Cardiology

PHILADELPHIA – Two clinical trials of the combination therapy of the neprilysin inhibitor sacubitril and the angiotensin II receptor blocker valsartan in patients with heart failure and reduced ejection fraction found that it lowered rates of all-cause death, compared to a renin-angiotensin-system inhibitor alone.

Furthermore, the treatment produced a more beneficial effect in women, who are more prone to heart failure and preserved ejection fraction (HFpEF), lead investigators reported at the American Heart Association scientific sessions.

A prespecified subgroup analysis of 4,796 patients in the PARAGON-HF trial found that the sacubitril/valsartan, or sac/val, combination had a significantly more beneficial risk reduction of first and recurrent hospitalizations for heart failure, as well as cardiovascular death, in women than men. A prespecified pooled analysis of 13,195 patients in the PARAGON-HF and the PARADIGM-HF trials also found women derived a greater benefit from the combination therapy than men, but also concluded that patients with heart failure and even mildly reduced ejection fraction had better outcomes. The results of both studies were published simultaneously with the presentations on Nov. 17 in Circulation (doi: 10.1161/circulationaha.119.044491; doi: 10.1161/circulationaha.119.044586).

The findings underscore the effectiveness of sac/val combination in patients with HF and EF in the lower ranges, defined as 40% or less, commented discussant Lynne Warner Stevenson, MD, of Vanderbilt Heart and Vascular Institute in Nashville, Tenn. “We all agree now that the use of sacubitril/valsartan is very appropriate to improve outcomes in those patients, even if they’ve never been hospitalized,” she said in an interview.
 

PARAGON-HF subanalysis

John J.V. McMurray, MD, of the University of Glasgow presented the PARAGON-HF subgroup analysis. He said it initially focused on 12 subgroups, but that only two baseline variables showed a modified effect of sac/val: sex and left-ventricle ejection fraction (LVEF). The findings, he said, “stood up in a very robust, multivariable analysis.”

The women in the subgroup analysis were older, had higher baseline New York Heart Association class status, and worse quality of life as measured by Kansas City Cardiomyopathy Questionnaire clinical summary score. At baseline, women also had higher average LVEF (59% vs. 56%), lower N-terminal prohormone brain natriuretic peptide levels, and higher rates of renal dysfunction and chronic kidney disease, but lower incidence of a previous MI and coronary artery disease. Prestudy treatments were similar between the sexes.

In terms of the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – “there was an apparent 27% relative risk reduction in women and no overall effect in men,” Dr. McMurray said of the treatment group. “The difference was driven completely by hospitalizations.” Rates of CV death were similar between the valsartan-only and sac/val groups in both men and women, he said.

In the analysis of LVEF, women in the treatment group seemed to cross over to a heightened risk of hospitalization and CV death at an LVEF in the 60%-65% range, Dr. McMurray said, whereas men made that cross over in the 50%-55% range. “It looks as though women might be getting more benefit from this treatment up to a higher EF than in men,” he said.

However, the differences between men and women did not hold up in the analysis of secondary outcomes. At 8 months, women in the sac/val group had a 0.6-point greater decline than did the valsartan-only patients in KCCQ-CSS score, whereas men on sac/val had a 2.8-point lesser decline than did those on valsartan only. Similar differences were seen between the treatment and valsartan-only groups within the sexes, with women showing a noticeable improvement surpassing the men.

Posttreatment hypotension rates in both sexes were higher in the sac/val groups, and the risk of renal dysfunction was a bit less in both treatment groups. Women in the treatment group had significantly higher rates of angioedema than did the valsartan-only group and men in either group.

“Compared to valsartan, it’s important to say that sacubitril/valsartan seemed to reduce the risk of heart failure and hospitalization more in women than men, but we didn’t find a similar differential for other endpoints,” Dr. McMurray said. “Therefore, we’re not sure this is a real effect or a chance finding. It’s very statistically robust, but it could still be a chance finding.”

A possible explanation could be than men may not be responding to sac/val, or that valsartan alone may be more effective in men than women, he said. “This possible effect modification of sac/val vs. valsartan by sex deserves further investigation,” he said.

PARAGON-HF and PARADIGM-HF pooled analysis

Likewise, the prespecified pooled analysis of the PARADIGM-HF and PARAGON-HF trials found a greater benefit of sac/val in women, according to results presented by Scott D. Solomon, MD, of Brigham and Women’s Hospital in Boston. Where PARAGON-HF compared combination therapy with valsartan 160 mg twice daily alone, PARADIGM-HF used enalapril 10 mg twice daily alone as the comparator renin-angiotensin-system (RAS) inhibitor.

“These data suggest that the therapeutic effect of sacubitril/valsartan vs. RAS inhibition alone appear to extend to patients with heart failure and mildly reduced EF, with therapeutic benefits that extend to a higher left-ventricle EF range in women compared to men,” Dr. Solomon said.

The pooled analysis divided patients into six different EF groups: up to 22.5%, then in 10-point increments from 22.5% to 62.5%, and 62.5% or greater. PARADIGM-HF enrolled patients age 18 years and older, whereas PARAGON-HF involved those aged 50 years and older.

The analysis showed that, as LVEF rates increased across the EF groups, the rates of the primary composite outcome – HF hospitalizations, CV death, and all-cause mortality – decreased, but the decline was greatest for CV death and less so for HF hospitalization. And while rates of all-cause mortality decreased as EF increased, rates of non-CV death increased substantially with increasing LVEF.

“For each of these endpoints, there are significant benefits to sacubitril/valsartan in the pooled analysis, and this includes HF hospitalization, CV death, either total or first events, and all-cause mortality, which was reduced overall by 12% in the combination group,” Dr. Solomon said. That benefit was seen in the first five categories of EF, but all but disappeared in the highest category (at least 62.5%), he said.

At the lower end of the EF spectrum, the effect of sac/val is more pronounced and similar for men and women, Dr. Solomon said. “But as EF goes up, we see an attenuation of that effect in both men and women, but it occurs at a different point,” he said. “Women seem to derive a benefit to a higher ejection fraction than men.” As in Dr. McMurray’s research, the benefit seems to extend to LVEF of 55%-60% in men and 65%-70% in women.

“These findings were driven by an observed benefit in patients with chronic heart failure and LVEF below the normal range,” he said. “The benefit in the EF range above the ranking ‘reduced’ but below normal was driven primarily by reduction in HF hospitalization.”

Dr. Stevenson said that these findings indicate that a previous hospitalization for HF with preserved EF may be a telling marker for the effectiveness of sac/val. “As opposed to the patient who has exertional dyspnea but has never decompensated to the level needing hospitalization, if they have pEF, our current analyses would suggest sac/val may not offer them much benefit,” she said.

In real-world practice, cost would be an issue, Dr. Stevenson said. “This drug is very expensive; the majority of patients pay more than $100 a month in out-of-pocket costs, and we have to recognize this is not a therapy that everyone can afford,” she said in an interview. “In many areas, and particularly in the disadvantaged populations, this is not going to be a therapy that we’re going to be able to offer everyone, and that gives me great concern as we move toward trying to treat the whole disease that we’re developing therapies that will be limited by finance rather than by physiology. That’s a major call to action for all of us.”

Novartis sponsored the studies. Dr. McMurray has no disclosures. Dr. Solomon disclosed financial relationships with trial sponsor Novartis along with numerous pharmaceutical companies and the National Heart, Lung, and Blood Institute.

SOURCE: McMurray JJ and Solomon SD. AHA 2019, Late Breaking Science Session 5.

PHILADELPHIA – Two clinical trials of the combination therapy of the neprilysin inhibitor sacubitril and the angiotensin II receptor blocker valsartan in patients with heart failure and reduced ejection fraction found that it lowered rates of all-cause death, compared to a renin-angiotensin-system inhibitor alone.

Furthermore, the treatment produced a more beneficial effect in women, who are more prone to heart failure and preserved ejection fraction (HFpEF), lead investigators reported at the American Heart Association scientific sessions.

A prespecified subgroup analysis of 4,796 patients in the PARAGON-HF trial found that the sacubitril/valsartan, or sac/val, combination had a significantly more beneficial risk reduction of first and recurrent hospitalizations for heart failure, as well as cardiovascular death, in women than men. A prespecified pooled analysis of 13,195 patients in the PARAGON-HF and the PARADIGM-HF trials also found women derived a greater benefit from the combination therapy than men, but also concluded that patients with heart failure and even mildly reduced ejection fraction had better outcomes. The results of both studies were published simultaneously with the presentations on Nov. 17 in Circulation (doi: 10.1161/circulationaha.119.044491; doi: 10.1161/circulationaha.119.044586).

The findings underscore the effectiveness of sac/val combination in patients with HF and EF in the lower ranges, defined as 40% or less, commented discussant Lynne Warner Stevenson, MD, of Vanderbilt Heart and Vascular Institute in Nashville, Tenn. “We all agree now that the use of sacubitril/valsartan is very appropriate to improve outcomes in those patients, even if they’ve never been hospitalized,” she said in an interview.
 

PARAGON-HF subanalysis

John J.V. McMurray, MD, of the University of Glasgow presented the PARAGON-HF subgroup analysis. He said it initially focused on 12 subgroups, but that only two baseline variables showed a modified effect of sac/val: sex and left-ventricle ejection fraction (LVEF). The findings, he said, “stood up in a very robust, multivariable analysis.”

The women in the subgroup analysis were older, had higher baseline New York Heart Association class status, and worse quality of life as measured by Kansas City Cardiomyopathy Questionnaire clinical summary score. At baseline, women also had higher average LVEF (59% vs. 56%), lower N-terminal prohormone brain natriuretic peptide levels, and higher rates of renal dysfunction and chronic kidney disease, but lower incidence of a previous MI and coronary artery disease. Prestudy treatments were similar between the sexes.

In terms of the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – “there was an apparent 27% relative risk reduction in women and no overall effect in men,” Dr. McMurray said of the treatment group. “The difference was driven completely by hospitalizations.” Rates of CV death were similar between the valsartan-only and sac/val groups in both men and women, he said.

In the analysis of LVEF, women in the treatment group seemed to cross over to a heightened risk of hospitalization and CV death at an LVEF in the 60%-65% range, Dr. McMurray said, whereas men made that cross over in the 50%-55% range. “It looks as though women might be getting more benefit from this treatment up to a higher EF than in men,” he said.

However, the differences between men and women did not hold up in the analysis of secondary outcomes. At 8 months, women in the sac/val group had a 0.6-point greater decline than did the valsartan-only patients in KCCQ-CSS score, whereas men on sac/val had a 2.8-point lesser decline than did those on valsartan only. Similar differences were seen between the treatment and valsartan-only groups within the sexes, with women showing a noticeable improvement surpassing the men.

Posttreatment hypotension rates in both sexes were higher in the sac/val groups, and the risk of renal dysfunction was a bit less in both treatment groups. Women in the treatment group had significantly higher rates of angioedema than did the valsartan-only group and men in either group.

“Compared to valsartan, it’s important to say that sacubitril/valsartan seemed to reduce the risk of heart failure and hospitalization more in women than men, but we didn’t find a similar differential for other endpoints,” Dr. McMurray said. “Therefore, we’re not sure this is a real effect or a chance finding. It’s very statistically robust, but it could still be a chance finding.”

A possible explanation could be than men may not be responding to sac/val, or that valsartan alone may be more effective in men than women, he said. “This possible effect modification of sac/val vs. valsartan by sex deserves further investigation,” he said.

PARAGON-HF and PARADIGM-HF pooled analysis

Likewise, the prespecified pooled analysis of the PARADIGM-HF and PARAGON-HF trials found a greater benefit of sac/val in women, according to results presented by Scott D. Solomon, MD, of Brigham and Women’s Hospital in Boston. Where PARAGON-HF compared combination therapy with valsartan 160 mg twice daily alone, PARADIGM-HF used enalapril 10 mg twice daily alone as the comparator renin-angiotensin-system (RAS) inhibitor.

“These data suggest that the therapeutic effect of sacubitril/valsartan vs. RAS inhibition alone appear to extend to patients with heart failure and mildly reduced EF, with therapeutic benefits that extend to a higher left-ventricle EF range in women compared to men,” Dr. Solomon said.

The pooled analysis divided patients into six different EF groups: up to 22.5%, then in 10-point increments from 22.5% to 62.5%, and 62.5% or greater. PARADIGM-HF enrolled patients age 18 years and older, whereas PARAGON-HF involved those aged 50 years and older.

The analysis showed that, as LVEF rates increased across the EF groups, the rates of the primary composite outcome – HF hospitalizations, CV death, and all-cause mortality – decreased, but the decline was greatest for CV death and less so for HF hospitalization. And while rates of all-cause mortality decreased as EF increased, rates of non-CV death increased substantially with increasing LVEF.

