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Optimal antiplatelet regimen in ‘bi-risk’ ACS?
Among “bi-risk” patients with acute coronary syndrome (ACS) who received a stent and completed 9-12 months of dual-antiplatelet therapy (DAPT), those who de-escalated therapy to clopidogrel alone as opposed to continuing on clopidogrel and aspirin for 9 months had 25% less bleeding without increased ischemic risk.
The findings are from the OPT-BIRISK trial in more than 7,700 patients in China deemed “bi-risk” because they had both a high risk of clinically relevant bleeding and a high risk of major adverse cardiac and cerebral events (MACCE).
Yaling Han, MD, from General Hospital of Northern Theater Command in Shenyang, China, presented the trial in a hotline session at the annual congress of the European Society of Cardiology.
Dr. Han said in an interview.
She acknowledged that the findings may not be generalizable to non-Asian cohorts. Also, these patients were event-free after 9 months on DAPT, so they were relatively stable. Moreover, the finding that clopidogrel monotherapy was superior to DAPT for MACCE is only hypothesis-generating.
Renato D. Lopes, MD, PhD, Duke University, Durham, N.C., the assigned discussant at the session, congratulated the authors “for an important trial in the understudied East Asian population. The OPT-BIRISK trial adds information to the complex puzzle of antithrombotic therapy after ACS,” he said.
However, he brought up a few points that should be taken into consideration when interpreting this trial, including the ones noted by Dr. Han.
In an interview, Dr. Lopes cautioned that OPT-BIRISK tested an antiplatelet strategy “in challenging patients at increased risk for bleeding and ischemic events, but I don’t think we can say this is truly a high-risk population.” Invited to reply, Dr. Han conceded that these patients constituted a relatively low-risk subset of bi-risk patients.
Double-edged sword
“Antiplatelet therapy is a double-edged sword: it reduces ischemic risk but increases bleeding risk. Optimal antiplatelet therapy for bi-risk ACS patients remains a clinical challenge, and unsolved problem for the cardiovascular physician,” Dr. Han said in a press briefing.
The rationale and design of OPT-BIRISK were published in the American Heart Journal in 2020.
Between February 2018 and December 2020, the researchers enrolled and randomly assigned 7,758 bi-risk patients in 101 centers in China who had completed 9-12 months of DAPT (aspirin plus either clopidogrel or ticagrelor) after drug-eluting stent implantation for ACS.
The patients were randomly assigned to receive either clopidogrel plus aspirin or clopidogrel plus placebo for 9 months, followed by 3 months of aspirin.
The primary endpoint was clinically relevant Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding, at 9 months after randomization.
Key secondary endpoints were MACCE (all-cause mortality, MI, stroke, or clinically driven revascularization), individual components of MACCE, any bleeding, and stent thrombosis at 9 months after randomization.
The patient criteria for having bi-risk ACS were:
- < 65 years old with at least one high-bleeding risk criterion and at least one high-ischemia risk criterion.
- 65-78 years old with at least one high-bleeding risk criterion or at least one high-ischemia risk criterion.
- > 75 years old.
The high bleeding risk criteria were female gender, iron deficiency anemia, stroke, taking a type 2 diabetes medication, and chronic kidney disease.
The high ischemic risk criteria included troponin-positive ACS, previous stent thrombosis, previous CV events (MI, stroke, peripheral artery disease [PAD], percutaneous coronary intervention [PCI]), on a type 2 diabetes medication, chronic kidney disease, and certain lesion characteristics.
The patients had a mean age of about 65 years and 41% were female.
About half (52%) had type 2 diabetes, 18% had previous MI, and 15% had previous ischemic stroke. The ACS was mainly unstable angina (62%), followed by NSTEMI (17%) or STEMI (21%).
The patients had a mean high ischemic risk criteria of 3.2 and a mean high bleeding risk criteria of 1.4.
The initial DAPT treatment was aspirin and clopidogrel in three quarters of the patients and aspirin and ticagrelor in the remaining patients.
At 9 months, the primary endpoint of BARC type 2-5 bleeding occurred in 2.5% of patients in the clopidogrel plus placebo group and in 3.3% of patients in the clopidogrel plus aspirin group (hazard ratio, 0.75; 95% confidence interval, 0.57-0.97, P = .03).
“The bleeding results are not surprising,” Dr. Lopes said. Monotherapy vs. DAPT will cause less bleeding, Dr. Han agreed.
At 9 months, MACCE occurred in 2.6% of patients in the clopidogrel plus placebo group and in 3.5% of patients in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96, P = .02).
Interpreting this latter finding as “reduced risk” of MACCE “is a stretch,” Dr. Lopes cautioned.
A potential explanation for this finding in the trial is that in the comparison group (aspirin plus clopidogrel), when patients had bleeding, they might have stopped all antiplatelet therapy, and this may have led to more ischemic events, he speculated.
“The observed reduction in MACCE is plausible,” Dr. Han said. “However, according to study protocol, we assumed that clopidogrel monotherapy would be noninferior to DAPT on the risk of MACCE. The superiority of clopidogrel alone vs. DAPT on MACCE should therefore be hypothesis-generating.”
“The increased rate of MACCE in the clopidogrel plus aspirin group was surprising,” she said in a press release from the ESC, “and may be because hemorrhagic events, which are more common with ongoing DAPT, could be associated with an adrenergic state with increased platelet aggregation due to hypotension, remedial procedures to treat bleeding, and the cessation of anti-ischemic medications.”
A low-risk subset of bi-risk patients, commonly seen in clinical practice
At the time of the index ACS, more than 60% of the patients had unstable angina, Dr. Lopes observed, “and we know these patients are lower risk.” Also, more than 1,000 of the patients did not have at least one high-risk factor for bleeding or ischemia. Moreover, these patients had not had any clinical events in the past 9-12 months on DAPT, “so they were not truly high risk when they were randomized.
“Patients aged 75 years and above are definitely bi-risk (even without any bleeding/ischemic criteria), especially post ACS, according to much literature,” Dr. Han said.
“Although patients met the bi-risk criteria for increased ischemia and bleeding at the time of index ACS and PCI, they were free from major events for at least 6 months on DAPT, thus constituting a relatively low-risk subset of bi-risk patients,” she conceded.
“Nonetheless, these patients (mean age nearly 65 years, 41% female, 52% diabetes, 18% MI history and 15% ischemic stroke history in bi-risk study) represent a large cohort seen in clinical practice,” she said. And “according to a real-world, nationwide registry from China (the OPT-CAD study), unstable angina accounted for about 50% of all ACS patients.”
There have been more data with shorter times for stopping aspirin, so it’s difficult to reconcile those studies with data from OPT-BIRISK, according to Dr. Lopes.
For example, the 2019 TWILIGHT study in patients undergoing PCI at high risk for bleeding showed that it seems to be safe to stop aspirin after 3 months and continue ticagrelor, without an increase in ischemic events.
“The question is almost in the wrong time,” he said, noting that the field is moving in the direction of stopping aspirin earlier, according to five or six recently published trials.
It is hard to generalize from an Asian population, he agreed. “In the U.S., we have other data that suggests that for high-risk patients, you can stop aspirin earlier than 9 months. That’s what most practices are doing.”
“When you look at different drugs, different doses, different duration,” Dr. Lopes summarized, “you have thousands of different permutations,” for antiplatelet therapy strategies. “Every time we have some data in large studies it adds a piece to the puzzle.”
The study was funded by the National Key Research and Development Project in China, and by a grant from Sanofi-Aventis. Dr. Han reports no relevant financial relationships. Disclosures for the other coauthors can be found with the original article.
A version of this article first appeared on Medscape.com.
Among “bi-risk” patients with acute coronary syndrome (ACS) who received a stent and completed 9-12 months of dual-antiplatelet therapy (DAPT), those who de-escalated therapy to clopidogrel alone as opposed to continuing on clopidogrel and aspirin for 9 months had 25% less bleeding without increased ischemic risk.
The findings are from the OPT-BIRISK trial in more than 7,700 patients in China deemed “bi-risk” because they had both a high risk of clinically relevant bleeding and a high risk of major adverse cardiac and cerebral events (MACCE).
Yaling Han, MD, from General Hospital of Northern Theater Command in Shenyang, China, presented the trial in a hotline session at the annual congress of the European Society of Cardiology.
Dr. Han said in an interview.
She acknowledged that the findings may not be generalizable to non-Asian cohorts. Also, these patients were event-free after 9 months on DAPT, so they were relatively stable. Moreover, the finding that clopidogrel monotherapy was superior to DAPT for MACCE is only hypothesis-generating.
Renato D. Lopes, MD, PhD, Duke University, Durham, N.C., the assigned discussant at the session, congratulated the authors “for an important trial in the understudied East Asian population. The OPT-BIRISK trial adds information to the complex puzzle of antithrombotic therapy after ACS,” he said.
However, he brought up a few points that should be taken into consideration when interpreting this trial, including the ones noted by Dr. Han.
In an interview, Dr. Lopes cautioned that OPT-BIRISK tested an antiplatelet strategy “in challenging patients at increased risk for bleeding and ischemic events, but I don’t think we can say this is truly a high-risk population.” Invited to reply, Dr. Han conceded that these patients constituted a relatively low-risk subset of bi-risk patients.
Double-edged sword
“Antiplatelet therapy is a double-edged sword: it reduces ischemic risk but increases bleeding risk. Optimal antiplatelet therapy for bi-risk ACS patients remains a clinical challenge, and unsolved problem for the cardiovascular physician,” Dr. Han said in a press briefing.
The rationale and design of OPT-BIRISK were published in the American Heart Journal in 2020.
Between February 2018 and December 2020, the researchers enrolled and randomly assigned 7,758 bi-risk patients in 101 centers in China who had completed 9-12 months of DAPT (aspirin plus either clopidogrel or ticagrelor) after drug-eluting stent implantation for ACS.
The patients were randomly assigned to receive either clopidogrel plus aspirin or clopidogrel plus placebo for 9 months, followed by 3 months of aspirin.
The primary endpoint was clinically relevant Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding, at 9 months after randomization.
Key secondary endpoints were MACCE (all-cause mortality, MI, stroke, or clinically driven revascularization), individual components of MACCE, any bleeding, and stent thrombosis at 9 months after randomization.
The patient criteria for having bi-risk ACS were:
- < 65 years old with at least one high-bleeding risk criterion and at least one high-ischemia risk criterion.
- 65-78 years old with at least one high-bleeding risk criterion or at least one high-ischemia risk criterion.
- > 75 years old.
The high bleeding risk criteria were female gender, iron deficiency anemia, stroke, taking a type 2 diabetes medication, and chronic kidney disease.
The high ischemic risk criteria included troponin-positive ACS, previous stent thrombosis, previous CV events (MI, stroke, peripheral artery disease [PAD], percutaneous coronary intervention [PCI]), on a type 2 diabetes medication, chronic kidney disease, and certain lesion characteristics.
The patients had a mean age of about 65 years and 41% were female.
About half (52%) had type 2 diabetes, 18% had previous MI, and 15% had previous ischemic stroke. The ACS was mainly unstable angina (62%), followed by NSTEMI (17%) or STEMI (21%).
The patients had a mean high ischemic risk criteria of 3.2 and a mean high bleeding risk criteria of 1.4.
The initial DAPT treatment was aspirin and clopidogrel in three quarters of the patients and aspirin and ticagrelor in the remaining patients.
At 9 months, the primary endpoint of BARC type 2-5 bleeding occurred in 2.5% of patients in the clopidogrel plus placebo group and in 3.3% of patients in the clopidogrel plus aspirin group (hazard ratio, 0.75; 95% confidence interval, 0.57-0.97, P = .03).
“The bleeding results are not surprising,” Dr. Lopes said. Monotherapy vs. DAPT will cause less bleeding, Dr. Han agreed.
At 9 months, MACCE occurred in 2.6% of patients in the clopidogrel plus placebo group and in 3.5% of patients in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96, P = .02).
Interpreting this latter finding as “reduced risk” of MACCE “is a stretch,” Dr. Lopes cautioned.
A potential explanation for this finding in the trial is that in the comparison group (aspirin plus clopidogrel), when patients had bleeding, they might have stopped all antiplatelet therapy, and this may have led to more ischemic events, he speculated.
“The observed reduction in MACCE is plausible,” Dr. Han said. “However, according to study protocol, we assumed that clopidogrel monotherapy would be noninferior to DAPT on the risk of MACCE. The superiority of clopidogrel alone vs. DAPT on MACCE should therefore be hypothesis-generating.”
“The increased rate of MACCE in the clopidogrel plus aspirin group was surprising,” she said in a press release from the ESC, “and may be because hemorrhagic events, which are more common with ongoing DAPT, could be associated with an adrenergic state with increased platelet aggregation due to hypotension, remedial procedures to treat bleeding, and the cessation of anti-ischemic medications.”
A low-risk subset of bi-risk patients, commonly seen in clinical practice
At the time of the index ACS, more than 60% of the patients had unstable angina, Dr. Lopes observed, “and we know these patients are lower risk.” Also, more than 1,000 of the patients did not have at least one high-risk factor for bleeding or ischemia. Moreover, these patients had not had any clinical events in the past 9-12 months on DAPT, “so they were not truly high risk when they were randomized.
“Patients aged 75 years and above are definitely bi-risk (even without any bleeding/ischemic criteria), especially post ACS, according to much literature,” Dr. Han said.
“Although patients met the bi-risk criteria for increased ischemia and bleeding at the time of index ACS and PCI, they were free from major events for at least 6 months on DAPT, thus constituting a relatively low-risk subset of bi-risk patients,” she conceded.
“Nonetheless, these patients (mean age nearly 65 years, 41% female, 52% diabetes, 18% MI history and 15% ischemic stroke history in bi-risk study) represent a large cohort seen in clinical practice,” she said. And “according to a real-world, nationwide registry from China (the OPT-CAD study), unstable angina accounted for about 50% of all ACS patients.”
There have been more data with shorter times for stopping aspirin, so it’s difficult to reconcile those studies with data from OPT-BIRISK, according to Dr. Lopes.
For example, the 2019 TWILIGHT study in patients undergoing PCI at high risk for bleeding showed that it seems to be safe to stop aspirin after 3 months and continue ticagrelor, without an increase in ischemic events.
“The question is almost in the wrong time,” he said, noting that the field is moving in the direction of stopping aspirin earlier, according to five or six recently published trials.
It is hard to generalize from an Asian population, he agreed. “In the U.S., we have other data that suggests that for high-risk patients, you can stop aspirin earlier than 9 months. That’s what most practices are doing.”
“When you look at different drugs, different doses, different duration,” Dr. Lopes summarized, “you have thousands of different permutations,” for antiplatelet therapy strategies. “Every time we have some data in large studies it adds a piece to the puzzle.”
The study was funded by the National Key Research and Development Project in China, and by a grant from Sanofi-Aventis. Dr. Han reports no relevant financial relationships. Disclosures for the other coauthors can be found with the original article.
A version of this article first appeared on Medscape.com.
Among “bi-risk” patients with acute coronary syndrome (ACS) who received a stent and completed 9-12 months of dual-antiplatelet therapy (DAPT), those who de-escalated therapy to clopidogrel alone as opposed to continuing on clopidogrel and aspirin for 9 months had 25% less bleeding without increased ischemic risk.
The findings are from the OPT-BIRISK trial in more than 7,700 patients in China deemed “bi-risk” because they had both a high risk of clinically relevant bleeding and a high risk of major adverse cardiac and cerebral events (MACCE).
Yaling Han, MD, from General Hospital of Northern Theater Command in Shenyang, China, presented the trial in a hotline session at the annual congress of the European Society of Cardiology.
Dr. Han said in an interview.
She acknowledged that the findings may not be generalizable to non-Asian cohorts. Also, these patients were event-free after 9 months on DAPT, so they were relatively stable. Moreover, the finding that clopidogrel monotherapy was superior to DAPT for MACCE is only hypothesis-generating.
Renato D. Lopes, MD, PhD, Duke University, Durham, N.C., the assigned discussant at the session, congratulated the authors “for an important trial in the understudied East Asian population. The OPT-BIRISK trial adds information to the complex puzzle of antithrombotic therapy after ACS,” he said.
However, he brought up a few points that should be taken into consideration when interpreting this trial, including the ones noted by Dr. Han.
In an interview, Dr. Lopes cautioned that OPT-BIRISK tested an antiplatelet strategy “in challenging patients at increased risk for bleeding and ischemic events, but I don’t think we can say this is truly a high-risk population.” Invited to reply, Dr. Han conceded that these patients constituted a relatively low-risk subset of bi-risk patients.
Double-edged sword
“Antiplatelet therapy is a double-edged sword: it reduces ischemic risk but increases bleeding risk. Optimal antiplatelet therapy for bi-risk ACS patients remains a clinical challenge, and unsolved problem for the cardiovascular physician,” Dr. Han said in a press briefing.
The rationale and design of OPT-BIRISK were published in the American Heart Journal in 2020.
Between February 2018 and December 2020, the researchers enrolled and randomly assigned 7,758 bi-risk patients in 101 centers in China who had completed 9-12 months of DAPT (aspirin plus either clopidogrel or ticagrelor) after drug-eluting stent implantation for ACS.
The patients were randomly assigned to receive either clopidogrel plus aspirin or clopidogrel plus placebo for 9 months, followed by 3 months of aspirin.
The primary endpoint was clinically relevant Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding, at 9 months after randomization.
Key secondary endpoints were MACCE (all-cause mortality, MI, stroke, or clinically driven revascularization), individual components of MACCE, any bleeding, and stent thrombosis at 9 months after randomization.
The patient criteria for having bi-risk ACS were:
- < 65 years old with at least one high-bleeding risk criterion and at least one high-ischemia risk criterion.
- 65-78 years old with at least one high-bleeding risk criterion or at least one high-ischemia risk criterion.
- > 75 years old.
The high bleeding risk criteria were female gender, iron deficiency anemia, stroke, taking a type 2 diabetes medication, and chronic kidney disease.
The high ischemic risk criteria included troponin-positive ACS, previous stent thrombosis, previous CV events (MI, stroke, peripheral artery disease [PAD], percutaneous coronary intervention [PCI]), on a type 2 diabetes medication, chronic kidney disease, and certain lesion characteristics.
The patients had a mean age of about 65 years and 41% were female.
About half (52%) had type 2 diabetes, 18% had previous MI, and 15% had previous ischemic stroke. The ACS was mainly unstable angina (62%), followed by NSTEMI (17%) or STEMI (21%).
The patients had a mean high ischemic risk criteria of 3.2 and a mean high bleeding risk criteria of 1.4.
