients had to be at least 50 years old and on anti-hyperglycemic medications for at least 6 months to participate. Patients in the overall study had a baseline age of 66 years, and 31% were female. Most patients were white (71%).
Stable coronary artery disease (CAD) was defined by having any of a previous history of PCI, coronary artery bypass grafting, or angiographically documented stenosis of at least 50% in at least one coronary artery.
During the study period, Dr. Bhatt explained, ticagrelor dosage was reduced from 90 to 60 mg daily as other studies yielded data about improved safety and tolerability without compromise in efficacy at the lower ticagrelor dose.
Permanent treatment discontinuation was common, but more common in patients taking ticagrelor, compared with placebo (34.5% vs. 25.4%). The most frequent reasons for ticagrelor discontinuation were dyspnea and bleeding. All patients who were randomized, save those at a study site that was closed before unblinding, were included in the modified intention-to-treat population for calculation of efficacy outcomes for both THEMIS and THEMIS-PCI.
Given the large number of patients who discontinued the study drug, an estimation was made of the number of events that would have occurred had patients remained in the trial, and outcomes were calculated using these estimations to account for missing data.
Safety outcomes were calculated by including all patients who received at least one dose of a study drug.
An exploratory composite outcome of “net irreversible harm” included all-cause death, myocardial infarction, and stroke, but also fatal bleeding and intracranial hemorrhage. In the full study population, this outcome was seen in 10.1% of the placebo group and 10.8% of the placebo group, for a nonsignificant hazard ratio of 0.93, said Dr. Bhatt.
An additional composite pre-specified exploratory outcome included acute limb ischemia or major amputation; here, the HR of 0.45 favored ticagrelor.
Dr. Bhatt made the point that these pragmatic, patient-centered outcomes are valuable tools when weighing the potential risks and benefits of therapy for a particular patient, and provide a discussion point for individualized, shared decision making.
Results of a pre-specified subgroup analysis of the 58% of THEMIS participants (n = 5,558) with prior PCI were presented by THEMIS’ co-principal investigator, Philippe Gabriel Steg, MD, of the University of Paris and the French National Institute of Health and Medical Research.
“In the history of PCI subgroup, 92% of patients had a history of receiving a stent, and 61% had received at least one drug-eluting stent,” said Dr. Steg.
Patients with PCI saw a slightly greater reduction in relative risk for ischemic events when they received ticagrelor, compared with placebo; the PCI group had a HR of 0.85 for ischemic events (P = .013), compared with a HR of 0.98 for those with no PCI history (P = .76). This meant that ticagrelor DAPT’s efficacy as measured by the primary endpoint of ischemic events lost significance when the non-PCI group was evaluated (P = .76, with P for interaction between the groups of .16).
Some secondary endpoints showed statistical significance for the interaction between PCI status and study drug status. These included the composite outcome of all-cause death, MI, or stroke (P for interaction, .021), and another “mega-composite ischemia” outcome that folded in major amputation of vascular etiology along with all-cause death, MI, and stroke (P = .023).
Looking at bleeding endpoints, there was no significant difference between the groups for TIMI major bleeding, the primary safety endpoint. Patients in the full study cohort as well as the PCI subgroup had significantly more TIMI major bleeding on ticagrelor.
Bleeding measured by Bleeding Academic Research Consortium (BARC) criteria was a secondary endpoint, and the P for interaction just reached statistical significance for the aggregate of all levels of BARC bleeding.
“But the two observations I would draw your attention to are the fact that in patients with a history of PCI, fatal bleeding occurred in the same number of patients in each group – 6 patients in each group,” added Dr. Steg. “And even more importantly, intracranial hemorrhage occurred in 33 patients in the ticagrelor group and 31 patients in the placebo group for patients with a history of PCI, whereas it was 37 and 15 for patients without a history of PCI.” This yielded a significant P value for the interaction of .036.