“For each of these endpoints, there are significant benefits to sacubitril/valsartan in the pooled analysis, and this includes HF hospitalization, CV death, either total or first events, and all-cause mortality, which was reduced overall by 12% in the combination group,” Dr. Solomon said. That benefit was seen in the first five categories of EF, but all but disappeared in the highest category (at least 62.5%), he said.

At the lower end of the EF spectrum, the effect of sac/val is more pronounced and similar for men and women, Dr. Solomon said. “But as EF goes up, we see an attenuation of that effect in both men and women, but it occurs at a different point,” he said. “Women seem to derive a benefit to a higher ejection fraction than men.” As in Dr. McMurray’s research, the benefit seems to extend to LVEF of 55%-60% in men and 65%-70% in women.

“These findings were driven by an observed benefit in patients with chronic heart failure and LVEF below the normal range,” he said. “The benefit in the EF range above the ranking ‘reduced’ but below normal was driven primarily by reduction in HF hospitalization.”

Dr. Stevenson said that these findings indicate that a previous hospitalization for HF with preserved EF may be a telling marker for the effectiveness of sac/val. “As opposed to the patient who has exertional dyspnea but has never decompensated to the level needing hospitalization, if they have pEF, our current analyses would suggest sac/val may not offer them much benefit,” she said.

In real-world practice, cost would be an issue, Dr. Stevenson said. “This drug is very expensive; the majority of patients pay more than $100 a month in out-of-pocket costs, and we have to recognize this is not a therapy that everyone can afford,” she said in an interview. “In many areas, and particularly in the disadvantaged populations, this is not going to be a therapy that we’re going to be able to offer everyone, and that gives me great concern as we move toward trying to treat the whole disease that we’re developing therapies that will be limited by finance rather than by physiology. That’s a major call to action for all of us.”

Novartis sponsored the studies. Dr. McMurray has no disclosures. Dr. Solomon disclosed financial relationships with trial sponsor Novartis along with numerous pharmaceutical companies and the National Heart, Lung, and Blood Institute.

SOURCE: McMurray JJ and Solomon SD. AHA 2019, Late Breaking Science Session 5.

PHILADELPHIA – Two clinical trials of the combination therapy of the neprilysin inhibitor sacubitril and the angiotensin II receptor blocker valsartan in patients with heart failure and reduced ejection fraction found that it lowered rates of all-cause death, compared to a renin-angiotensin-system inhibitor alone.

Furthermore, the treatment produced a more beneficial effect in women, who are more prone to heart failure and preserved ejection fraction (HFpEF), lead investigators reported at the American Heart Association scientific sessions.

A prespecified subgroup analysis of 4,796 patients in the PARAGON-HF trial found that the sacubitril/valsartan, or sac/val, combination had a significantly more beneficial risk reduction of first and recurrent hospitalizations for heart failure, as well as cardiovascular death, in women than men. A prespecified pooled analysis of 13,195 patients in the PARAGON-HF and the PARADIGM-HF trials also found women derived a greater benefit from the combination therapy than men, but also concluded that patients with heart failure and even mildly reduced ejection fraction had better outcomes. The results of both studies were published simultaneously with the presentations on Nov. 17 in Circulation (doi: 10.1161/circulationaha.119.044491; doi: 10.1161/circulationaha.119.044586).

The findings underscore the effectiveness of sac/val combination in patients with HF and EF in the lower ranges, defined as 40% or less, commented discussant Lynne Warner Stevenson, MD, of Vanderbilt Heart and Vascular Institute in Nashville, Tenn. “We all agree now that the use of sacubitril/valsartan is very appropriate to improve outcomes in those patients, even if they’ve never been hospitalized,” she said in an interview.
 

PARAGON-HF subanalysis

John J.V. McMurray, MD, of the University of Glasgow presented the PARAGON-HF subgroup analysis. He said it initially focused on 12 subgroups, but that only two baseline variables showed a modified effect of sac/val: sex and left-ventricle ejection fraction (LVEF). The findings, he said, “stood up in a very robust, multivariable analysis.”

The women in the subgroup analysis were older, had higher baseline New York Heart Association class status, and worse quality of life as measured by Kansas City Cardiomyopathy Questionnaire clinical summary score. At baseline, women also had higher average LVEF (59% vs. 56%), lower N-terminal prohormone brain natriuretic peptide levels, and higher rates of renal dysfunction and chronic kidney disease, but lower incidence of a previous MI and coronary artery disease. Prestudy treatments were similar between the sexes.

In terms of the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – “there was an apparent 27% relative risk reduction in women and no overall effect in men,” Dr. McMurray said of the treatment group. “The difference was driven completely by hospitalizations.” Rates of CV death were similar between the valsartan-only and sac/val groups in both men and women, he said.

In the analysis of LVEF, women in the treatment group seemed to cross over to a heightened risk of hospitalization and CV death at an LVEF in the 60%-65% range, Dr. McMurray said, whereas men made that cross over in the 50%-55% range. “It looks as though women might be getting more benefit from this treatment up to a higher EF than in men,” he said.

However, the differences between men and women did not hold up in the analysis of secondary outcomes. At 8 months, women in the sac/val group had a 0.6-point greater decline than did the valsartan-only patients in KCCQ-CSS score, whereas men on sac/val had a 2.8-point lesser decline than did those on valsartan only. Similar differences were seen between the treatment and valsartan-only groups within the sexes, with women showing a noticeable improvement surpassing the men.

Posttreatment hypotension rates in both sexes were higher in the sac/val groups, and the risk of renal dysfunction was a bit less in both treatment groups. Women in the treatment group had significantly higher rates of angioedema than did the valsartan-only group and men in either group.

“Compared to valsartan, it’s important to say that sacubitril/valsartan seemed to reduce the risk of heart failure and hospitalization more in women than men, but we didn’t find a similar differential for other endpoints,” Dr. McMurray said. “Therefore, we’re not sure this is a real effect or a chance finding. It’s very statistically robust, but it could still be a chance finding.”

A possible explanation could be than men may not be responding to sac/val, or that valsartan alone may be more effective in men than women, he said. “This possible effect modification of sac/val vs. valsartan by sex deserves further investigation,” he said.

PARAGON-HF and PARADIGM-HF pooled analysis

Likewise, the prespecified pooled analysis of the PARADIGM-HF and PARAGON-HF trials found a greater benefit of sac/val in women, according to results presented by Scott D. Solomon, MD, of Brigham and Women’s Hospital in Boston. Where PARAGON-HF compared combination therapy with valsartan 160 mg twice daily alone, PARADIGM-HF used enalapril 10 mg twice daily alone as the comparator renin-angiotensin-system (RAS) inhibitor.

“These data suggest that the therapeutic effect of sacubitril/valsartan vs. RAS inhibition alone appear to extend to patients with heart failure and mildly reduced EF, with therapeutic benefits that extend to a higher left-ventricle EF range in women compared to men,” Dr. Solomon said.

The pooled analysis divided patients into six different EF groups: up to 22.5%, then in 10-point increments from 22.5% to 62.5%, and 62.5% or greater. PARADIGM-HF enrolled patients age 18 years and older, whereas PARAGON-HF involved those aged 50 years and older.

The analysis showed that, as LVEF rates increased across the EF groups, the rates of the primary composite outcome – HF hospitalizations, CV death, and all-cause mortality – decreased, but the decline was greatest for CV death and less so for HF hospitalization. And while rates of all-cause mortality decreased as EF increased, rates of non-CV death increased substantially with increasing LVEF.

“For each of these endpoints, there are significant benefits to sacubitril/valsartan in the pooled analysis, and this includes HF hospitalization, CV death, either total or first events, and all-cause mortality, which was reduced overall by 12% in the combination group,” Dr. Solomon said. That benefit was seen in the first five categories of EF, but all but disappeared in the highest category (at least 62.5%), he said.

At the lower end of the EF spectrum, the effect of sac/val is more pronounced and similar for men and women, Dr. Solomon said. “But as EF goes up, we see an attenuation of that effect in both men and women, but it occurs at a different point,” he said. “Women seem to derive a benefit to a higher ejection fraction than men.” As in Dr. McMurray’s research, the benefit seems to extend to LVEF of 55%-60% in men and 65%-70% in women.

“These findings were driven by an observed benefit in patients with chronic heart failure and LVEF below the normal range,” he said. “The benefit in the EF range above the ranking ‘reduced’ but below normal was driven primarily by reduction in HF hospitalization.”

Dr. Stevenson said that these findings indicate that a previous hospitalization for HF with preserved EF may be a telling marker for the effectiveness of sac/val. “As opposed to the patient who has exertional dyspnea but has never decompensated to the level needing hospitalization, if they have pEF, our current analyses would suggest sac/val may not offer them much benefit,” she said.

In real-world practice, cost would be an issue, Dr. Stevenson said. “This drug is very expensive; the majority of patients pay more than $100 a month in out-of-pocket costs, and we have to recognize this is not a therapy that everyone can afford,” she said in an interview. “In many areas, and particularly in the disadvantaged populations, this is not going to be a therapy that we’re going to be able to offer everyone, and that gives me great concern as we move toward trying to treat the whole disease that we’re developing therapies that will be limited by finance rather than by physiology. That’s a major call to action for all of us.”

Novartis sponsored the studies. Dr. McMurray has no disclosures. Dr. Solomon disclosed financial relationships with trial sponsor Novartis along with numerous pharmaceutical companies and the National Heart, Lung, and Blood Institute.

SOURCE: McMurray JJ and Solomon SD. AHA 2019, Late Breaking Science Session 5.

PHILADELPHIA – Treatment with the PCSK9 inhibitor alirocumab linked with a significant cut in the rates of peripheral artery disease events and ischemic strokes without increasing the rate of hemorrhagic strokes, and alirocumab treatment also showed a trend toward an association with a reduced rate of venous thromboembolic events in prespecified, ancillary analyses of data collected from more than 18,000 patients in the ODYSSEY Outcomes trial.

Mitchel L. Zoler/MDedge News

The analyses that looked at peripheral artery disease (PAD) events and venous thromboembolism (VTE) events also suggested that the apparent ability of alirocumab to reduce their incidence may have been largely mediated through a reduction in Lp(a) lipoprotein, with less of a contribution from the drug’s primary action of reducing LDL cholesterol, Gregory G. Schwartz, MD, said at the American Heart Association scientific sessions.

When used on top of intensive statin treatment, as in the ODYSSEY Outcomes trial, treatment with the PCSK9 inhibitor alirocumab “may be useful to prevent PAD events, particularly in patients with high levels of Lp(a),” said Dr. Schwartz, professor of medicine at the University of Colorado Denver in Aurora. In the analysis he reported, patients treated with alirocumab for a median of 2.8 years had a statistically significant 31% reduced rate of PAD or VTE event and a significant 31% reduced rate of PAD events alone, compared with control patients who received placebo, he reported. Alirocumab treatment was also associated with a 33% lower rate of VTE events only, but the overall rate of these events was low, and this difference just missed statistical significance with a P value of .06.

“Levels of Lp(a), but not LDL cholesterol, predicted the risk of PAD events,” and in patients on alirocumab treatment “the magnitude of Lp(a) reduction, but not LDL-cholesterol reduction, was associated with a reduction in PAD events and VTE.” The reduction in PAD events linked with alirocumab treatment “may be related to Lp(a) lowering,” Dr. Schwartz suggested.

The link between alirocumab treatment and a reduction in ischemic stroke with no increase in hemorrhagic strokes appeared in a separate prespecified analysis from ODYSSEY Outcomes that looked at the rates of ischemic stroke, hemorrhagic stroke, and their combined incidence during the median 2.8 year of study follow-up. Patients treated with alirocumab had a statistically significant 27% reduction in their rate of ischemic strokes compared with patients on placebo, and a statistically significant 28% relative reduction in the rate of any stroke with alirocumab treatment, J. Wouter Jukema, MD, said in a separate report at the meeting. The rate of hemorrhagic strokes was small, and showed a nominal 17% reduction in patients treated with alirocumab, compared with controls, a difference that was not statistically significant.

Mitchel L. Zoler/MDedge News

Further analysis of the stroke outcomes also showed that these reductions in total strokes occurred with alirocumab treatment at roughly similar rates regardless of baseline level of LDL cholesterol or history of a prior cerebrovascular event. Analysis also showed that the rate of hemorrhagic strokes was consistently low regardless of the on-treatment level of LDL cholesterol. Even among patients whose LDL cholesterol level fell below 25 mg/dL on alirocumab treatment, the incidence of hemorrhagic strokes during follow-up was 0.1%, “a very reassuring finding,” said Dr. Jukema, professor of cardiology at Leiden (The Netherlands) University. The stroke analyses did not examine possible linkages of these effects with changes in level of Lp(a).

ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) included 18,924 patients who had experienced an acute coronary syndrome event within the prior 12 months and had an LDL cholesterol level of at least 70 mg/dL despite maximally tolerated statin treatment and randomized them to treatment with alirocumab or placebo. The primary endpoint was the combination of coronary heart disease death, nonfatal MI, ischemic stroke, and hospitalization for unstable angina, which alirocumab effectively reduced compared with placebo (N Engl J Med. 2018 Nov 29;379[22]:2097-107).

The PAD analysis tallied the combined rate of acute limb ischemia, revascularization, or amputation related to PAD, and the VTE cases included patients who developed deep vein thrombosis or pulmonary embolism. All cases were nonadjudicated reports from participating investigators. Because Lp(a) makes up a portion of LDL cholesterol, Dr. Schwartz and associates calculated adjusted values for LDL cholesterol that were independent of Lp(a).

In a multivariable analysis that adjusted for demographic and clinical characteristics as well as baseline Lp(a) and the calculated level of LDL cholesterol, every 1 mg/dL decrease in Lp(a) linked with a statistically significant, nearly 1% decrease in the rate of either a PAD or VTE event, while the change in LDL cholesterol had no significant relationship with this endpoint, said Dr. Schwartz.

The impact of Lp(a) lowering was most dramatic among the subgroups of patients who entered the study with the highest levels of Lp(a). “In the lowest quartile [for baseline level of Lp(a)] the effect of treatment [with alirocumab] was inconsequential; all of the action was in the upper two quartiles,” he said. Dr. Schwartz highlighted that 90% of patients in the study were on an “intense” statin dosage, and 97% received some statin treatment. Against that treatment background, the findings showed that patients still had residual cardiovascular disease risk that did not appear to respond to changes in LDL cholesterol but which did appear to respond to a reduction in Lp(a) produced by alirocumab. Dr. Schwartz further suggested that alirocumab’s reduction of Lp(a) might also mediate the drug’s apparent effect on reducing VTE incidence, possibly because Lp(a) is structurally similar to plasminogen and hence can have prothrombotic effects.

ODYSSEY Outcomes was sponsored by Sanofi and Regeneron, the companies that market alirocumab (Praluent). Dr. Schwartz has received research support from Sanofi and from Resverlogix, Roche, and The Medicines Company. Dr. Jukema has been a speaker for and received research support from Sanofi Regeneron, and has also been a speaker for Amgen, MSD, and Roche and has also received research support from Biotronik

mzoler@mdedge.com

SOURCE: Schwartz GG et al. AHA 2019, Abstract 309; Jukema JW et al. AHA 2019, Abstract 334.

PHILADELPHIA – Treatment with the PCSK9 inhibitor alirocumab linked with a significant cut in the rates of peripheral artery disease events and ischemic strokes without increasing the rate of hemorrhagic strokes, and alirocumab treatment also showed a trend toward an association with a reduced rate of venous thromboembolic events in prespecified, ancillary analyses of data collected from more than 18,000 patients in the ODYSSEY Outcomes trial.

Mitchel L. Zoler/MDedge News

The analyses that looked at peripheral artery disease (PAD) events and venous thromboembolism (VTE) events also suggested that the apparent ability of alirocumab to reduce their incidence may have been largely mediated through a reduction in Lp(a) lipoprotein, with less of a contribution from the drug’s primary action of reducing LDL cholesterol, Gregory G. Schwartz, MD, said at the American Heart Association scientific sessions.

When used on top of intensive statin treatment, as in the ODYSSEY Outcomes trial, treatment with the PCSK9 inhibitor alirocumab “may be useful to prevent PAD events, particularly in patients with high levels of Lp(a),” said Dr. Schwartz, professor of medicine at the University of Colorado Denver in Aurora. In the analysis he reported, patients treated with alirocumab for a median of 2.8 years had a statistically significant 31% reduced rate of PAD or VTE event and a significant 31% reduced rate of PAD events alone, compared with control patients who received placebo, he reported. Alirocumab treatment was also associated with a 33% lower rate of VTE events only, but the overall rate of these events was low, and this difference just missed statistical significance with a P value of .06.

“Levels of Lp(a), but not LDL cholesterol, predicted the risk of PAD events,” and in patients on alirocumab treatment “the magnitude of Lp(a) reduction, but not LDL-cholesterol reduction, was associated with a reduction in PAD events and VTE.” The reduction in PAD events linked with alirocumab treatment “may be related to Lp(a) lowering,” Dr. Schwartz suggested.

The link between alirocumab treatment and a reduction in ischemic stroke with no increase in hemorrhagic strokes appeared in a separate prespecified analysis from ODYSSEY Outcomes that looked at the rates of ischemic stroke, hemorrhagic stroke, and their combined incidence during the median 2.8 year of study follow-up. Patients treated with alirocumab had a statistically significant 27% reduction in their rate of ischemic strokes compared with patients on placebo, and a statistically significant 28% relative reduction in the rate of any stroke with alirocumab treatment, J. Wouter Jukema, MD, said in a separate report at the meeting. The rate of hemorrhagic strokes was small, and showed a nominal 17% reduction in patients treated with alirocumab, compared with controls, a difference that was not statistically significant.

Mitchel L. Zoler/MDedge News

Further analysis of the stroke outcomes also showed that these reductions in total strokes occurred with alirocumab treatment at roughly similar rates regardless of baseline level of LDL cholesterol or history of a prior cerebrovascular event. Analysis also showed that the rate of hemorrhagic strokes was consistently low regardless of the on-treatment level of LDL cholesterol. Even among patients whose LDL cholesterol level fell below 25 mg/dL on alirocumab treatment, the incidence of hemorrhagic strokes during follow-up was 0.1%, “a very reassuring finding,” said Dr. Jukema, professor of cardiology at Leiden (The Netherlands) University. The stroke analyses did not examine possible linkages of these effects with changes in level of Lp(a).

ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) included 18,924 patients who had experienced an acute coronary syndrome event within the prior 12 months and had an LDL cholesterol level of at least 70 mg/dL despite maximally tolerated statin treatment and randomized them to treatment with alirocumab or placebo. The primary endpoint was the combination of coronary heart disease death, nonfatal MI, ischemic stroke, and hospitalization for unstable angina, which alirocumab effectively reduced compared with placebo (N Engl J Med. 2018 Nov 29;379[22]:2097-107).

The PAD analysis tallied the combined rate of acute limb ischemia, revascularization, or amputation related to PAD, and the VTE cases included patients who developed deep vein thrombosis or pulmonary embolism. All cases were nonadjudicated reports from participating investigators. Because Lp(a) makes up a portion of LDL cholesterol, Dr. Schwartz and associates calculated adjusted values for LDL cholesterol that were independent of Lp(a).

In a multivariable analysis that adjusted for demographic and clinical characteristics as well as baseline Lp(a) and the calculated level of LDL cholesterol, every 1 mg/dL decrease in Lp(a) linked with a statistically significant, nearly 1% decrease in the rate of either a PAD or VTE event, while the change in LDL cholesterol had no significant relationship with this endpoint, said Dr. Schwartz.

The impact of Lp(a) lowering was most dramatic among the subgroups of patients who entered the study with the highest levels of Lp(a). “In the lowest quartile [for baseline level of Lp(a)] the effect of treatment [with alirocumab] was inconsequential; all of the action was in the upper two quartiles,” he said. Dr. Schwartz highlighted that 90% of patients in the study were on an “intense” statin dosage, and 97% received some statin treatment. Against that treatment background, the findings showed that patients still had residual cardiovascular disease risk that did not appear to respond to changes in LDL cholesterol but which did appear to respond to a reduction in Lp(a) produced by alirocumab. Dr. Schwartz further suggested that alirocumab’s reduction of Lp(a) might also mediate the drug’s apparent effect on reducing VTE incidence, possibly because Lp(a) is structurally similar to plasminogen and hence can have prothrombotic effects.

ODYSSEY Outcomes was sponsored by Sanofi and Regeneron, the companies that market alirocumab (Praluent). Dr. Schwartz has received research support from Sanofi and from Resverlogix, Roche, and The Medicines Company. Dr. Jukema has been a speaker for and received research support from Sanofi Regeneron, and has also been a speaker for Amgen, MSD, and Roche and has also received research support from Biotronik

mzoler@mdedge.com

SOURCE: Schwartz GG et al. AHA 2019, Abstract 309; Jukema JW et al. AHA 2019, Abstract 334.

PHILADELPHIA – Treatment with the PCSK9 inhibitor alirocumab linked with a significant cut in the rates of peripheral artery disease events and ischemic strokes without increasing the rate of hemorrhagic strokes, and alirocumab treatment also showed a trend toward an association with a reduced rate of venous thromboembolic events in prespecified, ancillary analyses of data collected from more than 18,000 patients in the ODYSSEY Outcomes trial.

Mitchel L. Zoler/MDedge News

The analyses that looked at peripheral artery disease (PAD) events and venous thromboembolism (VTE) events also suggested that the apparent ability of alirocumab to reduce their incidence may have been largely mediated through a reduction in Lp(a) lipoprotein, with less of a contribution from the drug’s primary action of reducing LDL cholesterol, Gregory G. Schwartz, MD, said at the American Heart Association scientific sessions.

When used on top of intensive statin treatment, as in the ODYSSEY Outcomes trial, treatment with the PCSK9 inhibitor alirocumab “may be useful to prevent PAD events, particularly in patients with high levels of Lp(a),” said Dr. Schwartz, professor of medicine at the University of Colorado Denver in Aurora. In the analysis he reported, patients treated with alirocumab for a median of 2.8 years had a statistically significant 31% reduced rate of PAD or VTE event and a significant 31% reduced rate of PAD events alone, compared with control patients who received placebo, he reported. Alirocumab treatment was also associated with a 33% lower rate of VTE events only, but the overall rate of these events was low, and this difference just missed statistical significance with a P value of .06.

“Levels of Lp(a), but not LDL cholesterol, predicted the risk of PAD events,” and in patients on alirocumab treatment “the magnitude of Lp(a) reduction, but not LDL-cholesterol reduction, was associated with a reduction in PAD events and VTE.” The reduction in PAD events linked with alirocumab treatment “may be related to Lp(a) lowering,” Dr. Schwartz suggested.

The link between alirocumab treatment and a reduction in ischemic stroke with no increase in hemorrhagic strokes appeared in a separate prespecified analysis from ODYSSEY Outcomes that looked at the rates of ischemic stroke, hemorrhagic stroke, and their combined incidence during the median 2.8 year of study follow-up. Patients treated with alirocumab had a statistically significant 27% reduction in their rate of ischemic strokes compared with patients on placebo, and a statistically significant 28% relative reduction in the rate of any stroke with alirocumab treatment, J. Wouter Jukema, MD, said in a separate report at the meeting. The rate of hemorrhagic strokes was small, and showed a nominal 17% reduction in patients treated with alirocumab, compared with controls, a difference that was not statistically significant.

Mitchel L. Zoler/MDedge News

Further analysis of the stroke outcomes also showed that these reductions in total strokes occurred with alirocumab treatment at roughly similar rates regardless of baseline level of LDL cholesterol or history of a prior cerebrovascular event. Analysis also showed that the rate of hemorrhagic strokes was consistently low regardless of the on-treatment level of LDL cholesterol. Even among patients whose LDL cholesterol level fell below 25 mg/dL on alirocumab treatment, the incidence of hemorrhagic strokes during follow-up was 0.1%, “a very reassuring finding,” said Dr. Jukema, professor of cardiology at Leiden (The Netherlands) University. The stroke analyses did not examine possible linkages of these effects with changes in level of Lp(a).

ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) included 18,924 patients who had experienced an acute coronary syndrome event within the prior 12 months and had an LDL cholesterol level of at least 70 mg/dL despite maximally tolerated statin treatment and randomized them to treatment with alirocumab or placebo. The primary endpoint was the combination of coronary heart disease death, nonfatal MI, ischemic stroke, and hospitalization for unstable angina, which alirocumab effectively reduced compared with placebo (N Engl J Med. 2018 Nov 29;379[22]:2097-107).

The PAD analysis tallied the combined rate of acute limb ischemia, revascularization, or amputation related to PAD, and the VTE cases included patients who developed deep vein thrombosis or pulmonary embolism. All cases were nonadjudicated reports from participating investigators. Because Lp(a) makes up a portion of LDL cholesterol, Dr. Schwartz and associates calculated adjusted values for LDL cholesterol that were independent of Lp(a).

In a multivariable analysis that adjusted for demographic and clinical characteristics as well as baseline Lp(a) and the calculated level of LDL cholesterol, every 1 mg/dL decrease in Lp(a) linked with a statistically significant, nearly 1% decrease in the rate of either a PAD or VTE event, while the change in LDL cholesterol had no significant relationship with this endpoint, said Dr. Schwartz.