The initial DAPT treatment was aspirin and clopidogrel in three quarters of the patients and aspirin and ticagrelor in the remaining patients.
At 9 months, the primary endpoint of BARC type 2-5 bleeding occurred in 2.5% of patients in the clopidogrel plus placebo group and in 3.3% of patients in the clopidogrel plus aspirin group (hazard ratio, 0.75; 95% confidence interval, 0.57-0.97, P = .03).
“The bleeding results are not surprising,” Dr. Lopes said. Monotherapy vs. DAPT will cause less bleeding, Dr. Han agreed.
At 9 months, MACCE occurred in 2.6% of patients in the clopidogrel plus placebo group and in 3.5% of patients in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96, P = .02).
Interpreting this latter finding as “reduced risk” of MACCE “is a stretch,” Dr. Lopes cautioned.
A potential explanation for this finding in the trial is that in the comparison group (aspirin plus clopidogrel), when patients had bleeding, they might have stopped all antiplatelet therapy, and this may have led to more ischemic events, he speculated.
“The observed reduction in MACCE is plausible,” Dr. Han said. “However, according to study protocol, we assumed that clopidogrel monotherapy would be noninferior to DAPT on the risk of MACCE. The superiority of clopidogrel alone vs. DAPT on MACCE should therefore be hypothesis-generating.”
“The increased rate of MACCE in the clopidogrel plus aspirin group was surprising,” she said in a press release from the ESC, “and may be because hemorrhagic events, which are more common with ongoing DAPT, could be associated with an adrenergic state with increased platelet aggregation due to hypotension, remedial procedures to treat bleeding, and the cessation of anti-ischemic medications.”
A low-risk subset of bi-risk patients, commonly seen in clinical practice
At the time of the index ACS, more than 60% of the patients had unstable angina, Dr. Lopes observed, “and we know these patients are lower risk.” Also, more than 1,000 of the patients did not have at least one high-risk factor for bleeding or ischemia. Moreover, these patients had not had any clinical events in the past 9-12 months on DAPT, “so they were not truly high risk when they were randomized.
“Patients aged 75 years and above are definitely bi-risk (even without any bleeding/ischemic criteria), especially post ACS, according to much literature,” Dr. Han said.
“Although patients met the bi-risk criteria for increased ischemia and bleeding at the time of index ACS and PCI, they were free from major events for at least 6 months on DAPT, thus constituting a relatively low-risk subset of bi-risk patients,” she conceded.
“Nonetheless, these patients (mean age nearly 65 years, 41% female, 52% diabetes, 18% MI history and 15% ischemic stroke history in bi-risk study) represent a large cohort seen in clinical practice,” she said. And “according to a real-world, nationwide registry from China (the OPT-CAD study), unstable angina accounted for about 50% of all ACS patients.”
There have been more data with shorter times for stopping aspirin, so it’s difficult to reconcile those studies with data from OPT-BIRISK, according to Dr. Lopes.
For example, the 2019 TWILIGHT study in patients undergoing PCI at high risk for bleeding showed that it seems to be safe to stop aspirin after 3 months and continue ticagrelor, without an increase in ischemic events.
“The question is almost in the wrong time,” he said, noting that the field is moving in the direction of stopping aspirin earlier, according to five or six recently published trials.
It is hard to generalize from an Asian population, he agreed. “In the U.S., we have other data that suggests that for high-risk patients, you can stop aspirin earlier than 9 months. That’s what most practices are doing.”
“When you look at different drugs, different doses, different duration,” Dr. Lopes summarized, “you have thousands of different permutations,” for antiplatelet therapy strategies. “Every time we have some data in large studies it adds a piece to the puzzle.”
The study was funded by the National Key Research and Development Project in China, and by a grant from Sanofi-Aventis. Dr. Han reports no relevant financial relationships. Disclosures for the other coauthors can be found with the original article.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2023
Longer edoxaban may benefit cancer patients with distal DVT
Patients with active cancer and newly diagnosed isolated distal deep vein thrombosis (DVT) who received 12 months of edoxaban (Savaysa) had fewer thrombotic events at 1 year than those who received 3 months of treatment, without significantly increased bleeding, in the ONCO-DVT trial.
However, lead author Yugo Yamashita, MD, of Kyoto University noted that caution is needed when determining anticoagulation strategies in individual patients with distal DVT, especially those with high risk for bleeding.
Dr. Yamashita presented the results at the annual congress of the European Society of Cardiology, and the trial was simultaneously published in the journal Circulation.
“This is the first and only randomized trial to show the superiority of longer duration over shorter duration of anticoagulation therapy for reducing thrombotic events in cancer patients with isolated distal DVT,” he said in a press briefing.
The results provide support for 12 months of edoxaban in patients with active cancer and isolated distal DVD, he said in an email.
However, “considering the risk of bleeding associated with anticoagulation therapy, physicians should make the decision of anticoagulation strategies for these patients based on risk-benefit balance of anticoagulation therapy in individual patients,” he stressed.
The take-home message for clinicians is that, “if you find minor DVT in cancer patients, please be careful, because their thrombotic risk was not low” in this trial, Dr. Yamashita said.
The study was conducted in Japan, so whether or not the results are generalizable to other populations is not clear. “Subgroup analysis based on body weight did not show any signal of different effect,” he noted, which suggests that the main results could be applied to other populations, including the U.S. population. However, “generalizability of the current results should be carried out carefully.”
Caution needed when translating findings into clinical practice
The assigned discussant, Teresa Lopez-Fernandez, MD, from La Paz University Hospital, Madrid, who was co-chairperson of 2022 ESC guidelines on cardio-oncology, noted that the optimal anticoagulation therapy strategy is unclear in patients with cancer and isolated distal DVT.
“2022 ESC guidelines on cardio-oncology and [European Society for Medical Oncology] guidelines from this year,” she said, “are both in agreement that we need to prolong anticoagulation [therapy to prevent venous thromboembolism (VTE)] when active cancer exists, and particularly in patients with metastatic cancer. The problem is that none of this text refers specifically to distal DVT.”
The ONCO-DVT trial sheds light on this, but there are a few points to consider when interpreting the findings.
Major bleeding was slightly increased in the 12-month vs 3-month edoxaban groups, although this was not statistically significant, she noted. Moreover, 75% of the patients were treated with low-dose edoxaban, mainly due to their low weight. Also, bleeding risk probably differs in different cancer types.
“These are important things that we need to keep in mind when we try to transfer this data to [inform] our clinical practice,” Dr. Lopez-Fernandez said.
She drew attention to a recent study based on RIETE registry data that suggests that “isolated distal DVT is a big problem for patients with cancer in comparison with noncancer patients, where it seems it’s a low-risk problem.”
The main takeaways from ONCO-DVT, Dr. Lopez-Fernandez said, are that it confirms that cancer-associated isolated distal DVT is a marker of poor prognosis, and it supports the need for extended anticoagulation in patients with active, ongoing cancer and isolated distal DVT.
However, “we need to be cautious to try to really understand what the bleeding risks of these patients are,” she said, “particularly because it is not always easy to transfer the results from an Asian population to other populations.”
There is also a need for further studies with other doses, with other novel oral anticoagulants, and in patients at high risk for bleeding, in clinical practice.
Dr. Yamashita said that the study suggests that there is a potential benefit of prolonged duration of anticoagulant therapy for some patients with isolated distal DVT, but not all patients should receive this dosing strategy, because some patients may be at high risk for bleeding or VTE recurrence. A subanalysis of data from ONCO-DVT study should shed further light on this.
“We need to individualize our risk stratification,” Dr. Lopez-Fernandez said, adding that notably, “a lot of patients in the 12-month group did not continue with the 12-month treatment,” which may have affected bleeding results. Dr. Yamashita agreed.
Study design and findings
From April 2019 to June 2022, the researchers enrolled and randomly assigned 604 patients with active cancer who had newly diagnosed isolated distal DVT, confirmed by ultrasonography, and were scheduled for DVT treatment with anticoagulation therapy, at 60 centers.
Active cancer was defined as a cancer diagnosis or cancer treatment (surgery, chemotherapy, radiotherapy, etc.) within 6 months of randomization, or current recurrence, local invasion, distant metastases, or hematopoietic malignancy without complete remission.
The most common reasons for ultrasonography were elevated D-dimer levels (62%) and suspected DVT because of symptoms (20%).
The patients had a mean age of 70.8 years and 28% were men. The most common cancer sites were ovaries (14%), uterus (13%), lung (11%), colon (9%), and pancreas (8%), followed by stomach, blood, and breast (each 5%).
The patients were randomly assigned 1:1 to receive 12 months or 3 months of oral edoxaban at a dose of 60 mg once daily or 30 mg once daily in patients with body weight of 60 kg or less, creatinine clearance of 30-50 mL/minute, or concomitant treatment with a potent P-glycoprotein inhibitor.
After excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group.
About 70% of patients had a body weight of 60 kg or less and about 22% had a creatinine clearance less than 50 mL/min. About three quarters received the lower dose of edoxaban.
In the 12-month edoxaban group, 223 patients completed the 1-year follow-up (66 patients had died and 7 were lost to follow-up). In the 3-month edoxaban group, 224 patients completed the 1-year follow-up (77 had died and 4 were lost to follow-up).
In the 12-month edoxaban group, 41% of the patients had discontinued treatment by 12 months. In the 3-month edoxaban group, 41% of patients had discontinued treatment by 3 months.
The primary endpoint – a symptomatic recurrent VTE event or VTE-related death – occurred in 3 of the 222 patients (1.2%) in the 12-month edoxaban group and in 22 of the 210 (8.5%) in the 3-month edoxaban group (odds ratio,0.13; 95% confidence interval, 0.03-0.44, P < .001). There were no VTE-related deaths.
The major secondary endpoint – major bleeding, according to International Society on Thrombosis and Hemostasis criteria – occurred in 28 of the 210 patients (10.2%) in the 12-month edoxaban group and in 22 of the 217 (7.6%) in the 3-month edoxaban group (OR, 1.34; 95% CI, 0.75-2.41, P = NS).
The researchers acknowledged that study limitations include an open-label design, a lower-than-expected primary endpoint rate, and less than high adherence to edoxaban, as well as the need for caution when generalizing the results to other populations.
The study was funded by Daiichi Sankyo. Dr. Yamashita disclosed receiving lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Lopez-Fernandez disclosed receiving speaker fees from Phillips, Janssen, Daiichi Sankyo, Myocardial Solutions, AstraZeneca, Pfizer, Beigene, and Bayer not related to this study.
A version of this article appeared on Medscape.com.
Patients with active cancer and newly diagnosed isolated distal deep vein thrombosis (DVT) who received 12 months of edoxaban (Savaysa) had fewer thrombotic events at 1 year than those who received 3 months of treatment, without significantly increased bleeding, in the ONCO-DVT trial.
However, lead author Yugo Yamashita, MD, of Kyoto University noted that caution is needed when determining anticoagulation strategies in individual patients with distal DVT, especially those with high risk for bleeding.
Dr. Yamashita presented the results at the annual congress of the European Society of Cardiology, and the trial was simultaneously published in the journal Circulation.
“This is the first and only randomized trial to show the superiority of longer duration over shorter duration of anticoagulation therapy for reducing thrombotic events in cancer patients with isolated distal DVT,” he said in a press briefing.
The results provide support for 12 months of edoxaban in patients with active cancer and isolated distal DVD, he said in an email.
However, “considering the risk of bleeding associated with anticoagulation therapy, physicians should make the decision of anticoagulation strategies for these patients based on risk-benefit balance of anticoagulation therapy in individual patients,” he stressed.
The take-home message for clinicians is that, “if you find minor DVT in cancer patients, please be careful, because their thrombotic risk was not low” in this trial, Dr. Yamashita said.
The study was conducted in Japan, so whether or not the results are generalizable to other populations is not clear. “Subgroup analysis based on body weight did not show any signal of different effect,” he noted, which suggests that the main results could be applied to other populations, including the U.S. population. However, “generalizability of the current results should be carried out carefully.”
Caution needed when translating findings into clinical practice
The assigned discussant, Teresa Lopez-Fernandez, MD, from La Paz University Hospital, Madrid, who was co-chairperson of 2022 ESC guidelines on cardio-oncology, noted that the optimal anticoagulation therapy strategy is unclear in patients with cancer and isolated distal DVT.
“2022 ESC guidelines on cardio-oncology and [European Society for Medical Oncology] guidelines from this year,” she said, “are both in agreement that we need to prolong anticoagulation [therapy to prevent venous thromboembolism (VTE)] when active cancer exists, and particularly in patients with metastatic cancer. The problem is that none of this text refers specifically to distal DVT.”
The ONCO-DVT trial sheds light on this, but there are a few points to consider when interpreting the findings.
Major bleeding was slightly increased in the 12-month vs 3-month edoxaban groups, although this was not statistically significant, she noted. Moreover, 75% of the patients were treated with low-dose edoxaban, mainly due to their low weight. Also, bleeding risk probably differs in different cancer types.
“These are important things that we need to keep in mind when we try to transfer this data to [inform] our clinical practice,” Dr. Lopez-Fernandez said.
She drew attention to a recent study based on RIETE registry data that suggests that “isolated distal DVT is a big problem for patients with cancer in comparison with noncancer patients, where it seems it’s a low-risk problem.”
The main takeaways from ONCO-DVT, Dr. Lopez-Fernandez said, are that it confirms that cancer-associated isolated distal DVT is a marker of poor prognosis, and it supports the need for extended anticoagulation in patients with active, ongoing cancer and isolated distal DVT.
However, “we need to be cautious to try to really understand what the bleeding risks of these patients are,” she said, “particularly because it is not always easy to transfer the results from an Asian population to other populations.”
There is also a need for further studies with other doses, with other novel oral anticoagulants, and in patients at high risk for bleeding, in clinical practice.
Dr. Yamashita said that the study suggests that there is a potential benefit of prolonged duration of anticoagulant therapy for some patients with isolated distal DVT, but not all patients should receive this dosing strategy, because some patients may be at high risk for bleeding or VTE recurrence. A subanalysis of data from ONCO-DVT study should shed further light on this.
“We need to individualize our risk stratification,” Dr. Lopez-Fernandez said, adding that notably, “a lot of patients in the 12-month group did not continue with the 12-month treatment,” which may have affected bleeding results. Dr. Yamashita agreed.
Study design and findings
From April 2019 to June 2022, the researchers enrolled and randomly assigned 604 patients with active cancer who had newly diagnosed isolated distal DVT, confirmed by ultrasonography, and were scheduled for DVT treatment with anticoagulation therapy, at 60 centers.
Active cancer was defined as a cancer diagnosis or cancer treatment (surgery, chemotherapy, radiotherapy, etc.) within 6 months of randomization, or current recurrence, local invasion, distant metastases, or hematopoietic malignancy without complete remission.
The most common reasons for ultrasonography were elevated D-dimer levels (62%) and suspected DVT because of symptoms (20%).
The patients had a mean age of 70.8 years and 28% were men. The most common cancer sites were ovaries (14%), uterus (13%), lung (11%), colon (9%), and pancreas (8%), followed by stomach, blood, and breast (each 5%).
The patients were randomly assigned 1:1 to receive 12 months or 3 months of oral edoxaban at a dose of 60 mg once daily or 30 mg once daily in patients with body weight of 60 kg or less, creatinine clearance of 30-50 mL/minute, or concomitant treatment with a potent P-glycoprotein inhibitor.
After excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group.
About 70% of patients had a body weight of 60 kg or less and about 22% had a creatinine clearance less than 50 mL/min. About three quarters received the lower dose of edoxaban.
In the 12-month edoxaban group, 223 patients completed the 1-year follow-up (66 patients had died and 7 were lost to follow-up). In the 3-month edoxaban group, 224 patients completed the 1-year follow-up (77 had died and 4 were lost to follow-up).
In the 12-month edoxaban group, 41% of the patients had discontinued treatment by 12 months. In the 3-month edoxaban group, 41% of patients had discontinued treatment by 3 months.
The primary endpoint – a symptomatic recurrent VTE event or VTE-related death – occurred in 3 of the 222 patients (1.2%) in the 12-month edoxaban group and in 22 of the 210 (8.5%) in the 3-month edoxaban group (odds ratio,0.13; 95% confidence interval, 0.03-0.44, P < .001). There were no VTE-related deaths.
The major secondary endpoint – major bleeding, according to International Society on Thrombosis and Hemostasis criteria – occurred in 28 of the 210 patients (10.2%) in the 12-month edoxaban group and in 22 of the 217 (7.6%) in the 3-month edoxaban group (OR, 1.34; 95% CI, 0.75-2.41, P = NS).
The researchers acknowledged that study limitations include an open-label design, a lower-than-expected primary endpoint rate, and less than high adherence to edoxaban, as well as the need for caution when generalizing the results to other populations.
The study was funded by Daiichi Sankyo. Dr. Yamashita disclosed receiving lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Lopez-Fernandez disclosed receiving speaker fees from Phillips, Janssen, Daiichi Sankyo, Myocardial Solutions, AstraZeneca, Pfizer, Beigene, and Bayer not related to this study.
A version of this article appeared on Medscape.com.
Patients with active cancer and newly diagnosed isolated distal deep vein thrombosis (DVT) who received 12 months of edoxaban (Savaysa) had fewer thrombotic events at 1 year than those who received 3 months of treatment, without significantly increased bleeding, in the ONCO-DVT trial.
However, lead author Yugo Yamashita, MD, of Kyoto University noted that caution is needed when determining anticoagulation strategies in individual patients with distal DVT, especially those with high risk for bleeding.
Dr. Yamashita presented the results at the annual congress of the European Society of Cardiology, and the trial was simultaneously published in the journal Circulation.
“This is the first and only randomized trial to show the superiority of longer duration over shorter duration of anticoagulation therapy for reducing thrombotic events in cancer patients with isolated distal DVT,” he said in a press briefing.
The results provide support for 12 months of edoxaban in patients with active cancer and isolated distal DVD, he said in an email.
However, “considering the risk of bleeding associated with anticoagulation therapy, physicians should make the decision of anticoagulation strategies for these patients based on risk-benefit balance of anticoagulation therapy in individual patients,” he stressed.
The take-home message for clinicians is that, “if you find minor DVT in cancer patients, please be careful, because their thrombotic risk was not low” in this trial, Dr. Yamashita said.
The study was conducted in Japan, so whether or not the results are generalizable to other populations is not clear. “Subgroup analysis based on body weight did not show any signal of different effect,” he noted, which suggests that the main results could be applied to other populations, including the U.S. population. However, “generalizability of the current results should be carried out carefully.”