The exploratory net clinical benefit score favored the PCI group, for a P for interaction of .012. Dr. Steg also shared an analysis showing a net benefit for ticagrelor vs. placebo as a function of the time elapsed between PCI and trial randomization, showing patient benefit to 6 years post drug initiation for the PCI group.
“The subgroup analysis of THEMIS PCI was pre-specified, from a large, clinically meaningful population; it’s plausible and it can be easily explained from the action of dual antiplatelet therapy, and it shows a net benefit,” Dr. Steg said.
The discussant for the presentations was Colin Baigent, , and he wasn’t convinced by the THEMIS-PCI data. He pointed out that looking at the absolute numbers overall for THEMIS yields an absolute benefit of about 8 per 1,000 participants, and an absolute risk of about 12 per 1,000 participants.
“The natural instinct is to then go to the subgroups and try to find people who will see a net benefit,” he said. “Why pick out ‘history of PCI?’” among the 18 pre-specified subgroups, he asked, noting that there was not significant evidence of heterogeneity of hazard ratios among the subgroups.
Overall, “The main results of THEMIS are consistent” with previous investigations into the benefits of ticagrelor DAPT, showing modest efficacy at the expense of a two-fold rise in major bleeding events, said Dr. Baigent, professor of epidemiology at the University of Oxford (England).
The THEMIS study and the subpopulation analysis were funded by AstraZeneca, which markets ticagrelor. Dr. Bhatt reported financial relationships with AstraZeneca and multiple other pharmaceutical companies. In addition to reporting a financial relationship with AstraZeneca, Dr. Steg also reported relationships with multiple pharmaceutical companies. Dr. Baigent reported a financial relationship with Boehringer Engelheim.
Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)
AT THE ESC CONGRESS 2019
Early post-ACS bleeding may signal cancer
PARIS –, according to work presented at the annual congress of the European Society of Cardiology.
Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).
Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.
This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.
“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.
Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.
Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”
In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.
“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”
Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.
Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.
Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.
Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”
The authors reported no conflicts of interest.
SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.
PARIS –, according to work presented at the annual congress of the European Society of Cardiology.
Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).
Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.
This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.
“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.
Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.
Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”
In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.
“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”
Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.
Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.
Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.
Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”
The authors reported no conflicts of interest.
SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.
PARIS –, according to work presented at the annual congress of the European Society of Cardiology.
Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).
Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.
This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.
“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.
Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.
Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”
In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.
“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”
Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.
Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.
Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.
Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”
The authors reported no conflicts of interest.
SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.
FROM ESC CONGRESS 2019
POP AGE shakes up DAPT in elderly
PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.
“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.
This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.
Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.
“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.
The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.
The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.
The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.
In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.
“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.
POP AGE is hailed as ‘a wake up call’
In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”
“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.
Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.
“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”
So is POP AGE a practice-changing study?
“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”
“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.
Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
SOURCE: Gimbel ME. ESC 2019, Abstract 84.
PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.
“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.
This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.
Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.
“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.
The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.
The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.
The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.
In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.
“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.
POP AGE is hailed as ‘a wake up call’
In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”
“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.
Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.
“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”
So is POP AGE a practice-changing study?
“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”
“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.
Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
SOURCE: Gimbel ME. ESC 2019, Abstract 84.
PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.
“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.
This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.
Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.
“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.
The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.
The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.
The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.
In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.
“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.
POP AGE is hailed as ‘a wake up call’
In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”
“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.
Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.
“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”
So is POP AGE a practice-changing study?
“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”
“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.
Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
SOURCE: Gimbel ME. ESC 2019, Abstract 84.
AT THE ESC CONGRESS 2019
Key clinical point:
Major finding: The rate of major and minor bleeding was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk.
Study details: POPular AGE, an 11-center Dutch RCT, included 1,003 patients age 70 or older with non-ST-elevation ACS.
Disclosures: The presenter reported having no financial conflicts regarding the study, funded by the Dutch government.
Source: Gimbel ME. ESC 2019, Abstract 84.