The impact of Lp(a) lowering was most dramatic among the subgroups of patients who entered the study with the highest levels of Lp(a). “In the lowest quartile [for baseline level of Lp(a)] the effect of treatment [with alirocumab] was inconsequential; all of the action was in the upper two quartiles,” he said. Dr. Schwartz highlighted that 90% of patients in the study were on an “intense” statin dosage, and 97% received some statin treatment. Against that treatment background, the findings showed that patients still had residual cardiovascular disease risk that did not appear to respond to changes in LDL cholesterol but which did appear to respond to a reduction in Lp(a) produced by alirocumab. Dr. Schwartz further suggested that alirocumab’s reduction of Lp(a) might also mediate the drug’s apparent effect on reducing VTE incidence, possibly because Lp(a) is structurally similar to plasminogen and hence can have prothrombotic effects.

ODYSSEY Outcomes was sponsored by Sanofi and Regeneron, the companies that market alirocumab (Praluent). Dr. Schwartz has received research support from Sanofi and from Resverlogix, Roche, and The Medicines Company. Dr. Jukema has been a speaker for and received research support from Sanofi Regeneron, and has also been a speaker for Amgen, MSD, and Roche and has also received research support from Biotronik

mzoler@mdedge.com

SOURCE: Schwartz GG et al. AHA 2019, Abstract 309; Jukema JW et al. AHA 2019, Abstract 334.

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

Persons who trained for a marathon showed improvement in age-related aortic stiffness and reduction in blood pressure in a study of 138 first-time completers of the London Marathon.

Pavel1964/Getty Images

Compared with pretraining values, the descending aortas of marathon completers were 9% more distensible at the level of the bifurcation of the pulmonary artery and 16% more distensible at the level of the diaphragm (P = .0009 and .002, respectively). There was no change in distensibility of the ascending aorta.

Additionally, central systolic BP dropped by 4 mm Hg and diastolic BP by 3 mm Hg by the time marathon training was completed.

“Training and completion of a first-time marathon result in beneficial reductions in BP and intrinsic aortic stiffening in healthy participants,” concluded Anish Bhuva, MBBS, and coinvestigators. “These changes are equivalent to approximately a 4-year reduction in vascular age.”

The study points to a role for exercise in the reduction of arterial stiffness, a known aging-related contributor to cardiovascular disease for which there currently is no good pharmacologic option, said Julio Chirinos, MD, Phd, in an accompanying editorial (J Am Coll Cardiol. 2020 Jan 6. doi: 10.1016/j.jacc.2019.11.007). The challenge lies in implementing exercise interventions on a large scale in societies where “there remains an immense paradoxical gap” between the known benefits of physical activity and increasingly sedentary populations, he added, calling for increased implementation research.

Using cardiovascular magnetic resonance to assess aortic distensibility, Dr. Bhuva, of the Institute of Cardiovascular Science, University College London, and colleagues assessed aortic BP and aortic stiffness at two points via the noninvasive imaging method. The first assessment was conducted before the study participants began marathon training; the second was obtained between 1 and 3 weeks after marathon completion, after any acute effects of the marathon had abated.

Anthropometric data, peripheral BP, and aerobic capacity (peak VO₂) were also assessed at both study points.

Although the study wasn’t designed to track individual training regimens, first-time London Marathon participants were given a 17-week “Beginner’s Training Plan” by event organizers, and asked to follow the plan while participating in the study. The goal of the beginner’s plan was marathon completion, with a schedule of about three runs weekly increasing in duration and intensity over the training period.

Participants had to be first-time marathon participants and running less than 2 hours per week at enrollment. Only those who completed the marathon were included in the data analysis, though baseline characteristics didn’t differ between completers and those who dropped out.

For 2016, the first study year, only participants aged 18-39 years were included, while in 2017, all ages were included in the study. The final age range was 21-69 years, with a mean age of 37; 51% of participants were female. Those with a history of hypertension or taking antihypertensive medication and those who had other significant medical conditions were excluded.

The differential increase in distensibility along the length of the aorta reflects known differences in tissue composition, agreed the authors and Dr. Chirinos, a cardiologist at the University of Pennsylvania, Philadelphia. In addition to the magnetic resonance–obtained distensibility measurements, the investigators conducted further calculations to adjust for baseline mean central arterial pressure, since arterial stiffness is a function both of intrinsic tissue characteristics and loading conditions.

In youth, aortic distensibility buffers the effect of pulse pressure on both the left ventricle and the peripheral vascular system. As the aorta and other large arteries stiffen predictably with age, isolated systolic hypertension can result. The stiffening “also favors adverse patterns of pulsatile left ventricular overload,” which can lead to left ventricular remodeling and, eventually, heart failure, noted Dr. Chirinos. Reduced aortic pliancy also allows pulse pressure variation to be transmitted downstream “into the microvasculature of target organs (such as the kidney and brain) that require high blood flow and thus operate at low arteriolar resistance,” he added.

The assessment that marathon training reversed aortic age by a median 3.9 years was derived from the baseline cross-sectional data regarding participants’ age and aortic stiffness. The effect size was largest in those older than 37 years and in those with higher baseline systolic BP, and men saw greater benefit by a median 1.4 years. Those with slower running times also saw greater benefit.

Study participants had small but significant reductions in heart rate, body fat percentage, and weight by the postmarathon assessment, but these differences were not associated with changes in aortic stiffness. Aerobic exercise capacity as measured by peak VO₂ didn’t change significantly from pre- to post training, but the fact that participants were semirecumbent during exercise testing (to allow concurrent echocardiography) may have affected results.

The real-world design of this study had the strengths of assessing free-living, healthy individuals who participated in a self-directed training plan. Dr. Bhuva and coauthors acknowledged that marathon training may include changes in diet, sleep, and other potentially confounding lifestyle factors, as well as improvement in lipid and glucose metabolism. Further, noted Dr. Chirinos, there was no control group. Also, results from individuals training for an endurance event may have limited generalizability to the general population.

Still, said Dr. Chirinos, the innovative study design took advantage of a large-scale athletic event to see how a realistic training regimen affected healthy individuals. “Perhaps the contemporary marathon can teach us some lessons about exploiting the confluence of interests of the general public, media, industry, scientific community, and government to accomplish worthy goals at the individual and societal levels.”

The study was funded by the British Heart Foundation, Cardiac Risk in the Young, and the Barts Cardiovascular Biomedical Research Centre. Exercise testing equipment and technical support were provided by COSMED. Dr. Bhuva reported receiving funding from the British Heart Foundation. Dr. Chirinos reported having been a consultant or receiving research funding from multiple pharmaceutical companies and Microsoft; he is also an inventor of University of Pennsylvania–held patents for cardiovascular pharmaceutical agents.

koakes@mdedge.com

SOURCE: Bhuva A et al. J Am Coll Cardiol. 2020 Jan;75(1):60-71.

Persons who trained for a marathon showed improvement in age-related aortic stiffness and reduction in blood pressure in a study of 138 first-time completers of the London Marathon.

Pavel1964/Getty Images

Compared with pretraining values, the descending aortas of marathon completers were 9% more distensible at the level of the bifurcation of the pulmonary artery and 16% more distensible at the level of the diaphragm (P = .0009 and .002, respectively). There was no change in distensibility of the ascending aorta.

Additionally, central systolic BP dropped by 4 mm Hg and diastolic BP by 3 mm Hg by the time marathon training was completed.

“Training and completion of a first-time marathon result in beneficial reductions in BP and intrinsic aortic stiffening in healthy participants,” concluded Anish Bhuva, MBBS, and coinvestigators. “These changes are equivalent to approximately a 4-year reduction in vascular age.”

The study points to a role for exercise in the reduction of arterial stiffness, a known aging-related contributor to cardiovascular disease for which there currently is no good pharmacologic option, said Julio Chirinos, MD, Phd, in an accompanying editorial (J Am Coll Cardiol. 2020 Jan 6. doi: 10.1016/j.jacc.2019.11.007). The challenge lies in implementing exercise interventions on a large scale in societies where “there remains an immense paradoxical gap” between the known benefits of physical activity and increasingly sedentary populations, he added, calling for increased implementation research.

Using cardiovascular magnetic resonance to assess aortic distensibility, Dr. Bhuva, of the Institute of Cardiovascular Science, University College London, and colleagues assessed aortic BP and aortic stiffness at two points via the noninvasive imaging method. The first assessment was conducted before the study participants began marathon training; the second was obtained between 1 and 3 weeks after marathon completion, after any acute effects of the marathon had abated.

Anthropometric data, peripheral BP, and aerobic capacity (peak VO₂) were also assessed at both study points.

Although the study wasn’t designed to track individual training regimens, first-time London Marathon participants were given a 17-week “Beginner’s Training Plan” by event organizers, and asked to follow the plan while participating in the study. The goal of the beginner’s plan was marathon completion, with a schedule of about three runs weekly increasing in duration and intensity over the training period.

Participants had to be first-time marathon participants and running less than 2 hours per week at enrollment. Only those who completed the marathon were included in the data analysis, though baseline characteristics didn’t differ between completers and those who dropped out.

For 2016, the first study year, only participants aged 18-39 years were included, while in 2017, all ages were included in the study. The final age range was 21-69 years, with a mean age of 37; 51% of participants were female. Those with a history of hypertension or taking antihypertensive medication and those who had other significant medical conditions were excluded.

The differential increase in distensibility along the length of the aorta reflects known differences in tissue composition, agreed the authors and Dr. Chirinos, a cardiologist at the University of Pennsylvania, Philadelphia. In addition to the magnetic resonance–obtained distensibility measurements, the investigators conducted further calculations to adjust for baseline mean central arterial pressure, since arterial stiffness is a function both of intrinsic tissue characteristics and loading conditions.

In youth, aortic distensibility buffers the effect of pulse pressure on both the left ventricle and the peripheral vascular system. As the aorta and other large arteries stiffen predictably with age, isolated systolic hypertension can result. The stiffening “also favors adverse patterns of pulsatile left ventricular overload,” which can lead to left ventricular remodeling and, eventually, heart failure, noted Dr. Chirinos. Reduced aortic pliancy also allows pulse pressure variation to be transmitted downstream “into the microvasculature of target organs (such as the kidney and brain) that require high blood flow and thus operate at low arteriolar resistance,” he added.

The assessment that marathon training reversed aortic age by a median 3.9 years was derived from the baseline cross-sectional data regarding participants’ age and aortic stiffness. The effect size was largest in those older than 37 years and in those with higher baseline systolic BP, and men saw greater benefit by a median 1.4 years. Those with slower running times also saw greater benefit.

Study participants had small but significant reductions in heart rate, body fat percentage, and weight by the postmarathon assessment, but these differences were not associated with changes in aortic stiffness. Aerobic exercise capacity as measured by peak VO₂ didn’t change significantly from pre- to post training, but the fact that participants were semirecumbent during exercise testing (to allow concurrent echocardiography) may have affected results.

The real-world design of this study had the strengths of assessing free-living, healthy individuals who participated in a self-directed training plan. Dr. Bhuva and coauthors acknowledged that marathon training may include changes in diet, sleep, and other potentially confounding lifestyle factors, as well as improvement in lipid and glucose metabolism. Further, noted Dr. Chirinos, there was no control group. Also, results from individuals training for an endurance event may have limited generalizability to the general population.

Still, said Dr. Chirinos, the innovative study design took advantage of a large-scale athletic event to see how a realistic training regimen affected healthy individuals. “Perhaps the contemporary marathon can teach us some lessons about exploiting the confluence of interests of the general public, media, industry, scientific community, and government to accomplish worthy goals at the individual and societal levels.”

The study was funded by the British Heart Foundation, Cardiac Risk in the Young, and the Barts Cardiovascular Biomedical Research Centre. Exercise testing equipment and technical support were provided by COSMED. Dr. Bhuva reported receiving funding from the British Heart Foundation. Dr. Chirinos reported having been a consultant or receiving research funding from multiple pharmaceutical companies and Microsoft; he is also an inventor of University of Pennsylvania–held patents for cardiovascular pharmaceutical agents.

koakes@mdedge.com

SOURCE: Bhuva A et al. J Am Coll Cardiol. 2020 Jan;75(1):60-71.

Persons who trained for a marathon showed improvement in age-related aortic stiffness and reduction in blood pressure in a study of 138 first-time completers of the London Marathon.

Pavel1964/Getty Images

Compared with pretraining values, the descending aortas of marathon completers were 9% more distensible at the level of the bifurcation of the pulmonary artery and 16% more distensible at the level of the diaphragm (P = .0009 and .002, respectively). There was no change in distensibility of the ascending aorta.

Additionally, central systolic BP dropped by 4 mm Hg and diastolic BP by 3 mm Hg by the time marathon training was completed.

“Training and completion of a first-time marathon result in beneficial reductions in BP and intrinsic aortic stiffening in healthy participants,” concluded Anish Bhuva, MBBS, and coinvestigators. “These changes are equivalent to approximately a 4-year reduction in vascular age.”