Caution needed when translating findings into clinical practice
The assigned discussant, Teresa Lopez-Fernandez, MD, from La Paz University Hospital, Madrid, who was co-chairperson of 2022 ESC guidelines on cardio-oncology, noted that the optimal anticoagulation therapy strategy is unclear in patients with cancer and isolated distal DVT.
“2022 ESC guidelines on cardio-oncology and [European Society for Medical Oncology] guidelines from this year,” she said, “are both in agreement that we need to prolong anticoagulation [therapy to prevent venous thromboembolism (VTE)] when active cancer exists, and particularly in patients with metastatic cancer. The problem is that none of this text refers specifically to distal DVT.”
The ONCO-DVT trial sheds light on this, but there are a few points to consider when interpreting the findings.
Major bleeding was slightly increased in the 12-month vs 3-month edoxaban groups, although this was not statistically significant, she noted. Moreover, 75% of the patients were treated with low-dose edoxaban, mainly due to their low weight. Also, bleeding risk probably differs in different cancer types.
“These are important things that we need to keep in mind when we try to transfer this data to [inform] our clinical practice,” Dr. Lopez-Fernandez said.
She drew attention to a recent study based on RIETE registry data that suggests that “isolated distal DVT is a big problem for patients with cancer in comparison with noncancer patients, where it seems it’s a low-risk problem.”
The main takeaways from ONCO-DVT, Dr. Lopez-Fernandez said, are that it confirms that cancer-associated isolated distal DVT is a marker of poor prognosis, and it supports the need for extended anticoagulation in patients with active, ongoing cancer and isolated distal DVT.
However, “we need to be cautious to try to really understand what the bleeding risks of these patients are,” she said, “particularly because it is not always easy to transfer the results from an Asian population to other populations.”
There is also a need for further studies with other doses, with other novel oral anticoagulants, and in patients at high risk for bleeding, in clinical practice.
Dr. Yamashita said that the study suggests that there is a potential benefit of prolonged duration of anticoagulant therapy for some patients with isolated distal DVT, but not all patients should receive this dosing strategy, because some patients may be at high risk for bleeding or VTE recurrence. A subanalysis of data from ONCO-DVT study should shed further light on this.
“We need to individualize our risk stratification,” Dr. Lopez-Fernandez said, adding that notably, “a lot of patients in the 12-month group did not continue with the 12-month treatment,” which may have affected bleeding results. Dr. Yamashita agreed.
Study design and findings
From April 2019 to June 2022, the researchers enrolled and randomly assigned 604 patients with active cancer who had newly diagnosed isolated distal DVT, confirmed by ultrasonography, and were scheduled for DVT treatment with anticoagulation therapy, at 60 centers.
Active cancer was defined as a cancer diagnosis or cancer treatment (surgery, chemotherapy, radiotherapy, etc.) within 6 months of randomization, or current recurrence, local invasion, distant metastases, or hematopoietic malignancy without complete remission.
The most common reasons for ultrasonography were elevated D-dimer levels (62%) and suspected DVT because of symptoms (20%).
The patients had a mean age of 70.8 years and 28% were men. The most common cancer sites were ovaries (14%), uterus (13%), lung (11%), colon (9%), and pancreas (8%), followed by stomach, blood, and breast (each 5%).
The patients were randomly assigned 1:1 to receive 12 months or 3 months of oral edoxaban at a dose of 60 mg once daily or 30 mg once daily in patients with body weight of 60 kg or less, creatinine clearance of 30-50 mL/minute, or concomitant treatment with a potent P-glycoprotein inhibitor.
After excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group.
About 70% of patients had a body weight of 60 kg or less and about 22% had a creatinine clearance less than 50 mL/min. About three quarters received the lower dose of edoxaban.
In the 12-month edoxaban group, 223 patients completed the 1-year follow-up (66 patients had died and 7 were lost to follow-up). In the 3-month edoxaban group, 224 patients completed the 1-year follow-up (77 had died and 4 were lost to follow-up).
In the 12-month edoxaban group, 41% of the patients had discontinued treatment by 12 months. In the 3-month edoxaban group, 41% of patients had discontinued treatment by 3 months.
The primary endpoint – a symptomatic recurrent VTE event or VTE-related death – occurred in 3 of the 222 patients (1.2%) in the 12-month edoxaban group and in 22 of the 210 (8.5%) in the 3-month edoxaban group (odds ratio,0.13; 95% confidence interval, 0.03-0.44, P < .001). There were no VTE-related deaths.
The major secondary endpoint – major bleeding, according to International Society on Thrombosis and Hemostasis criteria – occurred in 28 of the 210 patients (10.2%) in the 12-month edoxaban group and in 22 of the 217 (7.6%) in the 3-month edoxaban group (OR, 1.34; 95% CI, 0.75-2.41, P = NS).
The researchers acknowledged that study limitations include an open-label design, a lower-than-expected primary endpoint rate, and less than high adherence to edoxaban, as well as the need for caution when generalizing the results to other populations.
The study was funded by Daiichi Sankyo. Dr. Yamashita disclosed receiving lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Lopez-Fernandez disclosed receiving speaker fees from Phillips, Janssen, Daiichi Sankyo, Myocardial Solutions, AstraZeneca, Pfizer, Beigene, and Bayer not related to this study.
A version of this article appeared on Medscape.com.
FROM THE ESC CONGRESS 2023
Muvalaplin and olpasiran show early promise in lowering Lp(a)
researchers report.
In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.
Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
Phase 1 trial of muvalaplin
Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.
In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.
Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.
In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.
Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.
“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.
The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m2 or less, into two groups.
The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.
The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.
The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.
The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses.
There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.
Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.
The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
OCEAN (a)-DOSE extended study of olpasiran
In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).
Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).
Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.
The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.
At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).
The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.
The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).
The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.
Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”
The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.
These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).
In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.
The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.
A version of this article first appeared on Medscape.com.
researchers report.
In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.
Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
Phase 1 trial of muvalaplin
Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.
In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.
Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.
In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.
Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.
“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.
The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m2 or less, into two groups.
The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.
The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.
The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.
The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses.
There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.
Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.
The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
OCEAN (a)-DOSE extended study of olpasiran
In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).
Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).
Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.
The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.
At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).
The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.
The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).
The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.
Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”
The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.
These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).
In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.
The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.
A version of this article first appeared on Medscape.com.
researchers report.
In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.
Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
Phase 1 trial of muvalaplin
Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.
In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.
Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.
In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.
Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.
“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.
The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m2 or less, into two groups.
The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.
The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.
The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.
The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses.
There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.
Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.
The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
OCEAN (a)-DOSE extended study of olpasiran
In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).
Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).
Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.
The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.
At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).
The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.
The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).
The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.
Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”
The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.
These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).
In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.
The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.
A version of this article first appeared on Medscape.com.
FROM THE ESC CONGRESS 2023
Cardiac arrest centers no benefit in OHCA without STEMI
Survivors of out-of-hospital cardiac arrest (OHCA) without ST-segment elevation who were transported to the nearest hospital emergency department had outcomes similar to those of patients transported to specialist cardiac arrest centers, in the ARREST trial.
Both groups had the same 30-day survival, the primary outcome, as well as 3-month survival and neurologic outcomes.
senior author Simon R. Redwood, MD, principal investigator of ARREST, from Guy’s and St. Thomas’ NHS Trust Hospitals and King’s College, London, said during a press briefing. “These results may allow better resource allocation elsewhere.”
Importantly, this study excluded patients who clearly had myocardial infarction (MI), he stressed. Cardiac arrest can result from cardiac causes or from other events, including trauma, overdose, drowning, or electrocution, he noted.
On the other hand, patients with MI “will benefit from going straight to a heart attack center and having an attempt at reopening the artery,” he emphasized.
Tiffany Patterson, PhD, clinical lead of ARREST, with the same affiliations as Dr. Redwood, presented the trial findings at the annual congress of the European Society of Cardiology in Amsterdam, on Aug. 27. The study was simultaneously published online in The Lancet.
Observational studies of registry data suggest that postarrest care for patients resuscitated after cardiac arrest, without ST-segment elevation, may be best delivered in a specialized center, she noted.
The International Liaison Committee on Resuscitation called for a randomized clinical trial of patients resuscitated after cardiac arrest without ST-segment elevation to clarify this.
In the ARREST trial, among 800 patients with return of spontaneous circulation following OHCA without ST-segment elevation who were randomly assigned to be transported to specialized centers or an emergency department, there was no survival benefit, she summarized.
ARREST was “not simply a negative trial, but a new evidence-based starting point,” according to the trial discussant Lia Crotti, MD, PhD, IRCCS Istituto Auxologico Italiano and University Milano-Bicocca, Italy.
She drew attention to two findings: First, among the 862 patients who were enrolled, whom paramedics judged as being without an obvious noncardiac cause of the cardiac arrest, “only 60% ended up having a cardiac cause for their cardiac arrest and only around one quarter of the total had coronary artery disease.”
The small number of patients who could have benefited from early access to a catheterization laboratory probably contributed to the negative result obtained in this trial, with the loss of statistical power, she said.
Second, London is a dense urban area with high-quality acute care hospitals, so the standard of care in the nearest emergency department may be not so different from that in cardiac arrest centers, she noted. Furthermore, four of the seven cardiac arrest centers have an emergency department, and some of the standard care patients may have been transported there.
“If the clinical trial would be extended to the entire country, including rural areas, maybe the result would be different,” she said.
The study authors acknowledge that the main limitation of this study was that “it was done across London with a dense population in a small geographic area,” and “the London Ambulance Service has rapid response times and short transit times and delivers high quality prehospital care, which could limit generalizability.”
Asked during the press conference here why the results were so different from the registry study findings, Dr. Redwood said, “We’ve seen time and time again that registry data think they are telling us the answer. They’re actually not.”
The session cochairs, Rudolf de Boer, MD, PhD, of Erasmus University Medical Centre, Rotterdam, the Netherlands, and Faiez Zannad, MD, PhD, from University of Lorraine–Vandoeuvre-lès-Nancy, France, each congratulated the researchers on a well-done study.
Dr. de Boer wanted to know whether, for example, 100% of these resuscitated OHCA patients without ST-segment elevation had a cardiac cause, “Would results differ? Or is this just real life?” he asked. Dr. Patterson replied that the paramedics excluded obvious noncardiac causes and the findings were based on current facilities.
“Does this trial provide a definitive answer?” Dr. de Boer asked. Dr. Patterson replied that for the moment, subgroup analysis did not identify any subgroup that might benefit from expedited transport to a cardiac arrest center.
Dr. Zannad wanted to know how informed consent was obtained. Dr. Patterson noted that they have an excellent ethical committee that allowed them to undertake this research in vulnerable patients. Written informed consent was obtained from the patient once the initial emergency had passed if they had regained capacity.
Rationale and trial findings
“It’s very well established that early bystander CPR [cardiopulmonary resuscitation], early defibrillation, and advanced in-hospital care improves survival,” Dr. Redwood noted. “Despite this, only 1 in 10 survive to leave the hospital.”
Therefore, “a cardiac arrest center has been proposed as a way of improving outcome.” These centers have a catheterization laboratory, open 24 hours a day, 7 days a week, advanced critical care including advanced ventilation, temperature management of the patient, hemodynamic support, and neuroprognostication and rehab “because often these patients will have brain injury.
“There’s quite overwhelming registry data to suggest that these cardiac arrest centers improve outcome,” he said, “but these are limited by bias.”
Between January 2018 and December 2022, London Ambulance paramedics randomly assigned 862 patients who were successfully resuscitated and without a confirmed MI to be transported the nearest hospital emergency department or the catheterization laboratory in a cardiac arrest center.
Data were available for 822 participants. They had a mean age of 63 years, and 68% were male.
The primary endpoint, 30-day mortality, occurred in 258 (63%) of 411 participants in the cardiac arrest center group and in 258 (63%) of 412 in the standard care group (unadjusted risk ratio for survival, 1.00; 95% confidence interval [CI], 0.90-1.11; P = 0.96).
Mortality at 3 months was similar in both groups: 64% in the standard care group and 65% in the cardiac arrest center group.
Neurologic outcomes at discharge and 3 months were similar in both groups.
Eight (2%) of 414 patients in the cardiac arrest center group and three (1%) of 413 in the standard care group had serious adverse events, none of which were deemed related to the trial intervention.
A cardiac cause of arrest was identified in roughly 60% of patients in each group, and of these, roughly 42% were coronary causes, 33% were arrhythmia, and 17% were cardiomyopathy.
The median time from cardiac arrest to hospital arrival was 84 minutes in the cardiac arrest center group and 77 minutes in the standard care group.
“Surprising and important RCT evidence”
In an accompanying editorial, Carolina Malta Hansen, MD, PhD, University of Copenhagen, and colleagues wrote that “this study provides randomized trial evidence that in urban settings such as London, there is no survival advantage of a strategy of transporting patients who have been resuscitated to centres with specialty expertise in care of cardiac arrest.
“This result is surprising and important, since this complex and critically ill population would be expected to benefit from centres with more expertise.”
However, “it would be a mistake to conclude that the trial results apply to regions where local hospitals provide a lower quality of care than those in this trial,” they cautioned.
“Where does this leave the medical community, researchers, and society in general?” they asked rhetorically. “Prioritising a minimum standard of care at local hospitals caring for this population is at least as important as ensuring high-quality care or advanced treatment at tertiary centres.
“This trial also calls for more focus on the basics, including efforts to increase bystander cardiopulmonary resuscitation and early defibrillation, aspects of care that are currently being assessed in two ongoing clinical trials (NCT04660526 and NCT03835403) and are most strongly associated with improved survival, when coupled with high-quality prehospital care with trained staff and short response times,” they concluded.
The study was fully funded by the British Heart Foundation. The authors reported that they have no relevant financial disclosures. The financial disclosures of the editorialists are listed with the editorial.
A version of this article first appeared on Medscape.com.
Survivors of out-of-hospital cardiac arrest (OHCA) without ST-segment elevation who were transported to the nearest hospital emergency department had outcomes similar to those of patients transported to specialist cardiac arrest centers, in the ARREST trial.
Both groups had the same 30-day survival, the primary outcome, as well as 3-month survival and neurologic outcomes.
senior author Simon R. Redwood, MD, principal investigator of ARREST, from Guy’s and St. Thomas’ NHS Trust Hospitals and King’s College, London, said during a press briefing. “These results may allow better resource allocation elsewhere.”
Importantly, this study excluded patients who clearly had myocardial infarction (MI), he stressed. Cardiac arrest can result from cardiac causes or from other events, including trauma, overdose, drowning, or electrocution, he noted.
On the other hand, patients with MI “will benefit from going straight to a heart attack center and having an attempt at reopening the artery,” he emphasized.
Tiffany Patterson, PhD, clinical lead of ARREST, with the same affiliations as Dr. Redwood, presented the trial findings at the annual congress of the European Society of Cardiology in Amsterdam, on Aug. 27. The study was simultaneously published online in The Lancet.
Observational studies of registry data suggest that postarrest care for patients resuscitated after cardiac arrest, without ST-segment elevation, may be best delivered in a specialized center, she noted.
The International Liaison Committee on Resuscitation called for a randomized clinical trial of patients resuscitated after cardiac arrest without ST-segment elevation to clarify this.
In the ARREST trial, among 800 patients with return of spontaneous circulation following OHCA without ST-segment elevation who were randomly assigned to be transported to specialized centers or an emergency department, there was no survival benefit, she summarized.
ARREST was “not simply a negative trial, but a new evidence-based starting point,” according to the trial discussant Lia Crotti, MD, PhD, IRCCS Istituto Auxologico Italiano and University Milano-Bicocca, Italy.
She drew attention to two findings: First, among the 862 patients who were enrolled, whom paramedics judged as being without an obvious noncardiac cause of the cardiac arrest, “only 60% ended up having a cardiac cause for their cardiac arrest and only around one quarter of the total had coronary artery disease.”
The small number of patients who could have benefited from early access to a catheterization laboratory probably contributed to the negative result obtained in this trial, with the loss of statistical power, she said.
Second, London is a dense urban area with high-quality acute care hospitals, so the standard of care in the nearest emergency department may be not so different from that in cardiac arrest centers, she noted. Furthermore, four of the seven cardiac arrest centers have an emergency department, and some of the standard care patients may have been transported there.
“If the clinical trial would be extended to the entire country, including rural areas, maybe the result would be different,” she said.
The study authors acknowledge that the main limitation of this study was that “it was done across London with a dense population in a small geographic area,” and “the London Ambulance Service has rapid response times and short transit times and delivers high quality prehospital care, which could limit generalizability.”
Asked during the press conference here why the results were so different from the registry study findings, Dr. Redwood said, “We’ve seen time and time again that registry data think they are telling us the answer. They’re actually not.”
The session cochairs, Rudolf de Boer, MD, PhD, of Erasmus University Medical Centre, Rotterdam, the Netherlands, and Faiez Zannad, MD, PhD, from University of Lorraine–Vandoeuvre-lès-Nancy, France, each congratulated the researchers on a well-done study.
Dr. de Boer wanted to know whether, for example, 100% of these resuscitated OHCA patients without ST-segment elevation had a cardiac cause, “Would results differ? Or is this just real life?” he asked. Dr. Patterson replied that the paramedics excluded obvious noncardiac causes and the findings were based on current facilities.
“Does this trial provide a definitive answer?” Dr. de Boer asked. Dr. Patterson replied that for the moment, subgroup analysis did not identify any subgroup that might benefit from expedited transport to a cardiac arrest center.
Dr. Zannad wanted to know how informed consent was obtained. Dr. Patterson noted that they have an excellent ethical committee that allowed them to undertake this research in vulnerable patients. Written informed consent was obtained from the patient once the initial emergency had passed if they had regained capacity.
Rationale and trial findings
“It’s very well established that early bystander CPR [cardiopulmonary resuscitation], early defibrillation, and advanced in-hospital care improves survival,” Dr. Redwood noted. “Despite this, only 1 in 10 survive to leave the hospital.”
Therefore, “a cardiac arrest center has been proposed as a way of improving outcome.” These centers have a catheterization laboratory, open 24 hours a day, 7 days a week, advanced critical care including advanced ventilation, temperature management of the patient, hemodynamic support, and neuroprognostication and rehab “because often these patients will have brain injury.
“There’s quite overwhelming registry data to suggest that these cardiac arrest centers improve outcome,” he said, “but these are limited by bias.”
Between January 2018 and December 2022, London Ambulance paramedics randomly assigned 862 patients who were successfully resuscitated and without a confirmed MI to be transported the nearest hospital emergency department or the catheterization laboratory in a cardiac arrest center.
Data were available for 822 participants. They had a mean age of 63 years, and 68% were male.
