Conference Coverage

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

PORTLAND, ORE. – If a child presents with pseudoporphyria – a bullous photodermatosis with the clinical and histological features of porphyria cutanea tarda (PCT) but with normal porphyrins – chlorophyll water could be the culprit.

Commercially available, green pigment–infused chlorophyll water is marketed with claims that it supports cancer prevention and digestive health, facilitates weight loss, and improves skin complexion. “It also absorbs light, so lo and behold, if your patient is photosensitive, they might get pseudoporphyria,” Robert Sidbury, MD, MPH, chief of the division of dermatology at Seattle Children’s Hospital, said at the annual meeting of the Pacific Dermatologic Association.

This was one of the clinical pearls he shared during his presentation.

Dr. Sidbury added that the risk of photosensitivity increases in children who are taking other medications such as doxycycline, methotrexate, or even naproxen. At least two cases of pseudoporphyria following self-medication with chlorophyll have been described in the dermatology literature.
 

Is it SSSS or SJS?

Another clinical pearl that Dr. Sidbury shared at the meeting related to staphylococcal scalded skin syndrome (SSSS), which causes reddening and blistering of the skin that makes it appear scalded or burned. To rule out Stevens-Johnson Syndrome (SJS) in a child who presents with such skin manifestations, he routinely performs the unscientific lollipop test, which he learned from Bernard A. “Buddy” Cohen, MD, professor of dermatology and pediatrics at Johns Hopkins University, Baltimore.

kiliweb/Open Food Facts/CC BY-SA 3.0

“If they eat it, it’s Staph scalded skin,” said Dr. Sidbury, who is also professor of pediatrics at the University of Washington, Seattle. “If they don’t, it’s likely SJS. It’s not the most specific test, but it’s easy to do, because there’s no mucous membrane involvement in Staph scalded skin.”

In a poster presented during the 2022 annual meeting of the Society for Pediatric Dermatology, Sarah Cipriano, MD, MPH, and colleagues at the University of Utah, Salt Lake City, retrospectively study 85 patients aged younger than 18 years diagnosed with SSSS between Jan. 1, 2010, and Aug. 21, 2021. They found that ancillary blood cultures and CSF cultures did not improve diagnostic precision in SSSS patients.

“They don’t add anything unless there’s an indication beyond the Staph scalded skin,” said Dr. Sidbury, who was not involved in the study. “The researchers also found that clindamycin does not improve outcomes in these patients, so avoid using it.” Instead, a first-generation cephalosporin is indicated, and an alternate diagnosis should be considered if the patient does not improve within 48 hours.

Dr. Sidbury disclosed that he has conducted research for Regeneron, Galderma, and UCB. He is also an adviser for Leo Pharmaceuticals and a speaker for Biersdorf.

PORTLAND, ORE. – If a child presents with pseudoporphyria – a bullous photodermatosis with the clinical and histological features of porphyria cutanea tarda (PCT) but with normal porphyrins – chlorophyll water could be the culprit.

Commercially available, green pigment–infused chlorophyll water is marketed with claims that it supports cancer prevention and digestive health, facilitates weight loss, and improves skin complexion. “It also absorbs light, so lo and behold, if your patient is photosensitive, they might get pseudoporphyria,” Robert Sidbury, MD, MPH, chief of the division of dermatology at Seattle Children’s Hospital, said at the annual meeting of the Pacific Dermatologic Association.

This was one of the clinical pearls he shared during his presentation.

Dr. Sidbury added that the risk of photosensitivity increases in children who are taking other medications such as doxycycline, methotrexate, or even naproxen. At least two cases of pseudoporphyria following self-medication with chlorophyll have been described in the dermatology literature.
 

Is it SSSS or SJS?

Another clinical pearl that Dr. Sidbury shared at the meeting related to staphylococcal scalded skin syndrome (SSSS), which causes reddening and blistering of the skin that makes it appear scalded or burned. To rule out Stevens-Johnson Syndrome (SJS) in a child who presents with such skin manifestations, he routinely performs the unscientific lollipop test, which he learned from Bernard A. “Buddy” Cohen, MD, professor of dermatology and pediatrics at Johns Hopkins University, Baltimore.

kiliweb/Open Food Facts/CC BY-SA 3.0

“If they eat it, it’s Staph scalded skin,” said Dr. Sidbury, who is also professor of pediatrics at the University of Washington, Seattle. “If they don’t, it’s likely SJS. It’s not the most specific test, but it’s easy to do, because there’s no mucous membrane involvement in Staph scalded skin.”