The study points to a role for exercise in the reduction of arterial stiffness, a known aging-related contributor to cardiovascular disease for which there currently is no good pharmacologic option, said Julio Chirinos, MD, Phd, in an accompanying editorial (J Am Coll Cardiol. 2020 Jan 6. doi: 10.1016/j.jacc.2019.11.007). The challenge lies in implementing exercise interventions on a large scale in societies where “there remains an immense paradoxical gap” between the known benefits of physical activity and increasingly sedentary populations, he added, calling for increased implementation research.

Using cardiovascular magnetic resonance to assess aortic distensibility, Dr. Bhuva, of the Institute of Cardiovascular Science, University College London, and colleagues assessed aortic BP and aortic stiffness at two points via the noninvasive imaging method. The first assessment was conducted before the study participants began marathon training; the second was obtained between 1 and 3 weeks after marathon completion, after any acute effects of the marathon had abated.

Anthropometric data, peripheral BP, and aerobic capacity (peak VO₂) were also assessed at both study points.

Although the study wasn’t designed to track individual training regimens, first-time London Marathon participants were given a 17-week “Beginner’s Training Plan” by event organizers, and asked to follow the plan while participating in the study. The goal of the beginner’s plan was marathon completion, with a schedule of about three runs weekly increasing in duration and intensity over the training period.

Participants had to be first-time marathon participants and running less than 2 hours per week at enrollment. Only those who completed the marathon were included in the data analysis, though baseline characteristics didn’t differ between completers and those who dropped out.

For 2016, the first study year, only participants aged 18-39 years were included, while in 2017, all ages were included in the study. The final age range was 21-69 years, with a mean age of 37; 51% of participants were female. Those with a history of hypertension or taking antihypertensive medication and those who had other significant medical conditions were excluded.

The differential increase in distensibility along the length of the aorta reflects known differences in tissue composition, agreed the authors and Dr. Chirinos, a cardiologist at the University of Pennsylvania, Philadelphia. In addition to the magnetic resonance–obtained distensibility measurements, the investigators conducted further calculations to adjust for baseline mean central arterial pressure, since arterial stiffness is a function both of intrinsic tissue characteristics and loading conditions.

In youth, aortic distensibility buffers the effect of pulse pressure on both the left ventricle and the peripheral vascular system. As the aorta and other large arteries stiffen predictably with age, isolated systolic hypertension can result. The stiffening “also favors adverse patterns of pulsatile left ventricular overload,” which can lead to left ventricular remodeling and, eventually, heart failure, noted Dr. Chirinos. Reduced aortic pliancy also allows pulse pressure variation to be transmitted downstream “into the microvasculature of target organs (such as the kidney and brain) that require high blood flow and thus operate at low arteriolar resistance,” he added.

The assessment that marathon training reversed aortic age by a median 3.9 years was derived from the baseline cross-sectional data regarding participants’ age and aortic stiffness. The effect size was largest in those older than 37 years and in those with higher baseline systolic BP, and men saw greater benefit by a median 1.4 years. Those with slower running times also saw greater benefit.

Study participants had small but significant reductions in heart rate, body fat percentage, and weight by the postmarathon assessment, but these differences were not associated with changes in aortic stiffness. Aerobic exercise capacity as measured by peak VO₂ didn’t change significantly from pre- to post training, but the fact that participants were semirecumbent during exercise testing (to allow concurrent echocardiography) may have affected results.

The real-world design of this study had the strengths of assessing free-living, healthy individuals who participated in a self-directed training plan. Dr. Bhuva and coauthors acknowledged that marathon training may include changes in diet, sleep, and other potentially confounding lifestyle factors, as well as improvement in lipid and glucose metabolism. Further, noted Dr. Chirinos, there was no control group. Also, results from individuals training for an endurance event may have limited generalizability to the general population.

Still, said Dr. Chirinos, the innovative study design took advantage of a large-scale athletic event to see how a realistic training regimen affected healthy individuals. “Perhaps the contemporary marathon can teach us some lessons about exploiting the confluence of interests of the general public, media, industry, scientific community, and government to accomplish worthy goals at the individual and societal levels.”

The study was funded by the British Heart Foundation, Cardiac Risk in the Young, and the Barts Cardiovascular Biomedical Research Centre. Exercise testing equipment and technical support were provided by COSMED. Dr. Bhuva reported receiving funding from the British Heart Foundation. Dr. Chirinos reported having been a consultant or receiving research funding from multiple pharmaceutical companies and Microsoft; he is also an inventor of University of Pennsylvania–held patents for cardiovascular pharmaceutical agents.

koakes@mdedge.com

SOURCE: Bhuva A et al. J Am Coll Cardiol. 2020 Jan;75(1):60-71.

PHILADELPHIA – The American Heart Association and American College of Cardiology took a big step toward facilitating widespread U.S. application of the hypertension management guideline that the societies issued in 2017 by releasing a set of performance and quality measures for adults with high blood pressure based on the 2017 guideline.

Mitchel L. Zoler/MDedge News

This guideline notably set a treatment target for patients diagnosed with hypertension of less than 130/80 mg/dL, and also lowered the threshold for diagnosing stage 1 hypertension to a blood pressure at or above 130/80 mm Hg, adding in a stroke about 31 million adults with hypertension to the U.S. total.

Having performance and quality measures based on the guideline is “critical, because how else would you know whether you’re having an effect on accurately diagnosing and properly controlling hypertension?” said Donald E. Casey Jr., MD, chair of the performance measures writing committee. The next step is field testing of the measures “to show they are reliable and effective,” as well as other steps to encourage widespread U.S. uptake of the performance and quality measures and the specifics of the 2017 guideline, Dr. Casey said during a presentation of the revised measures at the American Heart Association scientific sessions.

He especially highlighted the important role of Target: BP, an education, recognition, and quality improvement program run by the AHA and American Medical Association, as a tool that medical practices, health systems, and even payers and employers can use to begin to apply the new performance and quality measures (J Am Coll Cardiol. 2019 Nov 26;74[21]:2661-706) and better align with the recommendations of the 2017 high blood pressure guideline (J Am Coll Cardiol. 2018 May;71[19]:e127-248).

“We’re trying now to promote Target: BP; it’s something you can take off the shelf and get going if it’s embedded in a real-life delivery model. I think Target: BP is the secret sauce. It will be the way we’ll convince people to adopt this,” said Dr. Casey, principal and founder of IPO 4 Health, a Chicago-based health care consulting firm.

He also advised practices and health systems not to feel compelled to introduce all of the specific performance and quality measures at once. “We don’t believe everyone has the resources to do all of it at once; the point is to move toward this system of care. We understand that people don’t have the resources to get it all done” immediately, Dr. Casey said in an interview.

Mitchel L. Zoler/MDedge News

A report during another session at the meeting documented the potential impact that Target: BP can have on blood pressure control within a health system. The Trinity Health of New England medical group based in Springfield, Mass., a system with about 140,000 patients – including 20,000 adults diagnosed with hypertension – and served by 230 health care providers in 13 offices in western Massachusetts, began using Target: BP’s MAP improvement program in its practices in November 2018. (MAP stands for measure accurately, act rapidly, and partner with patients.) Just before the MAP program began, 72% of patients diagnosed with hypertension in the medical group were at their goal blood pressure. Less than a year later, in September 2019, the hypertension control rate had jumped to 84%, a 12 percentage point improvement in control in practices that already had been doing a relatively good job, said Daniel W. Weiswasser, MD, director of quality and clinical informatics at Trinity Health of New England. Based on this success, Trinity Health plans to next involve the remaining regions of Trinity Health of New England in Target: BP, followed by the other regions of Trinity’s national organization, which operates in 21 states with nearly 4,000 staff physicians and about half a million patients diagnosed with hypertension, Dr. Weiswasser said.

Mitchel L. Zoler/MDedge News

“If clinicians do the three steps of the MAP then we will see substantial drops in blood pressures. It will occur,” declared Brent M. Egan, MD, vice president for cardiovascular disease prevention of the AMA in Greenville, S.C.

The new report includes six performance measures based on the strongest guideline recommendations and designed to document adherence levels for the purposes of public reporting and pay-for-performance programs. It also includes 16 quality measures designed for local quality review purposes, with 6 process quality measures and 10 structural quality measures. The report spells out that the authors designed the performance measures for use by major national organizations such as the Centers for Medicare & Medicaid Services and the National Committee for Quality Assurance (NCQA), while the quality measures are designed to support quality improvement efforts in any care-delivery setting.

The authors said that the writing committee is sensitive to the fact that the 2019 performance measures for controlling high blood pressure developed by the NCQA for the Healthcare Effectiveness Data and Information Set and currently in use in 2019 by CMS also does not incorporate the 2017 Hypertension Clinical Practice Guidelines classification scheme. “It is well understood that these measures are already in widespread use, especially for quality-related payment programs promulgated by CMS, such as the Medicare Advantage ‘Stars’ ratings, the Medicare Shared Savings Program, and the Physician Quality Payment Program, as well as many other programs promoted by commercial health insurers. In particular, the widespread use of the 2017 Hypertension Clinical Practice Guidelines classification scheme will also help to guide decision making about when to prescribe antihypertensive medications in accordance with its current recommendations for the ACC/AHA “stages” of stage 1 and stage 2 hypertension and elevated blood pressure,” they added.

The report also says that “the writing committee was sensitive to the fact that there is currently not complete consensus among other guidelines from the American College of Physicians and the American Academy of Family Physicians, and also the European Society of Cardiology and the European Society of Hypertension. Nonetheless, despite this ongoing debate, the writing committee felt strongly that it is now time to move the U.S. health care system ahead to reflect these differing points of view and expects that widespread use of this new measure set will help to achieve this goal.” The new report revises hypertension performance measures developed by the ACC and AHA in 2011 (J Am Coll Cardiol. 2011 Jul 12;58[3]: 316-36).

In short, the performance and quality measures give all the diverse components of the U.S. health care delivery system a road map for implementing the 2017 High Blood Pressure Guideline in a format that depends on those components electing to adopt and adhere to the 2017 guideline. (Although one of the new performance measures, 1a, harmonizes with an existing and widely applied performance measure.)

“Who is the audience for this, and how will they respond? These performance measures need to be appropriated” by health systems and by performance-assessment groups. “I hope the NCQA will adopt it,” said William C. Cushman, MD, professor of preventive medicine at the University of Tennessee Health Science Center in Memphis, and chief of preventive medicine at the Memphis Veterans Affairs Medical Center. “There are some negatives to performance measures, but on balance they have done good things and led to better care.” Dr. Cushman also approved of several specific performance and quality measures included in the report. “Most of what they emphasized is good,” particularly the importance of accurate pressure measurement, he said in an interview.

“Process drives outcomes” in hypertension management, and the new performance and quality measures “have some very good process metrics,” commented Dr. Egan. “I’d encourage health systems to select two or three measures that are key to what they do and make sense in their setting rather than try to implement it all at once,” he advised, echoing what Dr. Casey had suggested. “It’s ideal to do everything, but we know that if you give physicians a long list of performance measures they just get overwhelmed. The nice thing about hypertension is that we know that process drives outcomes. In the past, we’ve had some process metrics that did not drive outcomes. Getting these processes implemented will lead to better patient outcomes and save a ton of money.”

Mitchel L. Zoler/MDedge News

“We have introduced the 2017 guideline recommendations throughout Target: BP, but like any quality improvement program there is a question of how does it spread,” said Gregory Wozniak, PhD, director of outcomes analytics for the AMA in Chicago. “Our goal for Target: BP is to be impacting 20 million patients by 2021.”

Dr. Casey, Dr. Weiswasser, and Dr. Wozniak had no disclosures. Dr. Cushman has received honoraria as a speaker from Arbor and Sanofi-Aventis, and travel and research support from Eli Lilly. Dr. Egan has been a consultant to and speaker on behalf of Merck and a speaker for Emcure.

mzoler@mdedge.com

SOURCE: Casey DE et al. J Am Coll Cardiol. 2019 Nov 26;74[21]: 2661-706.

PHILADELPHIA – The American Heart Association and American College of Cardiology took a big step toward facilitating widespread U.S. application of the hypertension management guideline that the societies issued in 2017 by releasing a set of performance and quality measures for adults with high blood pressure based on the 2017 guideline.

Mitchel L. Zoler/MDedge News

This guideline notably set a treatment target for patients diagnosed with hypertension of less than 130/80 mg/dL, and also lowered the threshold for diagnosing stage 1 hypertension to a blood pressure at or above 130/80 mm Hg, adding in a stroke about 31 million adults with hypertension to the U.S. total.

Having performance and quality measures based on the guideline is “critical, because how else would you know whether you’re having an effect on accurately diagnosing and properly controlling hypertension?” said Donald E. Casey Jr., MD, chair of the performance measures writing committee. The next step is field testing of the measures “to show they are reliable and effective,” as well as other steps to encourage widespread U.S. uptake of the performance and quality measures and the specifics of the 2017 guideline, Dr. Casey said during a presentation of the revised measures at the American Heart Association scientific sessions.