The primary endpoint, 30-day mortality, occurred in 258 (63%) of 411 participants in the cardiac arrest center group and in 258 (63%) of 412 in the standard care group (unadjusted risk ratio for survival, 1.00; 95% confidence interval [CI], 0.90-1.11; P = 0.96).
Mortality at 3 months was similar in both groups: 64% in the standard care group and 65% in the cardiac arrest center group.
Neurologic outcomes at discharge and 3 months were similar in both groups.
Eight (2%) of 414 patients in the cardiac arrest center group and three (1%) of 413 in the standard care group had serious adverse events, none of which were deemed related to the trial intervention.
A cardiac cause of arrest was identified in roughly 60% of patients in each group, and of these, roughly 42% were coronary causes, 33% were arrhythmia, and 17% were cardiomyopathy.
The median time from cardiac arrest to hospital arrival was 84 minutes in the cardiac arrest center group and 77 minutes in the standard care group.
“Surprising and important RCT evidence”
In an accompanying editorial, Carolina Malta Hansen, MD, PhD, University of Copenhagen, and colleagues wrote that “this study provides randomized trial evidence that in urban settings such as London, there is no survival advantage of a strategy of transporting patients who have been resuscitated to centres with specialty expertise in care of cardiac arrest.
“This result is surprising and important, since this complex and critically ill population would be expected to benefit from centres with more expertise.”
However, “it would be a mistake to conclude that the trial results apply to regions where local hospitals provide a lower quality of care than those in this trial,” they cautioned.
“Where does this leave the medical community, researchers, and society in general?” they asked rhetorically. “Prioritising a minimum standard of care at local hospitals caring for this population is at least as important as ensuring high-quality care or advanced treatment at tertiary centres.
“This trial also calls for more focus on the basics, including efforts to increase bystander cardiopulmonary resuscitation and early defibrillation, aspects of care that are currently being assessed in two ongoing clinical trials (NCT04660526 and NCT03835403) and are most strongly associated with improved survival, when coupled with high-quality prehospital care with trained staff and short response times,” they concluded.
The study was fully funded by the British Heart Foundation. The authors reported that they have no relevant financial disclosures. The financial disclosures of the editorialists are listed with the editorial.
A version of this article first appeared on Medscape.com.
Survivors of out-of-hospital cardiac arrest (OHCA) without ST-segment elevation who were transported to the nearest hospital emergency department had outcomes similar to those of patients transported to specialist cardiac arrest centers, in the ARREST trial.
Both groups had the same 30-day survival, the primary outcome, as well as 3-month survival and neurologic outcomes.
senior author Simon R. Redwood, MD, principal investigator of ARREST, from Guy’s and St. Thomas’ NHS Trust Hospitals and King’s College, London, said during a press briefing. “These results may allow better resource allocation elsewhere.”
Importantly, this study excluded patients who clearly had myocardial infarction (MI), he stressed. Cardiac arrest can result from cardiac causes or from other events, including trauma, overdose, drowning, or electrocution, he noted.
On the other hand, patients with MI “will benefit from going straight to a heart attack center and having an attempt at reopening the artery,” he emphasized.
Tiffany Patterson, PhD, clinical lead of ARREST, with the same affiliations as Dr. Redwood, presented the trial findings at the annual congress of the European Society of Cardiology in Amsterdam, on Aug. 27. The study was simultaneously published online in The Lancet.
Observational studies of registry data suggest that postarrest care for patients resuscitated after cardiac arrest, without ST-segment elevation, may be best delivered in a specialized center, she noted.
The International Liaison Committee on Resuscitation called for a randomized clinical trial of patients resuscitated after cardiac arrest without ST-segment elevation to clarify this.
In the ARREST trial, among 800 patients with return of spontaneous circulation following OHCA without ST-segment elevation who were randomly assigned to be transported to specialized centers or an emergency department, there was no survival benefit, she summarized.
ARREST was “not simply a negative trial, but a new evidence-based starting point,” according to the trial discussant Lia Crotti, MD, PhD, IRCCS Istituto Auxologico Italiano and University Milano-Bicocca, Italy.
She drew attention to two findings: First, among the 862 patients who were enrolled, whom paramedics judged as being without an obvious noncardiac cause of the cardiac arrest, “only 60% ended up having a cardiac cause for their cardiac arrest and only around one quarter of the total had coronary artery disease.”
The small number of patients who could have benefited from early access to a catheterization laboratory probably contributed to the negative result obtained in this trial, with the loss of statistical power, she said.
Second, London is a dense urban area with high-quality acute care hospitals, so the standard of care in the nearest emergency department may be not so different from that in cardiac arrest centers, she noted. Furthermore, four of the seven cardiac arrest centers have an emergency department, and some of the standard care patients may have been transported there.
“If the clinical trial would be extended to the entire country, including rural areas, maybe the result would be different,” she said.
The study authors acknowledge that the main limitation of this study was that “it was done across London with a dense population in a small geographic area,” and “the London Ambulance Service has rapid response times and short transit times and delivers high quality prehospital care, which could limit generalizability.”
Asked during the press conference here why the results were so different from the registry study findings, Dr. Redwood said, “We’ve seen time and time again that registry data think they are telling us the answer. They’re actually not.”
The session cochairs, Rudolf de Boer, MD, PhD, of Erasmus University Medical Centre, Rotterdam, the Netherlands, and Faiez Zannad, MD, PhD, from University of Lorraine–Vandoeuvre-lès-Nancy, France, each congratulated the researchers on a well-done study.
Dr. de Boer wanted to know whether, for example, 100% of these resuscitated OHCA patients without ST-segment elevation had a cardiac cause, “Would results differ? Or is this just real life?” he asked. Dr. Patterson replied that the paramedics excluded obvious noncardiac causes and the findings were based on current facilities.
“Does this trial provide a definitive answer?” Dr. de Boer asked. Dr. Patterson replied that for the moment, subgroup analysis did not identify any subgroup that might benefit from expedited transport to a cardiac arrest center.
Dr. Zannad wanted to know how informed consent was obtained. Dr. Patterson noted that they have an excellent ethical committee that allowed them to undertake this research in vulnerable patients. Written informed consent was obtained from the patient once the initial emergency had passed if they had regained capacity.
Rationale and trial findings
“It’s very well established that early bystander CPR [cardiopulmonary resuscitation], early defibrillation, and advanced in-hospital care improves survival,” Dr. Redwood noted. “Despite this, only 1 in 10 survive to leave the hospital.”
Therefore, “a cardiac arrest center has been proposed as a way of improving outcome.” These centers have a catheterization laboratory, open 24 hours a day, 7 days a week, advanced critical care including advanced ventilation, temperature management of the patient, hemodynamic support, and neuroprognostication and rehab “because often these patients will have brain injury.
“There’s quite overwhelming registry data to suggest that these cardiac arrest centers improve outcome,” he said, “but these are limited by bias.”
Between January 2018 and December 2022, London Ambulance paramedics randomly assigned 862 patients who were successfully resuscitated and without a confirmed MI to be transported the nearest hospital emergency department or the catheterization laboratory in a cardiac arrest center.
Data were available for 822 participants. They had a mean age of 63 years, and 68% were male.
The primary endpoint, 30-day mortality, occurred in 258 (63%) of 411 participants in the cardiac arrest center group and in 258 (63%) of 412 in the standard care group (unadjusted risk ratio for survival, 1.00; 95% confidence interval [CI], 0.90-1.11; P = 0.96).
Mortality at 3 months was similar in both groups: 64% in the standard care group and 65% in the cardiac arrest center group.
Neurologic outcomes at discharge and 3 months were similar in both groups.
Eight (2%) of 414 patients in the cardiac arrest center group and three (1%) of 413 in the standard care group had serious adverse events, none of which were deemed related to the trial intervention.
A cardiac cause of arrest was identified in roughly 60% of patients in each group, and of these, roughly 42% were coronary causes, 33% were arrhythmia, and 17% were cardiomyopathy.
The median time from cardiac arrest to hospital arrival was 84 minutes in the cardiac arrest center group and 77 minutes in the standard care group.
“Surprising and important RCT evidence”
In an accompanying editorial, Carolina Malta Hansen, MD, PhD, University of Copenhagen, and colleagues wrote that “this study provides randomized trial evidence that in urban settings such as London, there is no survival advantage of a strategy of transporting patients who have been resuscitated to centres with specialty expertise in care of cardiac arrest.
“This result is surprising and important, since this complex and critically ill population would be expected to benefit from centres with more expertise.”
However, “it would be a mistake to conclude that the trial results apply to regions where local hospitals provide a lower quality of care than those in this trial,” they cautioned.
“Where does this leave the medical community, researchers, and society in general?” they asked rhetorically. “Prioritising a minimum standard of care at local hospitals caring for this population is at least as important as ensuring high-quality care or advanced treatment at tertiary centres.
“This trial also calls for more focus on the basics, including efforts to increase bystander cardiopulmonary resuscitation and early defibrillation, aspects of care that are currently being assessed in two ongoing clinical trials (NCT04660526 and NCT03835403) and are most strongly associated with improved survival, when coupled with high-quality prehospital care with trained staff and short response times,” they concluded.
The study was fully funded by the British Heart Foundation. The authors reported that they have no relevant financial disclosures. The financial disclosures of the editorialists are listed with the editorial.
A version of this article first appeared on Medscape.com.
FROM THE ESC CONGRESS 2023
ESC issues new guidelines on infective endocarditis
(IE) – a rare and potentially lethal infection of the heart’s lining and valves.
The document revises the 2015 version, based on advances in imaging and a trial of antibiotic prophylaxis, among other new developments.
Cochairpersons of the writing task force, Victoria Delgado, MD, PhD, and Michael A. Borger, MD, PhD, and other members presented and discussed the guidelines in three packed sessions at the annual congress of the European Society of Cardiology, and the document was simultaneously published online in the European Heart Journal.
Endocarditis “can present with so many different clinical scenarios, so making the diagnosis can be very challenging,” Dr. Borger, from the Heart Center of Leipzig, Germany, said in an interview.
Diagnosing a lethal, rare, but not uncommon disease such as endocarditis “is something that clinicians struggle with every day,” he noted, pointing to the large overflowing auditoriums where these guidelines were presented. Dr. Borger identified four main takeaways from the document:
- Increased level of recommendation and a clearer definition of prevention and prophylaxis of endocarditis in higher-risk patients.
- An increasing role of nonechocardiographic, advanced cardiac imaging techniques in the diagnosis of endocarditis. “The advanced cardiac imaging techniques achieved the same level of recommendation as echocardiography,” he noted.
- More precisely defined indications for surgery and the timing for surgery, as well as a couple of new surgical recommendations.
- More precisely defined criteria for diagnosing and managing cardiac electronic implantable device (CIED)–associated endocarditis.
The guidelines identify patients at high risk for IE as those with previous IE and patients with surgically implanted prosthetic valves, certain congenital heart diseases, surgery with prosthetic material, or a ventricular assist device as destination therapy and recommend giving them prophylactic antibiotics before oral or dental procedures.
Patients at intermediate risk for IE include those with rheumatic heart disease, nonrheumatic degenerative valve disease, congenital valve abnormalities, CIEDs, and hypertrophic cardiomyopathy. They should be evaluated on a case-by-case basis for this prophylaxis, the guideline authors write.
Making the diagnosis
Advances in imaging techniques necessitated a revised version of the endocarditis guidelines, Dr. Borger noted.
Patients are classified as having a definite, possible, or rejected diagnosis of IE (where a definite diagnosis requires two major criteria, or one major criterion and at least three minor criteria, or five minor criteria).
The two major criteria are blood cultures positive for IE and imaging positive for IE by transesophageal echocardiography, transthoracic echocardiography, or – what is new – cardiac computed tomography, 18F-fluorodeoxyglucose positron emission tomography, or white blood cell single photon emission tomography/CT.
The five minor criteria are predisposing conditions, fever (temperature > 38° C), embolic vascular dissemination, immunologic phenomena, and microbiological evidence.
Patient education
Patient education is “paramount to early diagnosis and treatment,” Dr. Delgado, from Germans Trias i Pujol Hospital, Barcelona, said in a press release from ESC. “Those with valvular heart disease or previous heart valve surgery should be particularly diligent with regards to prevention and recognizing symptoms.”
IE occurs when bacteria or fungi enter the bloodstream, for example through skin infections, dental procedures, and surgery. Symptoms include fever, night sweats, unexplained weight loss, cough, dizziness, and fainting, the press release notes.
“We have several clinical scenarios that are increasing,” Dr. Delgado said at an Ask the Experts session, including implanted cardiac electronic devices, new transcatheter therapies, and increasing endocarditis in people who use injection drugs, “and we have recommendation of evaluation of these patients at follow up.”
“The guidelines have 34 new recommendations,” she noted in a Guideline Overview session. She drew attention to a central figure, “where we tried to summarize the pathway of the patient who is diagnosed with endocarditis, and where we highlight the role of the endocarditis team,” she said.
The guidelines specify a prophylactic antibiotic regimen for high-risk dental procedures, for children and for adults with or without allergy to penicillin or ampicillin, given as a single dose 30-60 minutes before a procedure, she noted.
A new recommendation is that systemic antibiotic prophylaxis may be considered for high-risk patients undergoing invasive procedures of the respiratory, gastrointestinal, or genitourinary tract; skin; or musculoskeletal system.
“It is very important to have a well-educated population,” Dr. Delgado stressed.
Figure 2 of the guideline depicts what patients should do, she said, such as “maintain good dental hygiene, avoid tattoos and piercings, be mindful of infections, do not self-prescribe antibiotics.” This card can be given to the patient, and they can show it to doctors before interventions.
The main targets for antibiotic prophylaxis are oral streptococci, but the emerging and increasing resistance of these bacteria are reasons why patients should not self-prescribe, Dr. Delgado noted.
“Patients should not be self-medicating in order to try to lower their risk of endocarditis,” Dr. Borger said. “They should be speaking to their physicians and have their physician group them according to their risk category.”
“If they are low risk, there’s no reason to take antibiotic prophylaxis [before oral or dental procedures], but if they are high risk, they should not only be taking antibiotic prophylaxis, they should also be doing things like good dental hygiene – visiting the dentist once or twice a year, avoiding unnecessary procedures such as tattooing and piercings, and quick aseptic management of skin wounds.”
POET Trial: Earlier shift to oral antibiotics at home
“Another very important point is the increasing use of oral outpatient antibiotic therapy based on the Partial Oral Treatment of Endocarditis (POET) randomized trial,” Dr. Borger observed. “That’s a new recommendation,” he said, “with significant implications for the care of patients with this oftentimes life-threatening disease.”
In POET, patients in stable condition who had endocarditis on the left side of the heart caused by streptococci, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci were randomly assigned to continue treatment with intravenous antibiotics (199 patients) or to shift to step-down treatment with oral antibiotics (201 patients) after at least 10 days of initial treatment with IV antibiotics.
The 5-year results were published in 2019 in the New England Journal of Medicine and presented at ESC that year. “We were hoping or expecting to see that oral outpatient therapy would be equivalent to inpatient IV therapy,” Dr. Borger said, “but we were surprised to see that oral outpatient therapy was actually statistically significantly better in terms of survival, a very hard outcome, at 5 years after the randomization.”
“This was an important part of our new guideline document. In select patients who are ‘clinically stable’,” as defined in the guidelines, he said, “they could be successfully managed at home with oral antibiotics, rather than keeping them in hospital the whole 6 weeks.”
“In the U.S. and in Canada, a lot of patients are sent home for intravenous therapy, whereas that practice doesn’t exist in a lot of places in Europe. The patients are sitting in the hospital here for 6 weeks, oftentimes for no other reason – just to get their IV antibiotic therapy. The POET trial has shown us that that is probably the wrong thing to be doing.”
Earlier surgical intervention
The new guidelines also recommend that “once there is an indication to do cardiac surgery, it should be promptly performed,” Dr. Borger noted.
Surgery to remove infected material and drain abscesses is indicated for patients with heart failure or uncontrolled infection and to prevent embolism.
“We have defined emergency indications that should be done within 24 hours; urgent, which should be done within 3-5 days; and nonurgent, more than 5 days but within the same hospitalization,” he elaborated. “We’re basically trying to encourage surgeons and nonsurgeons that once there is an indication for surgery, there’s not a lot of benefit to just waiting. You should proceed with operation in a timely manner” to improve survival.
The guidelines recommend surgery for early prosthetic valve endocarditis, within 6 months of valve surgery, with new valve replacement and complete debridement.
Patients who present with stroke and require surgery are not uncommon, Dr. Borger noted. Ischemic stroke should not be a reason to delay surgery, and patients with hemorrhagic stoke, with favorable features, can undergo surgery.
The guidelines provide a figure for the management of CIED-related infective endocarditis. They also include a new section devoted to patient-centered care and shared decision-making.
The guidelines were endorsed by the European Association for Cardio-Thoracic Surgery and the European Association of Nuclear Medicine. The writing task force included representatives from EACTS, EANM, and the European Society of Clinical Microbiology and Infectious Diseases.
The complete guidelines, as well as pocket guidelines, essential messages, a pocket guidelines app, and an official guidelines slide set, all addressing endocarditis, are available from the ESC website.
The guidelines did not receive any funding. The disclosure forms of all experts involved in their development are available on the ESC website.
A version of this article appeared on Medscape.com.
(IE) – a rare and potentially lethal infection of the heart’s lining and valves.
The document revises the 2015 version, based on advances in imaging and a trial of antibiotic prophylaxis, among other new developments.
Cochairpersons of the writing task force, Victoria Delgado, MD, PhD, and Michael A. Borger, MD, PhD, and other members presented and discussed the guidelines in three packed sessions at the annual congress of the European Society of Cardiology, and the document was simultaneously published online in the European Heart Journal.
Endocarditis “can present with so many different clinical scenarios, so making the diagnosis can be very challenging,” Dr. Borger, from the Heart Center of Leipzig, Germany, said in an interview.
Diagnosing a lethal, rare, but not uncommon disease such as endocarditis “is something that clinicians struggle with every day,” he noted, pointing to the large overflowing auditoriums where these guidelines were presented. Dr. Borger identified four main takeaways from the document:
- Increased level of recommendation and a clearer definition of prevention and prophylaxis of endocarditis in higher-risk patients.
- An increasing role of nonechocardiographic, advanced cardiac imaging techniques in the diagnosis of endocarditis. “The advanced cardiac imaging techniques achieved the same level of recommendation as echocardiography,” he noted.
- More precisely defined indications for surgery and the timing for surgery, as well as a couple of new surgical recommendations.
- More precisely defined criteria for diagnosing and managing cardiac electronic implantable device (CIED)–associated endocarditis.