In a poster presented during the 2022 annual meeting of the Society for Pediatric Dermatology, Sarah Cipriano, MD, MPH, and colleagues at the University of Utah, Salt Lake City, retrospectively study 85 patients aged younger than 18 years diagnosed with SSSS between Jan. 1, 2010, and Aug. 21, 2021. They found that ancillary blood cultures and CSF cultures did not improve diagnostic precision in SSSS patients.

“They don’t add anything unless there’s an indication beyond the Staph scalded skin,” said Dr. Sidbury, who was not involved in the study. “The researchers also found that clindamycin does not improve outcomes in these patients, so avoid using it.” Instead, a first-generation cephalosporin is indicated, and an alternate diagnosis should be considered if the patient does not improve within 48 hours.

Dr. Sidbury disclosed that he has conducted research for Regeneron, Galderma, and UCB. He is also an adviser for Leo Pharmaceuticals and a speaker for Biersdorf.

PORTLAND, ORE. – If a child presents with pseudoporphyria – a bullous photodermatosis with the clinical and histological features of porphyria cutanea tarda (PCT) but with normal porphyrins – chlorophyll water could be the culprit.

Commercially available, green pigment–infused chlorophyll water is marketed with claims that it supports cancer prevention and digestive health, facilitates weight loss, and improves skin complexion. “It also absorbs light, so lo and behold, if your patient is photosensitive, they might get pseudoporphyria,” Robert Sidbury, MD, MPH, chief of the division of dermatology at Seattle Children’s Hospital, said at the annual meeting of the Pacific Dermatologic Association.

This was one of the clinical pearls he shared during his presentation.

Dr. Sidbury added that the risk of photosensitivity increases in children who are taking other medications such as doxycycline, methotrexate, or even naproxen. At least two cases of pseudoporphyria following self-medication with chlorophyll have been described in the dermatology literature.
 

Is it SSSS or SJS?

Another clinical pearl that Dr. Sidbury shared at the meeting related to staphylococcal scalded skin syndrome (SSSS), which causes reddening and blistering of the skin that makes it appear scalded or burned. To rule out Stevens-Johnson Syndrome (SJS) in a child who presents with such skin manifestations, he routinely performs the unscientific lollipop test, which he learned from Bernard A. “Buddy” Cohen, MD, professor of dermatology and pediatrics at Johns Hopkins University, Baltimore.

kiliweb/Open Food Facts/CC BY-SA 3.0

“If they eat it, it’s Staph scalded skin,” said Dr. Sidbury, who is also professor of pediatrics at the University of Washington, Seattle. “If they don’t, it’s likely SJS. It’s not the most specific test, but it’s easy to do, because there’s no mucous membrane involvement in Staph scalded skin.”

In a poster presented during the 2022 annual meeting of the Society for Pediatric Dermatology, Sarah Cipriano, MD, MPH, and colleagues at the University of Utah, Salt Lake City, retrospectively study 85 patients aged younger than 18 years diagnosed with SSSS between Jan. 1, 2010, and Aug. 21, 2021. They found that ancillary blood cultures and CSF cultures did not improve diagnostic precision in SSSS patients.

“They don’t add anything unless there’s an indication beyond the Staph scalded skin,” said Dr. Sidbury, who was not involved in the study. “The researchers also found that clindamycin does not improve outcomes in these patients, so avoid using it.” Instead, a first-generation cephalosporin is indicated, and an alternate diagnosis should be considered if the patient does not improve within 48 hours.

Dr. Sidbury disclosed that he has conducted research for Regeneron, Galderma, and UCB. He is also an adviser for Leo Pharmaceuticals and a speaker for Biersdorf.

New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).

At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.

“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.

The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.

“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”

Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
 

‘Compelling new evidence’

In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”

Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.

“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”

Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events. 

“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.

“So, I think it’s a good study – well conducted, good numbers –  that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
 

High-risk characteristics

Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”

But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”

The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.

High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.

Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.

At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.

Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).

Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.

POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer  outside the submitted work. Dr. Wilson reported no relevant disclosures.

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

New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).

At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.

“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.

The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.

“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”

Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
 

‘Compelling new evidence’

In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”

Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.

“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”

Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events. 

“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.

“So, I think it’s a good study – well conducted, good numbers –  that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
 

High-risk characteristics

Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”

But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”

The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.

High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.

Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.

At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.

Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).

Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.

POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer  outside the submitted work. Dr. Wilson reported no relevant disclosures.

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

New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).

At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.

“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.

The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.

“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”

Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
 

‘Compelling new evidence’

In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”

Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.

“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”

Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events. 

“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.

“So, I think it’s a good study – well conducted, good numbers –  that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
 

High-risk characteristics

Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”

But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”

The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.

High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.

Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.

At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.

Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).

Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.

POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer  outside the submitted work. Dr. Wilson reported no relevant disclosures.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.