He especially highlighted the important role of Target: BP, an education, recognition, and quality improvement program run by the AHA and American Medical Association, as a tool that medical practices, health systems, and even payers and employers can use to begin to apply the new performance and quality measures (J Am Coll Cardiol. 2019 Nov 26;74[21]:2661-706) and better align with the recommendations of the 2017 high blood pressure guideline (J Am Coll Cardiol. 2018 May;71[19]:e127-248).

“We’re trying now to promote Target: BP; it’s something you can take off the shelf and get going if it’s embedded in a real-life delivery model. I think Target: BP is the secret sauce. It will be the way we’ll convince people to adopt this,” said Dr. Casey, principal and founder of IPO 4 Health, a Chicago-based health care consulting firm.

He also advised practices and health systems not to feel compelled to introduce all of the specific performance and quality measures at once. “We don’t believe everyone has the resources to do all of it at once; the point is to move toward this system of care. We understand that people don’t have the resources to get it all done” immediately, Dr. Casey said in an interview.

Mitchel L. Zoler/MDedge News

A report during another session at the meeting documented the potential impact that Target: BP can have on blood pressure control within a health system. The Trinity Health of New England medical group based in Springfield, Mass., a system with about 140,000 patients – including 20,000 adults diagnosed with hypertension – and served by 230 health care providers in 13 offices in western Massachusetts, began using Target: BP’s MAP improvement program in its practices in November 2018. (MAP stands for measure accurately, act rapidly, and partner with patients.) Just before the MAP program began, 72% of patients diagnosed with hypertension in the medical group were at their goal blood pressure. Less than a year later, in September 2019, the hypertension control rate had jumped to 84%, a 12 percentage point improvement in control in practices that already had been doing a relatively good job, said Daniel W. Weiswasser, MD, director of quality and clinical informatics at Trinity Health of New England. Based on this success, Trinity Health plans to next involve the remaining regions of Trinity Health of New England in Target: BP, followed by the other regions of Trinity’s national organization, which operates in 21 states with nearly 4,000 staff physicians and about half a million patients diagnosed with hypertension, Dr. Weiswasser said.

Mitchel L. Zoler/MDedge News

“If clinicians do the three steps of the MAP then we will see substantial drops in blood pressures. It will occur,” declared Brent M. Egan, MD, vice president for cardiovascular disease prevention of the AMA in Greenville, S.C.

The new report includes six performance measures based on the strongest guideline recommendations and designed to document adherence levels for the purposes of public reporting and pay-for-performance programs. It also includes 16 quality measures designed for local quality review purposes, with 6 process quality measures and 10 structural quality measures. The report spells out that the authors designed the performance measures for use by major national organizations such as the Centers for Medicare & Medicaid Services and the National Committee for Quality Assurance (NCQA), while the quality measures are designed to support quality improvement efforts in any care-delivery setting.

The authors said that the writing committee is sensitive to the fact that the 2019 performance measures for controlling high blood pressure developed by the NCQA for the Healthcare Effectiveness Data and Information Set and currently in use in 2019 by CMS also does not incorporate the 2017 Hypertension Clinical Practice Guidelines classification scheme. “It is well understood that these measures are already in widespread use, especially for quality-related payment programs promulgated by CMS, such as the Medicare Advantage ‘Stars’ ratings, the Medicare Shared Savings Program, and the Physician Quality Payment Program, as well as many other programs promoted by commercial health insurers. In particular, the widespread use of the 2017 Hypertension Clinical Practice Guidelines classification scheme will also help to guide decision making about when to prescribe antihypertensive medications in accordance with its current recommendations for the ACC/AHA “stages” of stage 1 and stage 2 hypertension and elevated blood pressure,” they added.

The report also says that “the writing committee was sensitive to the fact that there is currently not complete consensus among other guidelines from the American College of Physicians and the American Academy of Family Physicians, and also the European Society of Cardiology and the European Society of Hypertension. Nonetheless, despite this ongoing debate, the writing committee felt strongly that it is now time to move the U.S. health care system ahead to reflect these differing points of view and expects that widespread use of this new measure set will help to achieve this goal.” The new report revises hypertension performance measures developed by the ACC and AHA in 2011 (J Am Coll Cardiol. 2011 Jul 12;58[3]: 316-36).

In short, the performance and quality measures give all the diverse components of the U.S. health care delivery system a road map for implementing the 2017 High Blood Pressure Guideline in a format that depends on those components electing to adopt and adhere to the 2017 guideline. (Although one of the new performance measures, 1a, harmonizes with an existing and widely applied performance measure.)

“Who is the audience for this, and how will they respond? These performance measures need to be appropriated” by health systems and by performance-assessment groups. “I hope the NCQA will adopt it,” said William C. Cushman, MD, professor of preventive medicine at the University of Tennessee Health Science Center in Memphis, and chief of preventive medicine at the Memphis Veterans Affairs Medical Center. “There are some negatives to performance measures, but on balance they have done good things and led to better care.” Dr. Cushman also approved of several specific performance and quality measures included in the report. “Most of what they emphasized is good,” particularly the importance of accurate pressure measurement, he said in an interview.

“Process drives outcomes” in hypertension management, and the new performance and quality measures “have some very good process metrics,” commented Dr. Egan. “I’d encourage health systems to select two or three measures that are key to what they do and make sense in their setting rather than try to implement it all at once,” he advised, echoing what Dr. Casey had suggested. “It’s ideal to do everything, but we know that if you give physicians a long list of performance measures they just get overwhelmed. The nice thing about hypertension is that we know that process drives outcomes. In the past, we’ve had some process metrics that did not drive outcomes. Getting these processes implemented will lead to better patient outcomes and save a ton of money.”

Mitchel L. Zoler/MDedge News

“We have introduced the 2017 guideline recommendations throughout Target: BP, but like any quality improvement program there is a question of how does it spread,” said Gregory Wozniak, PhD, director of outcomes analytics for the AMA in Chicago. “Our goal for Target: BP is to be impacting 20 million patients by 2021.”

Dr. Casey, Dr. Weiswasser, and Dr. Wozniak had no disclosures. Dr. Cushman has received honoraria as a speaker from Arbor and Sanofi-Aventis, and travel and research support from Eli Lilly. Dr. Egan has been a consultant to and speaker on behalf of Merck and a speaker for Emcure.

mzoler@mdedge.com

SOURCE: Casey DE et al. J Am Coll Cardiol. 2019 Nov 26;74[21]: 2661-706.

PHILADELPHIA – The American Heart Association and American College of Cardiology took a big step toward facilitating widespread U.S. application of the hypertension management guideline that the societies issued in 2017 by releasing a set of performance and quality measures for adults with high blood pressure based on the 2017 guideline.

Mitchel L. Zoler/MDedge News

This guideline notably set a treatment target for patients diagnosed with hypertension of less than 130/80 mg/dL, and also lowered the threshold for diagnosing stage 1 hypertension to a blood pressure at or above 130/80 mm Hg, adding in a stroke about 31 million adults with hypertension to the U.S. total.

Having performance and quality measures based on the guideline is “critical, because how else would you know whether you’re having an effect on accurately diagnosing and properly controlling hypertension?” said Donald E. Casey Jr., MD, chair of the performance measures writing committee. The next step is field testing of the measures “to show they are reliable and effective,” as well as other steps to encourage widespread U.S. uptake of the performance and quality measures and the specifics of the 2017 guideline, Dr. Casey said during a presentation of the revised measures at the American Heart Association scientific sessions.

He especially highlighted the important role of Target: BP, an education, recognition, and quality improvement program run by the AHA and American Medical Association, as a tool that medical practices, health systems, and even payers and employers can use to begin to apply the new performance and quality measures (J Am Coll Cardiol. 2019 Nov 26;74[21]:2661-706) and better align with the recommendations of the 2017 high blood pressure guideline (J Am Coll Cardiol. 2018 May;71[19]:e127-248).

“We’re trying now to promote Target: BP; it’s something you can take off the shelf and get going if it’s embedded in a real-life delivery model. I think Target: BP is the secret sauce. It will be the way we’ll convince people to adopt this,” said Dr. Casey, principal and founder of IPO 4 Health, a Chicago-based health care consulting firm.

He also advised practices and health systems not to feel compelled to introduce all of the specific performance and quality measures at once. “We don’t believe everyone has the resources to do all of it at once; the point is to move toward this system of care. We understand that people don’t have the resources to get it all done” immediately, Dr. Casey said in an interview.

Mitchel L. Zoler/MDedge News

A report during another session at the meeting documented the potential impact that Target: BP can have on blood pressure control within a health system. The Trinity Health of New England medical group based in Springfield, Mass., a system with about 140,000 patients – including 20,000 adults diagnosed with hypertension – and served by 230 health care providers in 13 offices in western Massachusetts, began using Target: BP’s MAP improvement program in its practices in November 2018. (MAP stands for measure accurately, act rapidly, and partner with patients.) Just before the MAP program began, 72% of patients diagnosed with hypertension in the medical group were at their goal blood pressure. Less than a year later, in September 2019, the hypertension control rate had jumped to 84%, a 12 percentage point improvement in control in practices that already had been doing a relatively good job, said Daniel W. Weiswasser, MD, director of quality and clinical informatics at Trinity Health of New England. Based on this success, Trinity Health plans to next involve the remaining regions of Trinity Health of New England in Target: BP, followed by the other regions of Trinity’s national organization, which operates in 21 states with nearly 4,000 staff physicians and about half a million patients diagnosed with hypertension, Dr. Weiswasser said.

Mitchel L. Zoler/MDedge News

“If clinicians do the three steps of the MAP then we will see substantial drops in blood pressures. It will occur,” declared Brent M. Egan, MD, vice president for cardiovascular disease prevention of the AMA in Greenville, S.C.

The new report includes six performance measures based on the strongest guideline recommendations and designed to document adherence levels for the purposes of public reporting and pay-for-performance programs. It also includes 16 quality measures designed for local quality review purposes, with 6 process quality measures and 10 structural quality measures. The report spells out that the authors designed the performance measures for use by major national organizations such as the Centers for Medicare & Medicaid Services and the National Committee for Quality Assurance (NCQA), while the quality measures are designed to support quality improvement efforts in any care-delivery setting.

The authors said that the writing committee is sensitive to the fact that the 2019 performance measures for controlling high blood pressure developed by the NCQA for the Healthcare Effectiveness Data and Information Set and currently in use in 2019 by CMS also does not incorporate the 2017 Hypertension Clinical Practice Guidelines classification scheme. “It is well understood that these measures are already in widespread use, especially for quality-related payment programs promulgated by CMS, such as the Medicare Advantage ‘Stars’ ratings, the Medicare Shared Savings Program, and the Physician Quality Payment Program, as well as many other programs promoted by commercial health insurers. In particular, the widespread use of the 2017 Hypertension Clinical Practice Guidelines classification scheme will also help to guide decision making about when to prescribe antihypertensive medications in accordance with its current recommendations for the ACC/AHA “stages” of stage 1 and stage 2 hypertension and elevated blood pressure,” they added.

The report also says that “the writing committee was sensitive to the fact that there is currently not complete consensus among other guidelines from the American College of Physicians and the American Academy of Family Physicians, and also the European Society of Cardiology and the European Society of Hypertension. Nonetheless, despite this ongoing debate, the writing committee felt strongly that it is now time to move the U.S. health care system ahead to reflect these differing points of view and expects that widespread use of this new measure set will help to achieve this goal.” The new report revises hypertension performance measures developed by the ACC and AHA in 2011 (J Am Coll Cardiol. 2011 Jul 12;58[3]: 316-36).

In short, the performance and quality measures give all the diverse components of the U.S. health care delivery system a road map for implementing the 2017 High Blood Pressure Guideline in a format that depends on those components electing to adopt and adhere to the 2017 guideline. (Although one of the new performance measures, 1a, harmonizes with an existing and widely applied performance measure.)

“Who is the audience for this, and how will they respond? These performance measures need to be appropriated” by health systems and by performance-assessment groups. “I hope the NCQA will adopt it,” said William C. Cushman, MD, professor of preventive medicine at the University of Tennessee Health Science Center in Memphis, and chief of preventive medicine at the Memphis Veterans Affairs Medical Center. “There are some negatives to performance measures, but on balance they have done good things and led to better care.” Dr. Cushman also approved of several specific performance and quality measures included in the report. “Most of what they emphasized is good,” particularly the importance of accurate pressure measurement, he said in an interview.