The guidelines identify patients at high risk for IE as those with previous IE and patients with surgically implanted prosthetic valves, certain congenital heart diseases, surgery with prosthetic material, or a ventricular assist device as destination therapy and recommend giving them prophylactic antibiotics before oral or dental procedures.
Patients at intermediate risk for IE include those with rheumatic heart disease, nonrheumatic degenerative valve disease, congenital valve abnormalities, CIEDs, and hypertrophic cardiomyopathy. They should be evaluated on a case-by-case basis for this prophylaxis, the guideline authors write.
Making the diagnosis
Advances in imaging techniques necessitated a revised version of the endocarditis guidelines, Dr. Borger noted.
Patients are classified as having a definite, possible, or rejected diagnosis of IE (where a definite diagnosis requires two major criteria, or one major criterion and at least three minor criteria, or five minor criteria).
The two major criteria are blood cultures positive for IE and imaging positive for IE by transesophageal echocardiography, transthoracic echocardiography, or – what is new – cardiac computed tomography, 18F-fluorodeoxyglucose positron emission tomography, or white blood cell single photon emission tomography/CT.
The five minor criteria are predisposing conditions, fever (temperature > 38° C), embolic vascular dissemination, immunologic phenomena, and microbiological evidence.
Patient education
Patient education is “paramount to early diagnosis and treatment,” Dr. Delgado, from Germans Trias i Pujol Hospital, Barcelona, said in a press release from ESC. “Those with valvular heart disease or previous heart valve surgery should be particularly diligent with regards to prevention and recognizing symptoms.”
IE occurs when bacteria or fungi enter the bloodstream, for example through skin infections, dental procedures, and surgery. Symptoms include fever, night sweats, unexplained weight loss, cough, dizziness, and fainting, the press release notes.
“We have several clinical scenarios that are increasing,” Dr. Delgado said at an Ask the Experts session, including implanted cardiac electronic devices, new transcatheter therapies, and increasing endocarditis in people who use injection drugs, “and we have recommendation of evaluation of these patients at follow up.”
“The guidelines have 34 new recommendations,” she noted in a Guideline Overview session. She drew attention to a central figure, “where we tried to summarize the pathway of the patient who is diagnosed with endocarditis, and where we highlight the role of the endocarditis team,” she said.
The guidelines specify a prophylactic antibiotic regimen for high-risk dental procedures, for children and for adults with or without allergy to penicillin or ampicillin, given as a single dose 30-60 minutes before a procedure, she noted.
A new recommendation is that systemic antibiotic prophylaxis may be considered for high-risk patients undergoing invasive procedures of the respiratory, gastrointestinal, or genitourinary tract; skin; or musculoskeletal system.
“It is very important to have a well-educated population,” Dr. Delgado stressed.
Figure 2 of the guideline depicts what patients should do, she said, such as “maintain good dental hygiene, avoid tattoos and piercings, be mindful of infections, do not self-prescribe antibiotics.” This card can be given to the patient, and they can show it to doctors before interventions.
The main targets for antibiotic prophylaxis are oral streptococci, but the emerging and increasing resistance of these bacteria are reasons why patients should not self-prescribe, Dr. Delgado noted.
“Patients should not be self-medicating in order to try to lower their risk of endocarditis,” Dr. Borger said. “They should be speaking to their physicians and have their physician group them according to their risk category.”
“If they are low risk, there’s no reason to take antibiotic prophylaxis [before oral or dental procedures], but if they are high risk, they should not only be taking antibiotic prophylaxis, they should also be doing things like good dental hygiene – visiting the dentist once or twice a year, avoiding unnecessary procedures such as tattooing and piercings, and quick aseptic management of skin wounds.”
POET Trial: Earlier shift to oral antibiotics at home
“Another very important point is the increasing use of oral outpatient antibiotic therapy based on the Partial Oral Treatment of Endocarditis (POET) randomized trial,” Dr. Borger observed. “That’s a new recommendation,” he said, “with significant implications for the care of patients with this oftentimes life-threatening disease.”
In POET, patients in stable condition who had endocarditis on the left side of the heart caused by streptococci, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci were randomly assigned to continue treatment with intravenous antibiotics (199 patients) or to shift to step-down treatment with oral antibiotics (201 patients) after at least 10 days of initial treatment with IV antibiotics.
The 5-year results were published in 2019 in the New England Journal of Medicine and presented at ESC that year. “We were hoping or expecting to see that oral outpatient therapy would be equivalent to inpatient IV therapy,” Dr. Borger said, “but we were surprised to see that oral outpatient therapy was actually statistically significantly better in terms of survival, a very hard outcome, at 5 years after the randomization.”
“This was an important part of our new guideline document. In select patients who are ‘clinically stable’,” as defined in the guidelines, he said, “they could be successfully managed at home with oral antibiotics, rather than keeping them in hospital the whole 6 weeks.”
“In the U.S. and in Canada, a lot of patients are sent home for intravenous therapy, whereas that practice doesn’t exist in a lot of places in Europe. The patients are sitting in the hospital here for 6 weeks, oftentimes for no other reason – just to get their IV antibiotic therapy. The POET trial has shown us that that is probably the wrong thing to be doing.”
Earlier surgical intervention
The new guidelines also recommend that “once there is an indication to do cardiac surgery, it should be promptly performed,” Dr. Borger noted.
Surgery to remove infected material and drain abscesses is indicated for patients with heart failure or uncontrolled infection and to prevent embolism.
“We have defined emergency indications that should be done within 24 hours; urgent, which should be done within 3-5 days; and nonurgent, more than 5 days but within the same hospitalization,” he elaborated. “We’re basically trying to encourage surgeons and nonsurgeons that once there is an indication for surgery, there’s not a lot of benefit to just waiting. You should proceed with operation in a timely manner” to improve survival.
The guidelines recommend surgery for early prosthetic valve endocarditis, within 6 months of valve surgery, with new valve replacement and complete debridement.
Patients who present with stroke and require surgery are not uncommon, Dr. Borger noted. Ischemic stroke should not be a reason to delay surgery, and patients with hemorrhagic stoke, with favorable features, can undergo surgery.
The guidelines provide a figure for the management of CIED-related infective endocarditis. They also include a new section devoted to patient-centered care and shared decision-making.
The guidelines were endorsed by the European Association for Cardio-Thoracic Surgery and the European Association of Nuclear Medicine. The writing task force included representatives from EACTS, EANM, and the European Society of Clinical Microbiology and Infectious Diseases.
The complete guidelines, as well as pocket guidelines, essential messages, a pocket guidelines app, and an official guidelines slide set, all addressing endocarditis, are available from the ESC website.
The guidelines did not receive any funding. The disclosure forms of all experts involved in their development are available on the ESC website.
A version of this article appeared on Medscape.com.
(IE) – a rare and potentially lethal infection of the heart’s lining and valves.
The document revises the 2015 version, based on advances in imaging and a trial of antibiotic prophylaxis, among other new developments.
Cochairpersons of the writing task force, Victoria Delgado, MD, PhD, and Michael A. Borger, MD, PhD, and other members presented and discussed the guidelines in three packed sessions at the annual congress of the European Society of Cardiology, and the document was simultaneously published online in the European Heart Journal.
Endocarditis “can present with so many different clinical scenarios, so making the diagnosis can be very challenging,” Dr. Borger, from the Heart Center of Leipzig, Germany, said in an interview.
Diagnosing a lethal, rare, but not uncommon disease such as endocarditis “is something that clinicians struggle with every day,” he noted, pointing to the large overflowing auditoriums where these guidelines were presented. Dr. Borger identified four main takeaways from the document:
- Increased level of recommendation and a clearer definition of prevention and prophylaxis of endocarditis in higher-risk patients.
- An increasing role of nonechocardiographic, advanced cardiac imaging techniques in the diagnosis of endocarditis. “The advanced cardiac imaging techniques achieved the same level of recommendation as echocardiography,” he noted.
- More precisely defined indications for surgery and the timing for surgery, as well as a couple of new surgical recommendations.
- More precisely defined criteria for diagnosing and managing cardiac electronic implantable device (CIED)–associated endocarditis.
The guidelines identify patients at high risk for IE as those with previous IE and patients with surgically implanted prosthetic valves, certain congenital heart diseases, surgery with prosthetic material, or a ventricular assist device as destination therapy and recommend giving them prophylactic antibiotics before oral or dental procedures.
Patients at intermediate risk for IE include those with rheumatic heart disease, nonrheumatic degenerative valve disease, congenital valve abnormalities, CIEDs, and hypertrophic cardiomyopathy. They should be evaluated on a case-by-case basis for this prophylaxis, the guideline authors write.
Making the diagnosis
Advances in imaging techniques necessitated a revised version of the endocarditis guidelines, Dr. Borger noted.
Patients are classified as having a definite, possible, or rejected diagnosis of IE (where a definite diagnosis requires two major criteria, or one major criterion and at least three minor criteria, or five minor criteria).
The two major criteria are blood cultures positive for IE and imaging positive for IE by transesophageal echocardiography, transthoracic echocardiography, or – what is new – cardiac computed tomography, 18F-fluorodeoxyglucose positron emission tomography, or white blood cell single photon emission tomography/CT.
The five minor criteria are predisposing conditions, fever (temperature > 38° C), embolic vascular dissemination, immunologic phenomena, and microbiological evidence.
Patient education
Patient education is “paramount to early diagnosis and treatment,” Dr. Delgado, from Germans Trias i Pujol Hospital, Barcelona, said in a press release from ESC. “Those with valvular heart disease or previous heart valve surgery should be particularly diligent with regards to prevention and recognizing symptoms.”
IE occurs when bacteria or fungi enter the bloodstream, for example through skin infections, dental procedures, and surgery. Symptoms include fever, night sweats, unexplained weight loss, cough, dizziness, and fainting, the press release notes.
“We have several clinical scenarios that are increasing,” Dr. Delgado said at an Ask the Experts session, including implanted cardiac electronic devices, new transcatheter therapies, and increasing endocarditis in people who use injection drugs, “and we have recommendation of evaluation of these patients at follow up.”
“The guidelines have 34 new recommendations,” she noted in a Guideline Overview session. She drew attention to a central figure, “where we tried to summarize the pathway of the patient who is diagnosed with endocarditis, and where we highlight the role of the endocarditis team,” she said.
The guidelines specify a prophylactic antibiotic regimen for high-risk dental procedures, for children and for adults with or without allergy to penicillin or ampicillin, given as a single dose 30-60 minutes before a procedure, she noted.
A new recommendation is that systemic antibiotic prophylaxis may be considered for high-risk patients undergoing invasive procedures of the respiratory, gastrointestinal, or genitourinary tract; skin; or musculoskeletal system.
“It is very important to have a well-educated population,” Dr. Delgado stressed.
Figure 2 of the guideline depicts what patients should do, she said, such as “maintain good dental hygiene, avoid tattoos and piercings, be mindful of infections, do not self-prescribe antibiotics.” This card can be given to the patient, and they can show it to doctors before interventions.
The main targets for antibiotic prophylaxis are oral streptococci, but the emerging and increasing resistance of these bacteria are reasons why patients should not self-prescribe, Dr. Delgado noted.
“Patients should not be self-medicating in order to try to lower their risk of endocarditis,” Dr. Borger said. “They should be speaking to their physicians and have their physician group them according to their risk category.”
“If they are low risk, there’s no reason to take antibiotic prophylaxis [before oral or dental procedures], but if they are high risk, they should not only be taking antibiotic prophylaxis, they should also be doing things like good dental hygiene – visiting the dentist once or twice a year, avoiding unnecessary procedures such as tattooing and piercings, and quick aseptic management of skin wounds.”
POET Trial: Earlier shift to oral antibiotics at home
“Another very important point is the increasing use of oral outpatient antibiotic therapy based on the Partial Oral Treatment of Endocarditis (POET) randomized trial,” Dr. Borger observed. “That’s a new recommendation,” he said, “with significant implications for the care of patients with this oftentimes life-threatening disease.”
In POET, patients in stable condition who had endocarditis on the left side of the heart caused by streptococci, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci were randomly assigned to continue treatment with intravenous antibiotics (199 patients) or to shift to step-down treatment with oral antibiotics (201 patients) after at least 10 days of initial treatment with IV antibiotics.
The 5-year results were published in 2019 in the New England Journal of Medicine and presented at ESC that year. “We were hoping or expecting to see that oral outpatient therapy would be equivalent to inpatient IV therapy,” Dr. Borger said, “but we were surprised to see that oral outpatient therapy was actually statistically significantly better in terms of survival, a very hard outcome, at 5 years after the randomization.”
“This was an important part of our new guideline document. In select patients who are ‘clinically stable’,” as defined in the guidelines, he said, “they could be successfully managed at home with oral antibiotics, rather than keeping them in hospital the whole 6 weeks.”
“In the U.S. and in Canada, a lot of patients are sent home for intravenous therapy, whereas that practice doesn’t exist in a lot of places in Europe. The patients are sitting in the hospital here for 6 weeks, oftentimes for no other reason – just to get their IV antibiotic therapy. The POET trial has shown us that that is probably the wrong thing to be doing.”
Earlier surgical intervention
The new guidelines also recommend that “once there is an indication to do cardiac surgery, it should be promptly performed,” Dr. Borger noted.
Surgery to remove infected material and drain abscesses is indicated for patients with heart failure or uncontrolled infection and to prevent embolism.
“We have defined emergency indications that should be done within 24 hours; urgent, which should be done within 3-5 days; and nonurgent, more than 5 days but within the same hospitalization,” he elaborated. “We’re basically trying to encourage surgeons and nonsurgeons that once there is an indication for surgery, there’s not a lot of benefit to just waiting. You should proceed with operation in a timely manner” to improve survival.
The guidelines recommend surgery for early prosthetic valve endocarditis, within 6 months of valve surgery, with new valve replacement and complete debridement.
Patients who present with stroke and require surgery are not uncommon, Dr. Borger noted. Ischemic stroke should not be a reason to delay surgery, and patients with hemorrhagic stoke, with favorable features, can undergo surgery.
The guidelines provide a figure for the management of CIED-related infective endocarditis. They also include a new section devoted to patient-centered care and shared decision-making.
The guidelines were endorsed by the European Association for Cardio-Thoracic Surgery and the European Association of Nuclear Medicine. The writing task force included representatives from EACTS, EANM, and the European Society of Clinical Microbiology and Infectious Diseases.
The complete guidelines, as well as pocket guidelines, essential messages, a pocket guidelines app, and an official guidelines slide set, all addressing endocarditis, are available from the ESC website.
The guidelines did not receive any funding. The disclosure forms of all experts involved in their development are available on the ESC website.
A version of this article appeared on Medscape.com.
FROM ESC CONGRESS 2023
Lower is better for blood glucose to reduce heart disease
in a large, 12-year observational study of UK Biobank data.
The results highlight “the need for strategies to reduce risk of CVD across the [glycemic] spectrum,” Christopher T. Rentsch, MPH, PhD, and colleagues wrote in their study, which was published in the The Lancet Regional Health – Europe.
The findings suggest “that excess [CVD] risks in both men and women were largely explained by modifiable factors and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications.
“Addressing these risk factors could reduce sex disparities in [glycemia]-related risks of CVD,” according to the researchers.
After the researchers accounted for age, the absolute rate of CVD events was higher among men than women (16.9 vs. 9.1 events per 1,000 person-years); however, the relative risk was higher among women than men.
Compared with men, women were more likely to have obesity (63% vs. 53%) and were less likely to be using antihypertensive medications (64% vs. 69%) or a statin (71% vs. 75%).
“This is the largest study to date to investigate sex differences in the risk of CVD across the glycemic spectrum,” the researchers noted.
“The lower the better”
“We uncovered compelling evidence that for blood sugar levels within the ‘normal’ range, it was a case of ‘the lower the better’ in protecting against heart disease,” Dr. Rentsch, assistant professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, told this news organization.
Compared with people with normal blood glucose levels, those with lower than normal levels were at 10% lower risk of developing any form of heart disease, he noted.
The study findings “support women being proactive in asking about medications like statins and antihypertensives as an option to help lower their [CVD] risk, if clinically appropriate,” Dr. Rentsch added.
“We found that men and women with diagnosed diabetes remained at elevated risk for three types of heart disease – coronary artery disease, stroke, and heart failure – even after accounting for a large number of sociodemographic, lifestyle, and clinical characteristics,” he pointed out.
However, “total cholesterol, family history of CVD, estimated glomerular filtration rate, and C-reactive protein had relatively little impact on explaining the risk of heart disease associated with blood sugar.”
“It is well established that being overweight can lead to higher blood sugar levels as well as higher blood pressure, these being factors that contribute to higher risk of heart attack and stroke,” Robert Storey, DM, professor of cardiology, University of Sheffield (England), told the UK Science Media Centre.
“This very large UK Biobank study,” he said, “shows that the higher heart risk associated with blood sugar can be detected at a very early stage along the path towards the abnormally high blood sugar levels associated with diabetes.
“The study provides support for a strategy of assessing cardiovascular risk in people who are overweight, including assessment of blood sugar, cholesterol, and blood pressure levels, all of which can be effectively managed to markedly reduce the risk of future heart attack and stroke,” according to Dr. Storey.
More than 400,000 men, women
The researchers enrolled men and women aged 40-69 between 2006 to 2010 who were living in England, Scotland, and Wales. After excluding people with type 1 diabetes or those whose A1c data were missing, the current study included 427,435 people (46% of whom were men).
The participants were classified as having low-normal A1c (< 35 mmol/mol or < 5.5%), normal A1c (35-41 mmol/mol or 5.5%-5.9%), prediabetes (42-47 mmol/mol or 6.0%-6.4%), undiagnosed diabetes (≥ 48 mmol/mol or ≥ 6.5%), or diagnosed type 2 diabetes (medical history and in receipt of glucose-lowering medication).
The researchers determined the incidence of six CVD outcomes during a median 11.8-year follow-up: coronary artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolism, stroke, and heart failure.
Few participants (5%) had any of these outcomes prior to study enrollment.
During the follow-up, there were 51,288 incident CVD events.
After adjustment for age, compared to having normal A1c, having prediabetes or undiagnosed diabetes was associated with an increased risk of CVD for women and men (hazard ratio [HR], 1.30-1.47).
Among individuals with diagnosed type 2 diabetes, the age-adjusted risk of CVD was greater for women (HR, 2.00) than for men (HR, 1.55).
After further adjustment for clinical and lifestyle factors, especially obesity and antihypertensive or statin use, the risk of CVD decreased and became similar among men and women. The fully adjusted HR for CVD was 1.17 for women and 1.06 for men with diagnosed diabetes.
Compared with having normal A1c, women and men with low-normal A1c were at decreased risk of CVD (HR, 0.86 for both).
The study was funded by Diabetes UK and the British Heart Foundation. Dr. Rentsch and Dr. Storey have disclosed no relevant financial relationships. The disclosures of the other study authors are listed in the original article.
A version of this article appeared on Medscape.com.
in a large, 12-year observational study of UK Biobank data.
The results highlight “the need for strategies to reduce risk of CVD across the [glycemic] spectrum,” Christopher T. Rentsch, MPH, PhD, and colleagues wrote in their study, which was published in the The Lancet Regional Health – Europe.
The findings suggest “that excess [CVD] risks in both men and women were largely explained by modifiable factors and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications.
“Addressing these risk factors could reduce sex disparities in [glycemia]-related risks of CVD,” according to the researchers.
After the researchers accounted for age, the absolute rate of CVD events was higher among men than women (16.9 vs. 9.1 events per 1,000 person-years); however, the relative risk was higher among women than men.
Compared with men, women were more likely to have obesity (63% vs. 53%) and were less likely to be using antihypertensive medications (64% vs. 69%) or a statin (71% vs. 75%).
“This is the largest study to date to investigate sex differences in the risk of CVD across the glycemic spectrum,” the researchers noted.
“The lower the better”
“We uncovered compelling evidence that for blood sugar levels within the ‘normal’ range, it was a case of ‘the lower the better’ in protecting against heart disease,” Dr. Rentsch, assistant professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, told this news organization.
Compared with people with normal blood glucose levels, those with lower than normal levels were at 10% lower risk of developing any form of heart disease, he noted.
The study findings “support women being proactive in asking about medications like statins and antihypertensives as an option to help lower their [CVD] risk, if clinically appropriate,” Dr. Rentsch added.
“We found that men and women with diagnosed diabetes remained at elevated risk for three types of heart disease – coronary artery disease, stroke, and heart failure – even after accounting for a large number of sociodemographic, lifestyle, and clinical characteristics,” he pointed out.
However, “total cholesterol, family history of CVD, estimated glomerular filtration rate, and C-reactive protein had relatively little impact on explaining the risk of heart disease associated with blood sugar.”
“It is well established that being overweight can lead to higher blood sugar levels as well as higher blood pressure, these being factors that contribute to higher risk of heart attack and stroke,” Robert Storey, DM, professor of cardiology, University of Sheffield (England), told the UK Science Media Centre.
“This very large UK Biobank study,” he said, “shows that the higher heart risk associated with blood sugar can be detected at a very early stage along the path towards the abnormally high blood sugar levels associated with diabetes.
“The study provides support for a strategy of assessing cardiovascular risk in people who are overweight, including assessment of blood sugar, cholesterol, and blood pressure levels, all of which can be effectively managed to markedly reduce the risk of future heart attack and stroke,” according to Dr. Storey.
More than 400,000 men, women
The researchers enrolled men and women aged 40-69 between 2006 to 2010 who were living in England, Scotland, and Wales. After excluding people with type 1 diabetes or those whose A1c data were missing, the current study included 427,435 people (46% of whom were men).
The participants were classified as having low-normal A1c (< 35 mmol/mol or < 5.5%), normal A1c (35-41 mmol/mol or 5.5%-5.9%), prediabetes (42-47 mmol/mol or 6.0%-6.4%), undiagnosed diabetes (≥ 48 mmol/mol or ≥ 6.5%), or diagnosed type 2 diabetes (medical history and in receipt of glucose-lowering medication).
The researchers determined the incidence of six CVD outcomes during a median 11.8-year follow-up: coronary artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolism, stroke, and heart failure.
Few participants (5%) had any of these outcomes prior to study enrollment.
During the follow-up, there were 51,288 incident CVD events.
After adjustment for age, compared to having normal A1c, having prediabetes or undiagnosed diabetes was associated with an increased risk of CVD for women and men (hazard ratio [HR], 1.30-1.47).
Among individuals with diagnosed type 2 diabetes, the age-adjusted risk of CVD was greater for women (HR, 2.00) than for men (HR, 1.55).
After further adjustment for clinical and lifestyle factors, especially obesity and antihypertensive or statin use, the risk of CVD decreased and became similar among men and women. The fully adjusted HR for CVD was 1.17 for women and 1.06 for men with diagnosed diabetes.
Compared with having normal A1c, women and men with low-normal A1c were at decreased risk of CVD (HR, 0.86 for both).
The study was funded by Diabetes UK and the British Heart Foundation. Dr. Rentsch and Dr. Storey have disclosed no relevant financial relationships. The disclosures of the other study authors are listed in the original article.
A version of this article appeared on Medscape.com.
in a large, 12-year observational study of UK Biobank data.
The results highlight “the need for strategies to reduce risk of CVD across the [glycemic] spectrum,” Christopher T. Rentsch, MPH, PhD, and colleagues wrote in their study, which was published in the The Lancet Regional Health – Europe.
The findings suggest “that excess [CVD] risks in both men and women were largely explained by modifiable factors and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications.
“Addressing these risk factors could reduce sex disparities in [glycemia]-related risks of CVD,” according to the researchers.
After the researchers accounted for age, the absolute rate of CVD events was higher among men than women (16.9 vs. 9.1 events per 1,000 person-years); however, the relative risk was higher among women than men.
Compared with men, women were more likely to have obesity (63% vs. 53%) and were less likely to be using antihypertensive medications (64% vs. 69%) or a statin (71% vs. 75%).
“This is the largest study to date to investigate sex differences in the risk of CVD across the glycemic spectrum,” the researchers noted.
“The lower the better”
“We uncovered compelling evidence that for blood sugar levels within the ‘normal’ range, it was a case of ‘the lower the better’ in protecting against heart disease,” Dr. Rentsch, assistant professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, told this news organization.
Compared with people with normal blood glucose levels, those with lower than normal levels were at 10% lower risk of developing any form of heart disease, he noted.
The study findings “support women being proactive in asking about medications like statins and antihypertensives as an option to help lower their [CVD] risk, if clinically appropriate,” Dr. Rentsch added.
“We found that men and women with diagnosed diabetes remained at elevated risk for three types of heart disease – coronary artery disease, stroke, and heart failure – even after accounting for a large number of sociodemographic, lifestyle, and clinical characteristics,” he pointed out.
However, “total cholesterol, family history of CVD, estimated glomerular filtration rate, and C-reactive protein had relatively little impact on explaining the risk of heart disease associated with blood sugar.”
“It is well established that being overweight can lead to higher blood sugar levels as well as higher blood pressure, these being factors that contribute to higher risk of heart attack and stroke,” Robert Storey, DM, professor of cardiology, University of Sheffield (England), told the UK Science Media Centre.
“This very large UK Biobank study,” he said, “shows that the higher heart risk associated with blood sugar can be detected at a very early stage along the path towards the abnormally high blood sugar levels associated with diabetes.
“The study provides support for a strategy of assessing cardiovascular risk in people who are overweight, including assessment of blood sugar, cholesterol, and blood pressure levels, all of which can be effectively managed to markedly reduce the risk of future heart attack and stroke,” according to Dr. Storey.
More than 400,000 men, women
The researchers enrolled men and women aged 40-69 between 2006 to 2010 who were living in England, Scotland, and Wales. After excluding people with type 1 diabetes or those whose A1c data were missing, the current study included 427,435 people (46% of whom were men).
The participants were classified as having low-normal A1c (< 35 mmol/mol or < 5.5%), normal A1c (35-41 mmol/mol or 5.5%-5.9%), prediabetes (42-47 mmol/mol or 6.0%-6.4%), undiagnosed diabetes (≥ 48 mmol/mol or ≥ 6.5%), or diagnosed type 2 diabetes (medical history and in receipt of glucose-lowering medication).
The researchers determined the incidence of six CVD outcomes during a median 11.8-year follow-up: coronary artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolism, stroke, and heart failure.
Few participants (5%) had any of these outcomes prior to study enrollment.
During the follow-up, there were 51,288 incident CVD events.
After adjustment for age, compared to having normal A1c, having prediabetes or undiagnosed diabetes was associated with an increased risk of CVD for women and men (hazard ratio [HR], 1.30-1.47).
Among individuals with diagnosed type 2 diabetes, the age-adjusted risk of CVD was greater for women (HR, 2.00) than for men (HR, 1.55).
After further adjustment for clinical and lifestyle factors, especially obesity and antihypertensive or statin use, the risk of CVD decreased and became similar among men and women. The fully adjusted HR for CVD was 1.17 for women and 1.06 for men with diagnosed diabetes.
Compared with having normal A1c, women and men with low-normal A1c were at decreased risk of CVD (HR, 0.86 for both).
The study was funded by Diabetes UK and the British Heart Foundation. Dr. Rentsch and Dr. Storey have disclosed no relevant financial relationships. The disclosures of the other study authors are listed in the original article.
A version of this article appeared on Medscape.com.
FROM THE LANCET REGIONAL HEALTH – EUROPE
Certain genes predict abdominal fat regain after weight loss
People with a genetic predisposition for abdominal adiposity regained more weight around their waist after weight loss than other people.
However, people with a genetic predisposition for a higher body mass index did not regain more weight after weight loss than others.
These findings are from a secondary analysis of data from participants in the Look AHEAD trial who had type 2 diabetes and overweight/obesity and had lost at least 3% of their initial weight after 1 year of intensive lifestyle intervention or control, who were followed for another 3 years.
The study showed that change in waist circumference (aka abdominal obesity) is regulated by a separate pathway from overall obesity during weight regain, the researchers report in their paper, published in Diabetes.
“These findings are the first of their kind and provide new insights into the mechanisms of weight regain,” they conclude.
“It was already known in the scientific literature that genes that are associated with abdominal fat deposition are different from the ones associated with overall obesity,” Malene Revsbech Christiansen, a PhD student, and Tuomas O. Kilpeläinen, PhD, associate professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, said in a joint email to this news organization.
Genetic variants associated with obesity are expressed in the central nervous system. However, genetic variants associated with waist circumference are expressed in the adipose tissues and might be involved in insulin sensitivity, or fat cell shape and differentiation, influencing how much adipose cells can expand in size or in number.
If those genes can function as targets for therapeutic agents, this might benefit patients who possess the genetic variants that predispose them to a higher waist-to-hip ratio adjusted for BMI (WHR-adjBMI), they said.
“However, this is a preliminary study that discovered an association between genetic variants and abdominal fat changes during weight loss,” they cautioned.
Further study is needed, they said, to test the associations in people without obesity and type 2 diabetes and to investigate this research question in people who underwent bariatric surgery or took weight-loss medications, “especially now that Wegovy has increased in popularity.”
“Genetic profiling,” they noted, “is becoming more popular as the prices go down, and future treatments are moving towards precision medicine, where treatments are tailored towards individuals rather than ‘one size fits all.’ ”
In the future, genetic tests might identify people who are more predisposed to abdominal fat deposition, hence needing more follow-up and help with lifestyle changes.
“For now, it does not seem realistic to test individuals for all these 481 [genetic] variants [predisposing to abdominal adiposity]. Each of these genetic variants predisposes, but is not deterministic, for the outcome, because of their individual small effects on waist circumference.”
“It should be stated,” they added, “that changing the diet, physical activity pattern, and behavior are still the main factors when losing weight and maintaining a healthy body.”
Maintaining weight loss is the big challenge
“Lifestyle interventions typically result in an average weight loss of 7%-10 % within 6 months; however, maintaining the weight loss is a significant challenge, as participants often regain an average one-third of the lost weight within 1 year and 50%-100% within 5 years,” the researchers write.
They aimed to study whether genetic predisposition to general or abdominal obesity predicts weight gain after weight loss, based on data from 822 women and 593 men in the Look AHEAD trial.
On average, at 1 year after the intervention, the participants in the intensive lifestyle group lost 24 lbs (10.9 kg) and 3.55 inches (9 cm) around the waist, and participants in the control group lost 15 lbs (6.8 kg) pounds and 1.98 inches (5 cm) around the waist.
From year 1 to year 2, participants in the intensive lifestyle group regained 6.09 lbs and 0.98 inches around the waist, and participants in the control group lost 1.41 lbs and 0.17 inches around the waist.
From year 1 to year 4, participants in the intensive lifestyle group regained 11.05 lbs and 1.92 inches around the waist, and participants in the control group lost 2.24 lbs and 0.76 inches around the waist.
From genome-wide association studies (GWAS) in about 700,000 mainly White individuals of European origin, the researchers constructed a genetic risk score based on 894 independent single nucleotide polymorphisms (SNPs) associated with high BMI and another genetic risk score based on 481 SNPs associated with high WHR-adjBMI.
Having a genetic predisposition to higher WHR-adjBMI predicted an increase in abdominal obesity after weight loss, whereas having a genetic predisposition to higher BMI did not predict weight regain.
“These results suggest that genetic effects on abdominal obesity may be more pronounced than those on general obesity during weight regain,” the researchers conclude.
The researchers were supported by grants from the Novo Nordisk Foundation and the Danish Diabetes Academy (funded by the Novo Nordisk Foundation). The authors report no relevant financial relationships.
A version of this article appeared on Medscape.com.
People with a genetic predisposition for abdominal adiposity regained more weight around their waist after weight loss than other people.
However, people with a genetic predisposition for a higher body mass index did not regain more weight after weight loss than others.
These findings are from a secondary analysis of data from participants in the Look AHEAD trial who had type 2 diabetes and overweight/obesity and had lost at least 3% of their initial weight after 1 year of intensive lifestyle intervention or control, who were followed for another 3 years.
The study showed that change in waist circumference (aka abdominal obesity) is regulated by a separate pathway from overall obesity during weight regain, the researchers report in their paper, published in Diabetes.
“These findings are the first of their kind and provide new insights into the mechanisms of weight regain,” they conclude.
“It was already known in the scientific literature that genes that are associated with abdominal fat deposition are different from the ones associated with overall obesity,” Malene Revsbech Christiansen, a PhD student, and Tuomas O. Kilpeläinen, PhD, associate professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, said in a joint email to this news organization.
Genetic variants associated with obesity are expressed in the central nervous system. However, genetic variants associated with waist circumference are expressed in the adipose tissues and might be involved in insulin sensitivity, or fat cell shape and differentiation, influencing how much adipose cells can expand in size or in number.
If those genes can function as targets for therapeutic agents, this might benefit patients who possess the genetic variants that predispose them to a higher waist-to-hip ratio adjusted for BMI (WHR-adjBMI), they said.
“However, this is a preliminary study that discovered an association between genetic variants and abdominal fat changes during weight loss,” they cautioned.
Further study is needed, they said, to test the associations in people without obesity and type 2 diabetes and to investigate this research question in people who underwent bariatric surgery or took weight-loss medications, “especially now that Wegovy has increased in popularity.”
“Genetic profiling,” they noted, “is becoming more popular as the prices go down, and future treatments are moving towards precision medicine, where treatments are tailored towards individuals rather than ‘one size fits all.’ ”
In the future, genetic tests might identify people who are more predisposed to abdominal fat deposition, hence needing more follow-up and help with lifestyle changes.
“For now, it does not seem realistic to test individuals for all these 481 [genetic] variants [predisposing to abdominal adiposity]. Each of these genetic variants predisposes, but is not deterministic, for the outcome, because of their individual small effects on waist circumference.”
“It should be stated,” they added, “that changing the diet, physical activity pattern, and behavior are still the main factors when losing weight and maintaining a healthy body.”
Maintaining weight loss is the big challenge
“Lifestyle interventions typically result in an average weight loss of 7%-10 % within 6 months; however, maintaining the weight loss is a significant challenge, as participants often regain an average one-third of the lost weight within 1 year and 50%-100% within 5 years,” the researchers write.
They aimed to study whether genetic predisposition to general or abdominal obesity predicts weight gain after weight loss, based on data from 822 women and 593 men in the Look AHEAD trial.
On average, at 1 year after the intervention, the participants in the intensive lifestyle group lost 24 lbs (10.9 kg) and 3.55 inches (9 cm) around the waist, and participants in the control group lost 15 lbs (6.8 kg) pounds and 1.98 inches (5 cm) around the waist.
From year 1 to year 2, participants in the intensive lifestyle group regained 6.09 lbs and 0.98 inches around the waist, and participants in the control group lost 1.41 lbs and 0.17 inches around the waist.
From year 1 to year 4, participants in the intensive lifestyle group regained 11.05 lbs and 1.92 inches around the waist, and participants in the control group lost 2.24 lbs and 0.76 inches around the waist.
From genome-wide association studies (GWAS) in about 700,000 mainly White individuals of European origin, the researchers constructed a genetic risk score based on 894 independent single nucleotide polymorphisms (SNPs) associated with high BMI and another genetic risk score based on 481 SNPs associated with high WHR-adjBMI.
Having a genetic predisposition to higher WHR-adjBMI predicted an increase in abdominal obesity after weight loss, whereas having a genetic predisposition to higher BMI did not predict weight regain.
“These results suggest that genetic effects on abdominal obesity may be more pronounced than those on general obesity during weight regain,” the researchers conclude.
The researchers were supported by grants from the Novo Nordisk Foundation and the Danish Diabetes Academy (funded by the Novo Nordisk Foundation). The authors report no relevant financial relationships.
A version of this article appeared on Medscape.com.
People with a genetic predisposition for abdominal adiposity regained more weight around their waist after weight loss than other people.
However, people with a genetic predisposition for a higher body mass index did not regain more weight after weight loss than others.
These findings are from a secondary analysis of data from participants in the Look AHEAD trial who had type 2 diabetes and overweight/obesity and had lost at least 3% of their initial weight after 1 year of intensive lifestyle intervention or control, who were followed for another 3 years.
The study showed that change in waist circumference (aka abdominal obesity) is regulated by a separate pathway from overall obesity during weight regain, the researchers report in their paper, published in Diabetes.
“These findings are the first of their kind and provide new insights into the mechanisms of weight regain,” they conclude.
“It was already known in the scientific literature that genes that are associated with abdominal fat deposition are different from the ones associated with overall obesity,” Malene Revsbech Christiansen, a PhD student, and Tuomas O. Kilpeläinen, PhD, associate professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, said in a joint email to this news organization.
Genetic variants associated with obesity are expressed in the central nervous system. However, genetic variants associated with waist circumference are expressed in the adipose tissues and might be involved in insulin sensitivity, or fat cell shape and differentiation, influencing how much adipose cells can expand in size or in number.
If those genes can function as targets for therapeutic agents, this might benefit patients who possess the genetic variants that predispose them to a higher waist-to-hip ratio adjusted for BMI (WHR-adjBMI), they said.