“Process drives outcomes” in hypertension management, and the new performance and quality measures “have some very good process metrics,” commented Dr. Egan. “I’d encourage health systems to select two or three measures that are key to what they do and make sense in their setting rather than try to implement it all at once,” he advised, echoing what Dr. Casey had suggested. “It’s ideal to do everything, but we know that if you give physicians a long list of performance measures they just get overwhelmed. The nice thing about hypertension is that we know that process drives outcomes. In the past, we’ve had some process metrics that did not drive outcomes. Getting these processes implemented will lead to better patient outcomes and save a ton of money.”

Mitchel L. Zoler/MDedge News

“We have introduced the 2017 guideline recommendations throughout Target: BP, but like any quality improvement program there is a question of how does it spread,” said Gregory Wozniak, PhD, director of outcomes analytics for the AMA in Chicago. “Our goal for Target: BP is to be impacting 20 million patients by 2021.”

Dr. Casey, Dr. Weiswasser, and Dr. Wozniak had no disclosures. Dr. Cushman has received honoraria as a speaker from Arbor and Sanofi-Aventis, and travel and research support from Eli Lilly. Dr. Egan has been a consultant to and speaker on behalf of Merck and a speaker for Emcure.

mzoler@mdedge.com

SOURCE: Casey DE et al. J Am Coll Cardiol. 2019 Nov 26;74[21]: 2661-706.

The Food and Drug Administration has accepted a supplemental New Drug Application and granted Priority Review for dapagliflozin (Farxiga) for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The application was based on results from the landmark, phase 3 DAPA-HF trial, published in September 2019 in the New England Journal of Medicine. The study showed that dapagliflozin plus standard care reduced the incidence of cardiovascular death and worsening of heart failure versus placebo in patients with HFrEF.

Dapagliflozin was granted Fast Track designation for heart failure by the FDA in September 2019. In August 2019, the FDA also granted Fast Track designation to dapagliflozin for the delayed progression of renal failure and prevention of cardiovascular and renal death in patients with chronic kidney disease.

The drug is currently indicated for the improvement of glycemic control in adults with type 2 diabetes as either monotherapy or in combination. The FDA approved dapagliflozin in October 2019 for the reduction of heart failure hospitalization risk in patients with type 2 diabetes and cardiovascular risk factors.

“Farxiga is well established in the treatment of type 2 diabetes and this Priority Review shows its potential to also impact millions of patients with heart failure. If approved, Farxiga will be the first and only medicine of its kind indicated to treat patients with heart failure,” said Mene Pangalos, executive vice president of biopharmaceutical research and development at AstraZeneca.

Find the full press release on the AstraZeneca website.

lfranki@mdedge.com

The Food and Drug Administration has accepted a supplemental New Drug Application and granted Priority Review for dapagliflozin (Farxiga) for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The application was based on results from the landmark, phase 3 DAPA-HF trial, published in September 2019 in the New England Journal of Medicine. The study showed that dapagliflozin plus standard care reduced the incidence of cardiovascular death and worsening of heart failure versus placebo in patients with HFrEF.

Dapagliflozin was granted Fast Track designation for heart failure by the FDA in September 2019. In August 2019, the FDA also granted Fast Track designation to dapagliflozin for the delayed progression of renal failure and prevention of cardiovascular and renal death in patients with chronic kidney disease.

The drug is currently indicated for the improvement of glycemic control in adults with type 2 diabetes as either monotherapy or in combination. The FDA approved dapagliflozin in October 2019 for the reduction of heart failure hospitalization risk in patients with type 2 diabetes and cardiovascular risk factors.

“Farxiga is well established in the treatment of type 2 diabetes and this Priority Review shows its potential to also impact millions of patients with heart failure. If approved, Farxiga will be the first and only medicine of its kind indicated to treat patients with heart failure,” said Mene Pangalos, executive vice president of biopharmaceutical research and development at AstraZeneca.

Find the full press release on the AstraZeneca website.

lfranki@mdedge.com

The Food and Drug Administration has accepted a supplemental New Drug Application and granted Priority Review for dapagliflozin (Farxiga) for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The application was based on results from the landmark, phase 3 DAPA-HF trial, published in September 2019 in the New England Journal of Medicine. The study showed that dapagliflozin plus standard care reduced the incidence of cardiovascular death and worsening of heart failure versus placebo in patients with HFrEF.

Dapagliflozin was granted Fast Track designation for heart failure by the FDA in September 2019. In August 2019, the FDA also granted Fast Track designation to dapagliflozin for the delayed progression of renal failure and prevention of cardiovascular and renal death in patients with chronic kidney disease.

The drug is currently indicated for the improvement of glycemic control in adults with type 2 diabetes as either monotherapy or in combination. The FDA approved dapagliflozin in October 2019 for the reduction of heart failure hospitalization risk in patients with type 2 diabetes and cardiovascular risk factors.

“Farxiga is well established in the treatment of type 2 diabetes and this Priority Review shows its potential to also impact millions of patients with heart failure. If approved, Farxiga will be the first and only medicine of its kind indicated to treat patients with heart failure,” said Mene Pangalos, executive vice president of biopharmaceutical research and development at AstraZeneca.

Find the full press release on the AstraZeneca website.

lfranki@mdedge.com

The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.

“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”

It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.

Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.

The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.

As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.

Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.

This story first appeared on Medscape.com.

The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.

“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”

It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.

Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.

The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.

As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.

Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.

This story first appeared on Medscape.com.

The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.

“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”

It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.

Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.

The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.

As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.

Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.

This story first appeared on Medscape.com.

PHILADELPHIA – Treatment guidelines are clear about optimal treatment of heart failure in patients with reduced ejection fraction (HFrEF), but adherence breakdowns often occur.

So, Brigham and Women’s Hospital in Boston implemented a navigator-administered patient outreach program that led to improved medication adherence over usual care, according to study results reported at the American Heart Association scientific sessions.

Although the study was done at a major academic center, the findings have implications for community practitioners, lead study author Akshay S. Desai, MD, MPH, said in an interview. “The impact of the intervention is clearly greater in those practitioners who manage heart failure and have the least support around them,” he said.

“Our sense is that the kind of population where this intervention would have the greater impact would be a community-dwelling heart failure population managed by community cardiologists, where the infrastructure to provide longitudinal heart failure care is less robust than may be in an academic center,” Dr. Desai said.

The study evaluated adherence in guideline-directed medical therapy (GDMT) at 3 months. “The navigator-led remote medication optimization strategy improved utilization and dosing of all categories of GDMP and was associated with a lower rate of adverse events,” Dr. Desai said. “The impact was more pronounced in patients followed by general practitioners than by a HF specialist.” In the outreach, health navigators contacted patients by phone and managed medications based on remote surveillance of labs, blood pressure, and symptoms under supervision of a pharmacist, nurse practitioner, and heart failure specialist.

The study included 1,028 patients with chronic HFrEF who’d visited a cardiologist at Brigham and Women’s in the year prior to the study: 197 patients and their providers consented to participate in the program with the remainder serving as the reference usual-care group. Most HF specialists at Brigham and Women’s declined to participate in the navigator-led program, Dr. Desai said.

Treating providers were approached for consent to adjust medical therapy according to a sequential, stepped titration algorithm modeled on the current American College of Cardiology/American Heart Association HF Guidelines. The study population did not include patients with end-stage HF, those with a severe noncardiac illness with a life expectancy of less than a year, and patients with a pattern of nonadherence. Baseline characteristics of the two groups were well balanced, Dr. Desai said.

At baseline, 74% (759) participants were treated with ACE inhibitors/angiotensin receptor blockers/angiotensin-receptor neprilysin inhibitors (ACE/ARB/ARNi), 73% (746) with guideline-directed beta-blockers, and 29% (303) with mineralocorticoid receptor antagonists (MRAs), with 10% (107) and 11% (117) treated with target doses of ACE/ARB/ARNi and beta-blockers, respectively.

In the navigator-led group, beta-blocker adherence improved from 77.2% at baseline to 91.9% at 3 months (P less than 0.001) compared with an increase from 84.5% to 86.3% in the usual-care patients (P = 0.15), Dr. Desai said. ACE/ARB/ARNi adherence increased 16.2 percentage points to 86.3% (P less than 0.001) in the navigator-group versus 1.8 percentage points to 74.4% (P = 0.24) for usual care. In the MRA subgroup, 3-month adherence to GDMT was almost identical: 30.5% (P = 0.14) and 30.3% (P = 0.37) for the two treatment groups, respectively, although the navigator-led patients averaged a larger increase of 4.6 versus 1.4 percentage points from baseline.

Adverse event rates were similar in both groups, although the navigator group had “slightly higher rates” of hypotension and hyperkalemia but no serious events, Dr. Desai said. This group also had similarly higher rates of worsening renal function, but most were asymptomatic change in creatinine that was addressed with medication changes, he said. There were no hospitalizations for adverse events.

He said the navigator-led optimization has potential in a community setting because the referral nature of Brigham and Women’s HF population “reflects potentially a worst-case scenario for such a program.” The greatest impact was seen in patients managed by general cardiologists, he said. “If we were to move this forward, which we hope to do with scale, the impact might be greater in a community population where there are fewer specialists and less severe illnesses present.”

This study represents a proof of concept, Dr. Desai said in an interview. “What we would like to do is demonstrate that this can be done on a larger scale,” he said. “That might involve partnership with a payer or health care system to see if we can replicate these findings across a broader range of providers.”

Dr. Desai disclosed financial relationships with Novartis, AstraZeneca, Abbott, Boehringer-Ingelheim, Coston Scientific, Biofourmis, DalCor, Relypsa, Regeneron, and Alnylam. Novartis provided an unrestricted grant for the investigator-initiated trial.

SOURCE: Desai AS. AHA 2019 Featured Science session AOS.07.

PHILADELPHIA – Treatment guidelines are clear about optimal treatment of heart failure in patients with reduced ejection fraction (HFrEF), but adherence breakdowns often occur.

So, Brigham and Women’s Hospital in Boston implemented a navigator-administered patient outreach program that led to improved medication adherence over usual care, according to study results reported at the American Heart Association scientific sessions.

Although the study was done at a major academic center, the findings have implications for community practitioners, lead study author Akshay S. Desai, MD, MPH, said in an interview. “The impact of the intervention is clearly greater in those practitioners who manage heart failure and have the least support around them,” he said.

“Our sense is that the kind of population where this intervention would have the greater impact would be a community-dwelling heart failure population managed by community cardiologists, where the infrastructure to provide longitudinal heart failure care is less robust than may be in an academic center,” Dr. Desai said.

The study evaluated adherence in guideline-directed medical therapy (GDMT) at 3 months. “The navigator-led remote medication optimization strategy improved utilization and dosing of all categories of GDMP and was associated with a lower rate of adverse events,” Dr. Desai said. “The impact was more pronounced in patients followed by general practitioners than by a HF specialist.” In the outreach, health navigators contacted patients by phone and managed medications based on remote surveillance of labs, blood pressure, and symptoms under supervision of a pharmacist, nurse practitioner, and heart failure specialist.

The study included 1,028 patients with chronic HFrEF who’d visited a cardiologist at Brigham and Women’s in the year prior to the study: 197 patients and their providers consented to participate in the program with the remainder serving as the reference usual-care group. Most HF specialists at Brigham and Women’s declined to participate in the navigator-led program, Dr. Desai said.

Treating providers were approached for consent to adjust medical therapy according to a sequential, stepped titration algorithm modeled on the current American College of Cardiology/American Heart Association HF Guidelines. The study population did not include patients with end-stage HF, those with a severe noncardiac illness with a life expectancy of less than a year, and patients with a pattern of nonadherence. Baseline characteristics of the two groups were well balanced, Dr. Desai said.

At baseline, 74% (759) participants were treated with ACE inhibitors/angiotensin receptor blockers/angiotensin-receptor neprilysin inhibitors (ACE/ARB/ARNi), 73% (746) with guideline-directed beta-blockers, and 29% (303) with mineralocorticoid receptor antagonists (MRAs), with 10% (107) and 11% (117) treated with target doses of ACE/ARB/ARNi and beta-blockers, respectively.

In the navigator-led group, beta-blocker adherence improved from 77.2% at baseline to 91.9% at 3 months (P less than 0.001) compared with an increase from 84.5% to 86.3% in the usual-care patients (P = 0.15), Dr. Desai said. ACE/ARB/ARNi adherence increased 16.2 percentage points to 86.3% (P less than 0.001) in the navigator-group versus 1.8 percentage points to 74.4% (P = 0.24) for usual care. In the MRA subgroup, 3-month adherence to GDMT was almost identical: 30.5% (P = 0.14) and 30.3% (P = 0.37) for the two treatment groups, respectively, although the navigator-led patients averaged a larger increase of 4.6 versus 1.4 percentage points from baseline.

Adverse event rates were similar in both groups, although the navigator group had “slightly higher rates” of hypotension and hyperkalemia but no serious events, Dr. Desai said. This group also had similarly higher rates of worsening renal function, but most were asymptomatic change in creatinine that was addressed with medication changes, he said. There were no hospitalizations for adverse events.