“However, this is a preliminary study that discovered an association between genetic variants and abdominal fat changes during weight loss,” they cautioned.
Further study is needed, they said, to test the associations in people without obesity and type 2 diabetes and to investigate this research question in people who underwent bariatric surgery or took weight-loss medications, “especially now that Wegovy has increased in popularity.”
“Genetic profiling,” they noted, “is becoming more popular as the prices go down, and future treatments are moving towards precision medicine, where treatments are tailored towards individuals rather than ‘one size fits all.’ ”
In the future, genetic tests might identify people who are more predisposed to abdominal fat deposition, hence needing more follow-up and help with lifestyle changes.
“For now, it does not seem realistic to test individuals for all these 481 [genetic] variants [predisposing to abdominal adiposity]. Each of these genetic variants predisposes, but is not deterministic, for the outcome, because of their individual small effects on waist circumference.”
“It should be stated,” they added, “that changing the diet, physical activity pattern, and behavior are still the main factors when losing weight and maintaining a healthy body.”
Maintaining weight loss is the big challenge
“Lifestyle interventions typically result in an average weight loss of 7%-10 % within 6 months; however, maintaining the weight loss is a significant challenge, as participants often regain an average one-third of the lost weight within 1 year and 50%-100% within 5 years,” the researchers write.
They aimed to study whether genetic predisposition to general or abdominal obesity predicts weight gain after weight loss, based on data from 822 women and 593 men in the Look AHEAD trial.
On average, at 1 year after the intervention, the participants in the intensive lifestyle group lost 24 lbs (10.9 kg) and 3.55 inches (9 cm) around the waist, and participants in the control group lost 15 lbs (6.8 kg) pounds and 1.98 inches (5 cm) around the waist.
From year 1 to year 2, participants in the intensive lifestyle group regained 6.09 lbs and 0.98 inches around the waist, and participants in the control group lost 1.41 lbs and 0.17 inches around the waist.
From year 1 to year 4, participants in the intensive lifestyle group regained 11.05 lbs and 1.92 inches around the waist, and participants in the control group lost 2.24 lbs and 0.76 inches around the waist.
From genome-wide association studies (GWAS) in about 700,000 mainly White individuals of European origin, the researchers constructed a genetic risk score based on 894 independent single nucleotide polymorphisms (SNPs) associated with high BMI and another genetic risk score based on 481 SNPs associated with high WHR-adjBMI.
Having a genetic predisposition to higher WHR-adjBMI predicted an increase in abdominal obesity after weight loss, whereas having a genetic predisposition to higher BMI did not predict weight regain.
“These results suggest that genetic effects on abdominal obesity may be more pronounced than those on general obesity during weight regain,” the researchers conclude.
The researchers were supported by grants from the Novo Nordisk Foundation and the Danish Diabetes Academy (funded by the Novo Nordisk Foundation). The authors report no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM DIABETES
‘Water fasting’ benefits don’t last
Health benefits of prolonged “water fasting” (zero calories) or Buchinger fasting (200-300 calories/day) don’t last, according to authors of a review of eight studies.
Five days of fasting lowered weight by about 6%, but this weight was regained after 3 months of regular eating, the investigators found. The article was published in Nutrition Reviews.
“Water fasting led to improvements in blood pressure, cholesterol, and blood sugar levels, but these were short-lived,” senior author Krista A. Varady, PhD, told this news organization.
“Levels returned to baseline ... quickly after participants started eating. Most benefits disappeared in 3-4 months,” said Dr. Varady, professor of nutrition at the University of Illinois, Chicago.
“My overall conclusion,” she said, “is that I guess you could try it, but it just seems like a lot of work, and all those metabolic benefits disappear. I would encourage someone hoping to lose weight to try intermittent fasting instead of water fasting, because there’s a lot more data to show it can help with weight management.
“People should consult their doctor if they have diabetes or any other major obesity-related conditions before doing water fasting,” Dr. Varady cautioned.
“Healthy people with obesity can probably fast safely for 5 days on their own (if they don’t have any other conditions). However, no one should undertake one of these fasts for more than 5 days without medical supervision,” she stressed.
Eight studies of water and Buchinger fasting
Although several favorable effects of prolonged fasting have been observed, benefits must be weighed against risks, Dr. Varady and her coauthors wrote.
Most medically supervised fasting programs have reported only minor adverse events, which included hunger, headaches, nausea, vomiting, dry mouth, and fatigue. However, more severe events have been documented, including edema, abnormal results on liver function tests, decreased bone density, and metabolic acidosis.
The researchers aimed to determine the effect of prolonged fasting on weight, blood pressure, lipid levels, and glycemic control, as well as safety and the effects of refeeding.
They examined two types of prolonged fasting: water fasting and Buchinger fasting, which involves consuming 250 mL of fruit or vegetable juice for lunch and 250 mL of soup for dinner every day of the 5- to 20-day fast.
Buchinger fasting is popular in Central Europe. Water fasting “institutes” exist in the United States, such as one in California, Dr. Varady noted.
The researchers excluded fasting during Ramadan or fasting practiced by Seventh Day Adventists.
They identified four studies of water fasting and four studies of Buchinger fasting (of which one study of 1,422 participants assessed fasting for 5, 10, 15, and 20 days).
The review showed that prolonged fasting for 5-20 days produced large increases in circulating ketones, weight loss of 2%-10%, and decreases in systolic and diastolic blood pressure.
People who fasted 5 days typically lost 4%-6% of their weight; those who fasted 7-10 days lost 2%-10% of their weight; and those who fasted 15-20 days lost 7%-10% of their weight.
LDL cholesterol and triglyceride levels decreased in some trials.
Fasting glucose levels, fasting insulin levels, insulin resistance, and A1c decreased in adults without diabetes but remained unchanged in patients with type 1 or type 2 diabetes.
Some participants experienced metabolic acidosis, headaches, insomnia, or hunger.
About two-thirds of the weight lost was of lean mass, and one-third was of fat mass. The loss of lean mass loss suggests that prolonged fasting may increase the breakdown of muscle proteins, which is a concern, the researchers noted.
Few of the trials examined the effects of refeeding. In one study, normal-weight adults lost 6% of their weight after 5 days of water-only fasting but then gained it all back after 3 months of eating regularly.
In three trials, participants regained 1%-2% of their weight 2-4 months after fasting; however, those trials instructed participants to follow a calorie-restricted diet during the refeeding period.
Three to 4 months after the fast was completed, none of the metabolic benefits were maintained, even when weight loss was maintained.
The study did not receive external funding. Dr. Varady has received author fees from Hachette Book Group for “The Every Other Day Diet” and from Pan Macmillan Press for “The Fastest Diet.” The other authors have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Health benefits of prolonged “water fasting” (zero calories) or Buchinger fasting (200-300 calories/day) don’t last, according to authors of a review of eight studies.
Five days of fasting lowered weight by about 6%, but this weight was regained after 3 months of regular eating, the investigators found. The article was published in Nutrition Reviews.
“Water fasting led to improvements in blood pressure, cholesterol, and blood sugar levels, but these were short-lived,” senior author Krista A. Varady, PhD, told this news organization.
“Levels returned to baseline ... quickly after participants started eating. Most benefits disappeared in 3-4 months,” said Dr. Varady, professor of nutrition at the University of Illinois, Chicago.
“My overall conclusion,” she said, “is that I guess you could try it, but it just seems like a lot of work, and all those metabolic benefits disappear. I would encourage someone hoping to lose weight to try intermittent fasting instead of water fasting, because there’s a lot more data to show it can help with weight management.
“People should consult their doctor if they have diabetes or any other major obesity-related conditions before doing water fasting,” Dr. Varady cautioned.
“Healthy people with obesity can probably fast safely for 5 days on their own (if they don’t have any other conditions). However, no one should undertake one of these fasts for more than 5 days without medical supervision,” she stressed.
Eight studies of water and Buchinger fasting
Although several favorable effects of prolonged fasting have been observed, benefits must be weighed against risks, Dr. Varady and her coauthors wrote.
Most medically supervised fasting programs have reported only minor adverse events, which included hunger, headaches, nausea, vomiting, dry mouth, and fatigue. However, more severe events have been documented, including edema, abnormal results on liver function tests, decreased bone density, and metabolic acidosis.
The researchers aimed to determine the effect of prolonged fasting on weight, blood pressure, lipid levels, and glycemic control, as well as safety and the effects of refeeding.
They examined two types of prolonged fasting: water fasting and Buchinger fasting, which involves consuming 250 mL of fruit or vegetable juice for lunch and 250 mL of soup for dinner every day of the 5- to 20-day fast.
Buchinger fasting is popular in Central Europe. Water fasting “institutes” exist in the United States, such as one in California, Dr. Varady noted.
The researchers excluded fasting during Ramadan or fasting practiced by Seventh Day Adventists.
They identified four studies of water fasting and four studies of Buchinger fasting (of which one study of 1,422 participants assessed fasting for 5, 10, 15, and 20 days).
The review showed that prolonged fasting for 5-20 days produced large increases in circulating ketones, weight loss of 2%-10%, and decreases in systolic and diastolic blood pressure.
People who fasted 5 days typically lost 4%-6% of their weight; those who fasted 7-10 days lost 2%-10% of their weight; and those who fasted 15-20 days lost 7%-10% of their weight.
LDL cholesterol and triglyceride levels decreased in some trials.
Fasting glucose levels, fasting insulin levels, insulin resistance, and A1c decreased in adults without diabetes but remained unchanged in patients with type 1 or type 2 diabetes.
Some participants experienced metabolic acidosis, headaches, insomnia, or hunger.
About two-thirds of the weight lost was of lean mass, and one-third was of fat mass. The loss of lean mass loss suggests that prolonged fasting may increase the breakdown of muscle proteins, which is a concern, the researchers noted.
Few of the trials examined the effects of refeeding. In one study, normal-weight adults lost 6% of their weight after 5 days of water-only fasting but then gained it all back after 3 months of eating regularly.
In three trials, participants regained 1%-2% of their weight 2-4 months after fasting; however, those trials instructed participants to follow a calorie-restricted diet during the refeeding period.
Three to 4 months after the fast was completed, none of the metabolic benefits were maintained, even when weight loss was maintained.
The study did not receive external funding. Dr. Varady has received author fees from Hachette Book Group for “The Every Other Day Diet” and from Pan Macmillan Press for “The Fastest Diet.” The other authors have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Health benefits of prolonged “water fasting” (zero calories) or Buchinger fasting (200-300 calories/day) don’t last, according to authors of a review of eight studies.
Five days of fasting lowered weight by about 6%, but this weight was regained after 3 months of regular eating, the investigators found. The article was published in Nutrition Reviews.
“Water fasting led to improvements in blood pressure, cholesterol, and blood sugar levels, but these were short-lived,” senior author Krista A. Varady, PhD, told this news organization.
“Levels returned to baseline ... quickly after participants started eating. Most benefits disappeared in 3-4 months,” said Dr. Varady, professor of nutrition at the University of Illinois, Chicago.
“My overall conclusion,” she said, “is that I guess you could try it, but it just seems like a lot of work, and all those metabolic benefits disappear. I would encourage someone hoping to lose weight to try intermittent fasting instead of water fasting, because there’s a lot more data to show it can help with weight management.
“People should consult their doctor if they have diabetes or any other major obesity-related conditions before doing water fasting,” Dr. Varady cautioned.
“Healthy people with obesity can probably fast safely for 5 days on their own (if they don’t have any other conditions). However, no one should undertake one of these fasts for more than 5 days without medical supervision,” she stressed.
Eight studies of water and Buchinger fasting
Although several favorable effects of prolonged fasting have been observed, benefits must be weighed against risks, Dr. Varady and her coauthors wrote.
Most medically supervised fasting programs have reported only minor adverse events, which included hunger, headaches, nausea, vomiting, dry mouth, and fatigue. However, more severe events have been documented, including edema, abnormal results on liver function tests, decreased bone density, and metabolic acidosis.
The researchers aimed to determine the effect of prolonged fasting on weight, blood pressure, lipid levels, and glycemic control, as well as safety and the effects of refeeding.
They examined two types of prolonged fasting: water fasting and Buchinger fasting, which involves consuming 250 mL of fruit or vegetable juice for lunch and 250 mL of soup for dinner every day of the 5- to 20-day fast.
Buchinger fasting is popular in Central Europe. Water fasting “institutes” exist in the United States, such as one in California, Dr. Varady noted.
The researchers excluded fasting during Ramadan or fasting practiced by Seventh Day Adventists.
They identified four studies of water fasting and four studies of Buchinger fasting (of which one study of 1,422 participants assessed fasting for 5, 10, 15, and 20 days).
The review showed that prolonged fasting for 5-20 days produced large increases in circulating ketones, weight loss of 2%-10%, and decreases in systolic and diastolic blood pressure.
People who fasted 5 days typically lost 4%-6% of their weight; those who fasted 7-10 days lost 2%-10% of their weight; and those who fasted 15-20 days lost 7%-10% of their weight.
LDL cholesterol and triglyceride levels decreased in some trials.
Fasting glucose levels, fasting insulin levels, insulin resistance, and A1c decreased in adults without diabetes but remained unchanged in patients with type 1 or type 2 diabetes.
Some participants experienced metabolic acidosis, headaches, insomnia, or hunger.
About two-thirds of the weight lost was of lean mass, and one-third was of fat mass. The loss of lean mass loss suggests that prolonged fasting may increase the breakdown of muscle proteins, which is a concern, the researchers noted.
Few of the trials examined the effects of refeeding. In one study, normal-weight adults lost 6% of their weight after 5 days of water-only fasting but then gained it all back after 3 months of eating regularly.
In three trials, participants regained 1%-2% of their weight 2-4 months after fasting; however, those trials instructed participants to follow a calorie-restricted diet during the refeeding period.
Three to 4 months after the fast was completed, none of the metabolic benefits were maintained, even when weight loss was maintained.
The study did not receive external funding. Dr. Varady has received author fees from Hachette Book Group for “The Every Other Day Diet” and from Pan Macmillan Press for “The Fastest Diet.” The other authors have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Prioritize nutrients, limit ultraprocessed food in diabetes
In a large cohort of older adults with type 2 diabetes in Italy, those with the highest intake of ultraprocessed food and beverages (UPF) were more likely to die of all causes or cardiovascular disease (CVD) within a decade than those with the lowest intake – independent of adherence to a healthy Mediterranean diet.
Adults in the top quartile of UPF intake had a 64% increased risk of all-cause death and a 2.5-fold increased risk of CVD death during follow-up, compared with those in the lowest quartile, after adjusting for variables including Mediterranean diet score.
These findings from the Moli-sani study by Marialaura Bonaccio, PhD, from the Institute for Research, Hospitalization and Healthcare (IRCCS) Neuromed, in Pozzilli, Italy, and colleagues, were published online in the American Journal of Clinical Nutrition.
“Dietary recommendations for prevention and management of type 2 diabetes almost exclusively prioritize consumption of nutritionally balanced foods that are the source of fiber [and] healthy fats and [are] poor in free sugars, and promote dietary patterns – such as the Mediterranean diet and the DASH diet – that place a large emphasis on food groups (for example, whole grains, legumes, nuts, fruits, and vegetables) regardless of food processing,” the researchers note.
The research suggests that “besides prioritizing the adoption of a diet based on nutritional requirements, dietary guidelines for the management of type 2 diabetes should also recommend limiting UPF,” they conclude.
“In addition to the adoption of a diet based on well-known nutritional requirements, dietary recommendations should also suggest limiting the consumption of ultraprocessed foods as much as possible,” Giovanni de Gaetano, MD, PhD, president, IRCCS Neuromed, echoed, in a press release from the institute.
“In this context, and not only for people with diabetes, the front-of-pack nutrition labels should also include information on the degree of food processing,” he observed.
Caroline M. Apovian, MD, who was not involved with the study, agrees that it is wise to limit consumption of UPF.
However, we need more research to better understand which components of UPF are harmful and the biologic mechanisms, Dr. Apovian, who is codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, and a professor of medicine at Harvard Medical School, both in Boston, told this news organization in an interview.
She noted that in a randomized crossover trial in 20 patients who were instructed to eat as much or as little as they wanted, people ate more and gained weight during 2 weeks of a diet high in UPF, compared with 2 weeks of an unprocessed diet matched for presented calories, carbohydrate, sugar, fat, sodium, and fiber.
Ultraprocessed foods classed according to Nova system
UPF is “made mostly or entirely from substances derived from foods and additives, using a series of processes and containing minimal whole foods,” and they “are usually nutrient-poor, high in calories, added sugar, sodium, and unhealthy fats,” the Italian researchers write.
High intake of UPF, they add, may exacerbate health risks in people with type 2 diabetes, who are already at higher risk of premature mortality, mainly due to diabetes-related complications.
The researchers analyzed data from a subset of patients in the Moli-sani study of environmental and genetic factors underlying disease, which enrolled 24,325 individuals aged 35 and older who lived in Molise, in central-southern Italy, in 2005-2010.
The current analysis included 1,065 participants in Moli-sani who had type 2 diabetes at baseline and completed a food frequency questionnaire by which participants reported their consumption of 188 foods and beverages in the previous 12 months.
Participants were a mean age of 65 years, and 60% were men.
Most UPF intake was from processed meat (22.4%), crispbread/rusks (16.6%), nonhomemade pizza (11.2%), and cakes, pies, pastries, and puddings (8.8%).
Researchers categorized foods and beverages into four groups with increasing degrees of processing, based on the Nova Food Classification System:
- Group 1: Fresh or minimally processed foods and beverages (for example, fruit, meat, milk).
- Group 2: Processed culinary ingredients (for example, oils, butter).
- Group 3: Processed foods and beverages (for example, canned fish, bread).
- Group 4: UPF (22 foods and beverages including carbonated drinks, processed meats, sweet or savory packaged snacks, margarine, and foods and beverages with artificial sweeteners).
Participants were divided into four quartiles based on UPF consumption.
The mean percentage of UPF consumption out of total food and beverage intake was 2.8%, 5.2%, 7.7%, and 14.4% for quartiles 1, 2, 3, and 4, respectively. By sex, these rates for quartile 1 were < 4.7% for women and < 3.7% for men, and for quartile 4 were ≥ 10.5% for women and ≥ 9% for men.
Participants with the highest UPF intake were younger (mean age, 63 vs. 67 years) but otherwise had similar characteristics as other participants.
During a median follow-up of 11.6 years, 308 participants died from all causes, including 129 who died from CVD.
Compared with participants with the lowest intake of UPF (quartile 1), those with the highest intake (quartile 4) had a higher risk of all-cause mortality (hazard ratio, 1.70) and CVD mortality (HR, 2.64) during follow-up, after multivariable adjustment. The analysis adjusted for sex, age, energy intake, residence, education, housing, smoking, body mass index, leisure-time physical activity, history of cancer or cardiovascular disease, hypertension, hyperlipidemia, aspirin use, years since type 2 diabetes diagnosis, and special diet for blood glucose control.
After further adjusting for Mediterranean diet score, the risk of all-cause and CVD mortality during follow-up for patients with the highest versus lowest intake of UPF remained similar (HR, 1.64 and 2.55, respectively).
There was a linear dose–response relationship between UPF and all-cause and CVD mortality.
Increasing intake of fruit drinks, carbonated drinks, and salty biscuits was associated with higher all-cause and CVD mortality rates, and consumption of stock cubes and margarine was further related to higher CVD death.
The researchers acknowledge that the study was observational, and therefore cannot determine cause and effect, and was not designed to specifically collect dietary data according to the Nova classification. The findings may not be generalizable to other populations.
The analysis was partly funded by grants from the AIRC and Italian Ministry of Health. The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large cohort of older adults with type 2 diabetes in Italy, those with the highest intake of ultraprocessed food and beverages (UPF) were more likely to die of all causes or cardiovascular disease (CVD) within a decade than those with the lowest intake – independent of adherence to a healthy Mediterranean diet.
Adults in the top quartile of UPF intake had a 64% increased risk of all-cause death and a 2.5-fold increased risk of CVD death during follow-up, compared with those in the lowest quartile, after adjusting for variables including Mediterranean diet score.
These findings from the Moli-sani study by Marialaura Bonaccio, PhD, from the Institute for Research, Hospitalization and Healthcare (IRCCS) Neuromed, in Pozzilli, Italy, and colleagues, were published online in the American Journal of Clinical Nutrition.
“Dietary recommendations for prevention and management of type 2 diabetes almost exclusively prioritize consumption of nutritionally balanced foods that are the source of fiber [and] healthy fats and [are] poor in free sugars, and promote dietary patterns – such as the Mediterranean diet and the DASH diet – that place a large emphasis on food groups (for example, whole grains, legumes, nuts, fruits, and vegetables) regardless of food processing,” the researchers note.
The research suggests that “besides prioritizing the adoption of a diet based on nutritional requirements, dietary guidelines for the management of type 2 diabetes should also recommend limiting UPF,” they conclude.
“In addition to the adoption of a diet based on well-known nutritional requirements, dietary recommendations should also suggest limiting the consumption of ultraprocessed foods as much as possible,” Giovanni de Gaetano, MD, PhD, president, IRCCS Neuromed, echoed, in a press release from the institute.
“In this context, and not only for people with diabetes, the front-of-pack nutrition labels should also include information on the degree of food processing,” he observed.
Caroline M. Apovian, MD, who was not involved with the study, agrees that it is wise to limit consumption of UPF.
However, we need more research to better understand which components of UPF are harmful and the biologic mechanisms, Dr. Apovian, who is codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, and a professor of medicine at Harvard Medical School, both in Boston, told this news organization in an interview.
She noted that in a randomized crossover trial in 20 patients who were instructed to eat as much or as little as they wanted, people ate more and gained weight during 2 weeks of a diet high in UPF, compared with 2 weeks of an unprocessed diet matched for presented calories, carbohydrate, sugar, fat, sodium, and fiber.
Ultraprocessed foods classed according to Nova system
UPF is “made mostly or entirely from substances derived from foods and additives, using a series of processes and containing minimal whole foods,” and they “are usually nutrient-poor, high in calories, added sugar, sodium, and unhealthy fats,” the Italian researchers write.
High intake of UPF, they add, may exacerbate health risks in people with type 2 diabetes, who are already at higher risk of premature mortality, mainly due to diabetes-related complications.
The researchers analyzed data from a subset of patients in the Moli-sani study of environmental and genetic factors underlying disease, which enrolled 24,325 individuals aged 35 and older who lived in Molise, in central-southern Italy, in 2005-2010.
The current analysis included 1,065 participants in Moli-sani who had type 2 diabetes at baseline and completed a food frequency questionnaire by which participants reported their consumption of 188 foods and beverages in the previous 12 months.
Participants were a mean age of 65 years, and 60% were men.
Most UPF intake was from processed meat (22.4%), crispbread/rusks (16.6%), nonhomemade pizza (11.2%), and cakes, pies, pastries, and puddings (8.8%).
Researchers categorized foods and beverages into four groups with increasing degrees of processing, based on the Nova Food Classification System:
- Group 1: Fresh or minimally processed foods and beverages (for example, fruit, meat, milk).
- Group 2: Processed culinary ingredients (for example, oils, butter).
- Group 3: Processed foods and beverages (for example, canned fish, bread).
- Group 4: UPF (22 foods and beverages including carbonated drinks, processed meats, sweet or savory packaged snacks, margarine, and foods and beverages with artificial sweeteners).
Participants were divided into four quartiles based on UPF consumption.
The mean percentage of UPF consumption out of total food and beverage intake was 2.8%, 5.2%, 7.7%, and 14.4% for quartiles 1, 2, 3, and 4, respectively. By sex, these rates for quartile 1 were < 4.7% for women and < 3.7% for men, and for quartile 4 were ≥ 10.5% for women and ≥ 9% for men.
Participants with the highest UPF intake were younger (mean age, 63 vs. 67 years) but otherwise had similar characteristics as other participants.
During a median follow-up of 11.6 years, 308 participants died from all causes, including 129 who died from CVD.
Compared with participants with the lowest intake of UPF (quartile 1), those with the highest intake (quartile 4) had a higher risk of all-cause mortality (hazard ratio, 1.70) and CVD mortality (HR, 2.64) during follow-up, after multivariable adjustment. The analysis adjusted for sex, age, energy intake, residence, education, housing, smoking, body mass index, leisure-time physical activity, history of cancer or cardiovascular disease, hypertension, hyperlipidemia, aspirin use, years since type 2 diabetes diagnosis, and special diet for blood glucose control.
After further adjusting for Mediterranean diet score, the risk of all-cause and CVD mortality during follow-up for patients with the highest versus lowest intake of UPF remained similar (HR, 1.64 and 2.55, respectively).
There was a linear dose–response relationship between UPF and all-cause and CVD mortality.
Increasing intake of fruit drinks, carbonated drinks, and salty biscuits was associated with higher all-cause and CVD mortality rates, and consumption of stock cubes and margarine was further related to higher CVD death.
The researchers acknowledge that the study was observational, and therefore cannot determine cause and effect, and was not designed to specifically collect dietary data according to the Nova classification. The findings may not be generalizable to other populations.
The analysis was partly funded by grants from the AIRC and Italian Ministry of Health. The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large cohort of older adults with type 2 diabetes in Italy, those with the highest intake of ultraprocessed food and beverages (UPF) were more likely to die of all causes or cardiovascular disease (CVD) within a decade than those with the lowest intake – independent of adherence to a healthy Mediterranean diet.
Adults in the top quartile of UPF intake had a 64% increased risk of all-cause death and a 2.5-fold increased risk of CVD death during follow-up, compared with those in the lowest quartile, after adjusting for variables including Mediterranean diet score.
These findings from the Moli-sani study by Marialaura Bonaccio, PhD, from the Institute for Research, Hospitalization and Healthcare (IRCCS) Neuromed, in Pozzilli, Italy, and colleagues, were published online in the American Journal of Clinical Nutrition.
“Dietary recommendations for prevention and management of type 2 diabetes almost exclusively prioritize consumption of nutritionally balanced foods that are the source of fiber [and] healthy fats and [are] poor in free sugars, and promote dietary patterns – such as the Mediterranean diet and the DASH diet – that place a large emphasis on food groups (for example, whole grains, legumes, nuts, fruits, and vegetables) regardless of food processing,” the researchers note.
The research suggests that “besides prioritizing the adoption of a diet based on nutritional requirements, dietary guidelines for the management of type 2 diabetes should also recommend limiting UPF,” they conclude.
“In addition to the adoption of a diet based on well-known nutritional requirements, dietary recommendations should also suggest limiting the consumption of ultraprocessed foods as much as possible,” Giovanni de Gaetano, MD, PhD, president, IRCCS Neuromed, echoed, in a press release from the institute.
“In this context, and not only for people with diabetes, the front-of-pack nutrition labels should also include information on the degree of food processing,” he observed.
Caroline M. Apovian, MD, who was not involved with the study, agrees that it is wise to limit consumption of UPF.
However, we need more research to better understand which components of UPF are harmful and the biologic mechanisms, Dr. Apovian, who is codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, and a professor of medicine at Harvard Medical School, both in Boston, told this news organization in an interview.
She noted that in a randomized crossover trial in 20 patients who were instructed to eat as much or as little as they wanted, people ate more and gained weight during 2 weeks of a diet high in UPF, compared with 2 weeks of an unprocessed diet matched for presented calories, carbohydrate, sugar, fat, sodium, and fiber.
Ultraprocessed foods classed according to Nova system
UPF is “made mostly or entirely from substances derived from foods and additives, using a series of processes and containing minimal whole foods,” and they “are usually nutrient-poor, high in calories, added sugar, sodium, and unhealthy fats,” the Italian researchers write.
High intake of UPF, they add, may exacerbate health risks in people with type 2 diabetes, who are already at higher risk of premature mortality, mainly due to diabetes-related complications.
The researchers analyzed data from a subset of patients in the Moli-sani study of environmental and genetic factors underlying disease, which enrolled 24,325 individuals aged 35 and older who lived in Molise, in central-southern Italy, in 2005-2010.
The current analysis included 1,065 participants in Moli-sani who had type 2 diabetes at baseline and completed a food frequency questionnaire by which participants reported their consumption of 188 foods and beverages in the previous 12 months.
Participants were a mean age of 65 years, and 60% were men.
Most UPF intake was from processed meat (22.4%), crispbread/rusks (16.6%), nonhomemade pizza (11.2%), and cakes, pies, pastries, and puddings (8.8%).
Researchers categorized foods and beverages into four groups with increasing degrees of processing, based on the Nova Food Classification System:
- Group 1: Fresh or minimally processed foods and beverages (for example, fruit, meat, milk).
- Group 2: Processed culinary ingredients (for example, oils, butter).
- Group 3: Processed foods and beverages (for example, canned fish, bread).
- Group 4: UPF (22 foods and beverages including carbonated drinks, processed meats, sweet or savory packaged snacks, margarine, and foods and beverages with artificial sweeteners).
Participants were divided into four quartiles based on UPF consumption.
The mean percentage of UPF consumption out of total food and beverage intake was 2.8%, 5.2%, 7.7%, and 14.4% for quartiles 1, 2, 3, and 4, respectively. By sex, these rates for quartile 1 were < 4.7% for women and < 3.7% for men, and for quartile 4 were ≥ 10.5% for women and ≥ 9% for men.
Participants with the highest UPF intake were younger (mean age, 63 vs. 67 years) but otherwise had similar characteristics as other participants.
During a median follow-up of 11.6 years, 308 participants died from all causes, including 129 who died from CVD.
Compared with participants with the lowest intake of UPF (quartile 1), those with the highest intake (quartile 4) had a higher risk of all-cause mortality (hazard ratio, 1.70) and CVD mortality (HR, 2.64) during follow-up, after multivariable adjustment. The analysis adjusted for sex, age, energy intake, residence, education, housing, smoking, body mass index, leisure-time physical activity, history of cancer or cardiovascular disease, hypertension, hyperlipidemia, aspirin use, years since type 2 diabetes diagnosis, and special diet for blood glucose control.
After further adjusting for Mediterranean diet score, the risk of all-cause and CVD mortality during follow-up for patients with the highest versus lowest intake of UPF remained similar (HR, 1.64 and 2.55, respectively).
There was a linear dose–response relationship between UPF and all-cause and CVD mortality.
Increasing intake of fruit drinks, carbonated drinks, and salty biscuits was associated with higher all-cause and CVD mortality rates, and consumption of stock cubes and margarine was further related to higher CVD death.
The researchers acknowledge that the study was observational, and therefore cannot determine cause and effect, and was not designed to specifically collect dietary data according to the Nova classification. The findings may not be generalizable to other populations.
The analysis was partly funded by grants from the AIRC and Italian Ministry of Health. The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Quick, inexpensive test detects osteoporosis risk from blood
TOPLINE:
in a 15-minute, inexpensive test using an investigational electrochemical device.
METHODOLOGY:
- 10-mcL finger-prick blood samples from 15 people were diluted 1:5 and subjected to rapid thermolysis (30 seconds at 95° C) to extract the DNA.
- Blood samples with the lysed DNA, and negative controls, were applied to an investigational, generic, portable electrochemical device (Labman Automation), in which individual gold electrodes were covered with reverse primers for each of five osteoporosis-associated SNPs.
- DNA in the blood samples that matched the SNPs bound to these electrodes, and the reaction was amplified with recombinase polymerase labeled with ferrocene, which facilitates electrochemical detection.
- Five SNPs associated with an increased risk of developing osteoporosis and risk for fracture were detected in the 15 blood samples, and the results were validated using TaqMan SNP genotyping assays and Sanger sequencing.
TAKEAWAYS:
- Measuring bone mineral density by dual-energy x-ray absorptiometry reliably predicts fracture risk, but only when a significant amount of bone is already lost.
- Researchers developed and validated a generic, battery-operable, portable device to detect osteoporosis-associated SNPs from a finger-prick blood sample, with no need for DNA extraction or purification.
- The entire assay from the addition of the thermolyzed blood sample to the readout of the results was complete in just 15 minutes, with a cost per SNP, on a laboratory scale, including the cost of the electrode array and all reagents, of 0.3 euro (0.33 USD).
- The researchers previously showed that the device identified an SNP associated with rifampicin resistance in Mycobacterium tuberculosis in a sputum sample, and an SNP linked with cardiomyopathy in blood; they plan to test a scaled-up version of the device.
IN PRACTICE:
“The platform is completely generic and has immense potential for deployment at the point of need in an automated device for targeted SNP genotyping with the only required end-user intervention being sample addition,” said the authors in their report.
STUDY DETAILS:
The authors, from INTERFIBIO Research Group, Tarragona, Spain, as well as Austria, the Czech Republic, and the Netherlands, published their findings in ACS Central Science.
LIMITATIONS:
The researchers did not report any study limitations.
DISCLOSURES:
The study received no commercial funding. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
in a 15-minute, inexpensive test using an investigational electrochemical device.
METHODOLOGY:
- 10-mcL finger-prick blood samples from 15 people were diluted 1:5 and subjected to rapid thermolysis (30 seconds at 95° C) to extract the DNA.
- Blood samples with the lysed DNA, and negative controls, were applied to an investigational, generic, portable electrochemical device (Labman Automation), in which individual gold electrodes were covered with reverse primers for each of five osteoporosis-associated SNPs.
- DNA in the blood samples that matched the SNPs bound to these electrodes, and the reaction was amplified with recombinase polymerase labeled with ferrocene, which facilitates electrochemical detection.
- Five SNPs associated with an increased risk of developing osteoporosis and risk for fracture were detected in the 15 blood samples, and the results were validated using TaqMan SNP genotyping assays and Sanger sequencing.
TAKEAWAYS:
- Measuring bone mineral density by dual-energy x-ray absorptiometry reliably predicts fracture risk, but only when a significant amount of bone is already lost.
- Researchers developed and validated a generic, battery-operable, portable device to detect osteoporosis-associated SNPs from a finger-prick blood sample, with no need for DNA extraction or purification.
- The entire assay from the addition of the thermolyzed blood sample to the readout of the results was complete in just 15 minutes, with a cost per SNP, on a laboratory scale, including the cost of the electrode array and all reagents, of 0.3 euro (0.33 USD).
- The researchers previously showed that the device identified an SNP associated with rifampicin resistance in Mycobacterium tuberculosis in a sputum sample, and an SNP linked with cardiomyopathy in blood; they plan to test a scaled-up version of the device.
IN PRACTICE:
“The platform is completely generic and has immense potential for deployment at the point of need in an automated device for targeted SNP genotyping with the only required end-user intervention being sample addition,” said the authors in their report.
STUDY DETAILS:
The authors, from INTERFIBIO Research Group, Tarragona, Spain, as well as Austria, the Czech Republic, and the Netherlands, published their findings in ACS Central Science.
LIMITATIONS:
The researchers did not report any study limitations.
DISCLOSURES:
The study received no commercial funding. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
in a 15-minute, inexpensive test using an investigational electrochemical device.
METHODOLOGY:
- 10-mcL finger-prick blood samples from 15 people were diluted 1:5 and subjected to rapid thermolysis (30 seconds at 95° C) to extract the DNA.
- Blood samples with the lysed DNA, and negative controls, were applied to an investigational, generic, portable electrochemical device (Labman Automation), in which individual gold electrodes were covered with reverse primers for each of five osteoporosis-associated SNPs.
- DNA in the blood samples that matched the SNPs bound to these electrodes, and the reaction was amplified with recombinase polymerase labeled with ferrocene, which facilitates electrochemical detection.
- Five SNPs associated with an increased risk of developing osteoporosis and risk for fracture were detected in the 15 blood samples, and the results were validated using TaqMan SNP genotyping assays and Sanger sequencing.
TAKEAWAYS:
- Measuring bone mineral density by dual-energy x-ray absorptiometry reliably predicts fracture risk, but only when a significant amount of bone is already lost.
- Researchers developed and validated a generic, battery-operable, portable device to detect osteoporosis-associated SNPs from a finger-prick blood sample, with no need for DNA extraction or purification.
- The entire assay from the addition of the thermolyzed blood sample to the readout of the results was complete in just 15 minutes, with a cost per SNP, on a laboratory scale, including the cost of the electrode array and all reagents, of 0.3 euro (0.33 USD).
- The researchers previously showed that the device identified an SNP associated with rifampicin resistance in Mycobacterium tuberculosis in a sputum sample, and an SNP linked with cardiomyopathy in blood; they plan to test a scaled-up version of the device.
IN PRACTICE:
“The platform is completely generic and has immense potential for deployment at the point of need in an automated device for targeted SNP genotyping with the only required end-user intervention being sample addition,” said the authors in their report.
STUDY DETAILS:
The authors, from INTERFIBIO Research Group, Tarragona, Spain, as well as Austria, the Czech Republic, and the Netherlands, published their findings in ACS Central Science.
LIMITATIONS:
The researchers did not report any study limitations.
DISCLOSURES:
The study received no commercial funding. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACS CENTRAL SCIENCE