He said the navigator-led optimization has potential in a community setting because the referral nature of Brigham and Women’s HF population “reflects potentially a worst-case scenario for such a program.” The greatest impact was seen in patients managed by general cardiologists, he said. “If we were to move this forward, which we hope to do with scale, the impact might be greater in a community population where there are fewer specialists and less severe illnesses present.”

This study represents a proof of concept, Dr. Desai said in an interview. “What we would like to do is demonstrate that this can be done on a larger scale,” he said. “That might involve partnership with a payer or health care system to see if we can replicate these findings across a broader range of providers.”

Dr. Desai disclosed financial relationships with Novartis, AstraZeneca, Abbott, Boehringer-Ingelheim, Coston Scientific, Biofourmis, DalCor, Relypsa, Regeneron, and Alnylam. Novartis provided an unrestricted grant for the investigator-initiated trial.

SOURCE: Desai AS. AHA 2019 Featured Science session AOS.07.

PHILADELPHIA – Treatment guidelines are clear about optimal treatment of heart failure in patients with reduced ejection fraction (HFrEF), but adherence breakdowns often occur.

So, Brigham and Women’s Hospital in Boston implemented a navigator-administered patient outreach program that led to improved medication adherence over usual care, according to study results reported at the American Heart Association scientific sessions.

Although the study was done at a major academic center, the findings have implications for community practitioners, lead study author Akshay S. Desai, MD, MPH, said in an interview. “The impact of the intervention is clearly greater in those practitioners who manage heart failure and have the least support around them,” he said.

“Our sense is that the kind of population where this intervention would have the greater impact would be a community-dwelling heart failure population managed by community cardiologists, where the infrastructure to provide longitudinal heart failure care is less robust than may be in an academic center,” Dr. Desai said.

The study evaluated adherence in guideline-directed medical therapy (GDMT) at 3 months. “The navigator-led remote medication optimization strategy improved utilization and dosing of all categories of GDMP and was associated with a lower rate of adverse events,” Dr. Desai said. “The impact was more pronounced in patients followed by general practitioners than by a HF specialist.” In the outreach, health navigators contacted patients by phone and managed medications based on remote surveillance of labs, blood pressure, and symptoms under supervision of a pharmacist, nurse practitioner, and heart failure specialist.

The study included 1,028 patients with chronic HFrEF who’d visited a cardiologist at Brigham and Women’s in the year prior to the study: 197 patients and their providers consented to participate in the program with the remainder serving as the reference usual-care group. Most HF specialists at Brigham and Women’s declined to participate in the navigator-led program, Dr. Desai said.

Treating providers were approached for consent to adjust medical therapy according to a sequential, stepped titration algorithm modeled on the current American College of Cardiology/American Heart Association HF Guidelines. The study population did not include patients with end-stage HF, those with a severe noncardiac illness with a life expectancy of less than a year, and patients with a pattern of nonadherence. Baseline characteristics of the two groups were well balanced, Dr. Desai said.

At baseline, 74% (759) participants were treated with ACE inhibitors/angiotensin receptor blockers/angiotensin-receptor neprilysin inhibitors (ACE/ARB/ARNi), 73% (746) with guideline-directed beta-blockers, and 29% (303) with mineralocorticoid receptor antagonists (MRAs), with 10% (107) and 11% (117) treated with target doses of ACE/ARB/ARNi and beta-blockers, respectively.

In the navigator-led group, beta-blocker adherence improved from 77.2% at baseline to 91.9% at 3 months (P less than 0.001) compared with an increase from 84.5% to 86.3% in the usual-care patients (P = 0.15), Dr. Desai said. ACE/ARB/ARNi adherence increased 16.2 percentage points to 86.3% (P less than 0.001) in the navigator-group versus 1.8 percentage points to 74.4% (P = 0.24) for usual care. In the MRA subgroup, 3-month adherence to GDMT was almost identical: 30.5% (P = 0.14) and 30.3% (P = 0.37) for the two treatment groups, respectively, although the navigator-led patients averaged a larger increase of 4.6 versus 1.4 percentage points from baseline.

Adverse event rates were similar in both groups, although the navigator group had “slightly higher rates” of hypotension and hyperkalemia but no serious events, Dr. Desai said. This group also had similarly higher rates of worsening renal function, but most were asymptomatic change in creatinine that was addressed with medication changes, he said. There were no hospitalizations for adverse events.

He said the navigator-led optimization has potential in a community setting because the referral nature of Brigham and Women’s HF population “reflects potentially a worst-case scenario for such a program.” The greatest impact was seen in patients managed by general cardiologists, he said. “If we were to move this forward, which we hope to do with scale, the impact might be greater in a community population where there are fewer specialists and less severe illnesses present.”

This study represents a proof of concept, Dr. Desai said in an interview. “What we would like to do is demonstrate that this can be done on a larger scale,” he said. “That might involve partnership with a payer or health care system to see if we can replicate these findings across a broader range of providers.”

Dr. Desai disclosed financial relationships with Novartis, AstraZeneca, Abbott, Boehringer-Ingelheim, Coston Scientific, Biofourmis, DalCor, Relypsa, Regeneron, and Alnylam. Novartis provided an unrestricted grant for the investigator-initiated trial.

SOURCE: Desai AS. AHA 2019 Featured Science session AOS.07.

Suboptimal dosing of renin-angiotensin-aldosterone system (RAAS) inhibitors to reduce the risk of hyperkalemia could increase the risk of major adverse cardiac events (MACE) and all-cause mortality in patients with chronic kidney disease (CKD) or heart failure.

HYWARDS/Thinkstock

Researchers reported the outcomes of an observational study that explored the real-world associations between RAAS inhibitor dose, hyperkalemia, and clinical outcomes.

RAAS inhibitors – such as ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists – are known to reduce potassium excretion and therefore increase the risk of high potassium levels.

Dr. Cecilia Linde, from the Karolinska University Hospital and Karolinska Institutet in Stockholm, and coauthors wrote that management of serum potassium levels often requires reducing the dosage of RAAS inhibitors or stopping them altogether. However, this is also associated with risks in patients with heart failure or CKD.

In this study, researchers looked at data from 100,572 people with nondialysis CKD and 13,113 with new-onset heart failure who were prescribed RAAS inhibitors during 2006-2015.

Overall, 58% of patients with CKD and 63% of patients with heart failure spent the majority of follow-up on prescribed optimal doses of RAAS inhibitors – defined as at least 50% of the guidelines-recommended dose.

Patients with hyperkalemia were more likely to have down-titrations or discontinue their RAAS inhibitors, and this increased with increasing hyperkalemia severity.

The study found consistently lower mortality rates among patients who spent most of their follow-up time on at least 50% of the guideline-recommended dose of RAAS inhibitors.

In patients with CKD, mortality rates were 7.2 deaths per 1,000 patient-years in those taking at least 50% of the recommended dose, compared with 57.7 deaths per 1,000 patient-years for those on suboptimal doses. The rates of MACE were 73 and 130 per 1,000 patient-years, respectively.

The differences were even more pronounced in patients with heart failure. Those taking at least 50% of the recommended dose had mortality rates of 12.5 per 1000 patient-years, compared with 141.7 among those on suboptimal doses. The rates of MACE were 148.5 and 290.4, respectively.

“The results highlight the potential negative impact of suboptimal RAASi dosing, indicate the generalizability of [European Society of Cardiology–recommended] RAASi doses in HF to CKD patients, and emphasize the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation,” the authors wrote.

The study was funded by AstraZeneca. One author was an employee and stockholder of AstraZeneca, and five authors declared funding and support from the pharmaceutical sector, including AstraZeneca.

SOURCE: Linde C et al. J Am Heart Assoc. 2019 Nov 12. doi: 10.1161/JAHA.119.012655.

Suboptimal dosing of renin-angiotensin-aldosterone system (RAAS) inhibitors to reduce the risk of hyperkalemia could increase the risk of major adverse cardiac events (MACE) and all-cause mortality in patients with chronic kidney disease (CKD) or heart failure.

HYWARDS/Thinkstock

Researchers reported the outcomes of an observational study that explored the real-world associations between RAAS inhibitor dose, hyperkalemia, and clinical outcomes.

RAAS inhibitors – such as ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists – are known to reduce potassium excretion and therefore increase the risk of high potassium levels.

Dr. Cecilia Linde, from the Karolinska University Hospital and Karolinska Institutet in Stockholm, and coauthors wrote that management of serum potassium levels often requires reducing the dosage of RAAS inhibitors or stopping them altogether. However, this is also associated with risks in patients with heart failure or CKD.

In this study, researchers looked at data from 100,572 people with nondialysis CKD and 13,113 with new-onset heart failure who were prescribed RAAS inhibitors during 2006-2015.

Overall, 58% of patients with CKD and 63% of patients with heart failure spent the majority of follow-up on prescribed optimal doses of RAAS inhibitors – defined as at least 50% of the guidelines-recommended dose.

Patients with hyperkalemia were more likely to have down-titrations or discontinue their RAAS inhibitors, and this increased with increasing hyperkalemia severity.

The study found consistently lower mortality rates among patients who spent most of their follow-up time on at least 50% of the guideline-recommended dose of RAAS inhibitors.

In patients with CKD, mortality rates were 7.2 deaths per 1,000 patient-years in those taking at least 50% of the recommended dose, compared with 57.7 deaths per 1,000 patient-years for those on suboptimal doses. The rates of MACE were 73 and 130 per 1,000 patient-years, respectively.

The differences were even more pronounced in patients with heart failure. Those taking at least 50% of the recommended dose had mortality rates of 12.5 per 1000 patient-years, compared with 141.7 among those on suboptimal doses. The rates of MACE were 148.5 and 290.4, respectively.

“The results highlight the potential negative impact of suboptimal RAASi dosing, indicate the generalizability of [European Society of Cardiology–recommended] RAASi doses in HF to CKD patients, and emphasize the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation,” the authors wrote.

The study was funded by AstraZeneca. One author was an employee and stockholder of AstraZeneca, and five authors declared funding and support from the pharmaceutical sector, including AstraZeneca.

SOURCE: Linde C et al. J Am Heart Assoc. 2019 Nov 12. doi: 10.1161/JAHA.119.012655.

Suboptimal dosing of renin-angiotensin-aldosterone system (RAAS) inhibitors to reduce the risk of hyperkalemia could increase the risk of major adverse cardiac events (MACE) and all-cause mortality in patients with chronic kidney disease (CKD) or heart failure.

HYWARDS/Thinkstock

Researchers reported the outcomes of an observational study that explored the real-world associations between RAAS inhibitor dose, hyperkalemia, and clinical outcomes.

RAAS inhibitors – such as ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists – are known to reduce potassium excretion and therefore increase the risk of high potassium levels.

Dr. Cecilia Linde, from the Karolinska University Hospital and Karolinska Institutet in Stockholm, and coauthors wrote that management of serum potassium levels often requires reducing the dosage of RAAS inhibitors or stopping them altogether. However, this is also associated with risks in patients with heart failure or CKD.

In this study, researchers looked at data from 100,572 people with nondialysis CKD and 13,113 with new-onset heart failure who were prescribed RAAS inhibitors during 2006-2015.

Overall, 58% of patients with CKD and 63% of patients with heart failure spent the majority of follow-up on prescribed optimal doses of RAAS inhibitors – defined as at least 50% of the guidelines-recommended dose.

Patients with hyperkalemia were more likely to have down-titrations or discontinue their RAAS inhibitors, and this increased with increasing hyperkalemia severity.

The study found consistently lower mortality rates among patients who spent most of their follow-up time on at least 50% of the guideline-recommended dose of RAAS inhibitors.

In patients with CKD, mortality rates were 7.2 deaths per 1,000 patient-years in those taking at least 50% of the recommended dose, compared with 57.7 deaths per 1,000 patient-years for those on suboptimal doses. The rates of MACE were 73 and 130 per 1,000 patient-years, respectively.

The differences were even more pronounced in patients with heart failure. Those taking at least 50% of the recommended dose had mortality rates of 12.5 per 1000 patient-years, compared with 141.7 among those on suboptimal doses. The rates of MACE were 148.5 and 290.4, respectively.

“The results highlight the potential negative impact of suboptimal RAASi dosing, indicate the generalizability of [European Society of Cardiology–recommended] RAASi doses in HF to CKD patients, and emphasize the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation,” the authors wrote.

The study was funded by AstraZeneca. One author was an employee and stockholder of AstraZeneca, and five authors declared funding and support from the pharmaceutical sector, including AstraZeneca.

SOURCE: Linde C et al. J Am Heart Assoc. 2019 Nov 12. doi: 10.1161/JAHA.119.012655.

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

aotto@mdedge.com

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

aotto@mdedge.com

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

aotto@mdedge.com

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.