Hypertension

U.K. researchers have established that hypertension is associated with a 22% greater risk of severe COVID-19, with the odds of severe COVID-19 unaffected by medication type.

Hypertension “appears to be one of the commonest comorbidities in COVID-19 patients”, explained the authors of a new study, published in PLOS ONE. The authors highlighted that previous research had shown that hypertension was more prevalent in severe and fatal cases compared with all cases of COVID-19.

They pointed out, however, that whether hypertensive individuals have a higher risk of severe COVID-19, compared with nonhypertensives, and whether the absolute level of systolic blood pressure or the type of antihypertensive medication is related to this risk, remained “unclear.”

To try to answer these questions, the research team, led by University of Cambridge researchers, analyzed data from 16,134 individuals who tested positive for COVID-19 (mean age 65.3 years, 47% male, 90% white), 40% were diagnosed with essential hypertension at the analysis baseline – 22% of whom had developed severe COVID-19.

Systolic blood pressure (SBP) was categorized by 10–mm Hg ranges, starting from < 120 mm Hg up to 180+ mm Hg, with the reference category defined as 120-129 mm Hg, based on data from the SPRINT study, which demonstrated that intensive SBP lowering to below 120 mm Hg, as compared with the traditional threshold of 140 mm Hg, was beneficial. Diastolic blood pressure was categorized by 10–mm Hg ranges, starting from < 60 mm Hg up to 100+ mm Hg with 80-90 mm Hg being the reference category.

In their analyses the researchers adjusted for age, sex, body mass index, ethnicity, smoking status, diabetes status, socioeconomic status, and inflammation (C-reactive protein [CRP]), as these were proposed as potential confounders. To assess the direct effect of hypertension on COVID-19, they also adjusted for intermediate variables, including cardiovascular comorbidities and stroke, on the causal pathway between hypertension and severe COVID-19.
 

Majority of effect of hypertension on severe COVID-19 was direct

The unadjusted odds ratio of the association between hypertension and severe COVID-19 was 2.33 (95% confidence interval, 2.16-2.51), the authors emphasized. They found that, after adjusting for all confounding variables, hypertension was associated with 22% higher odds of severe COVID-19 (OR, 1.22; 95% CI, 1.12-1.33), compared with normotension.

Individuals with severe COVID-19 were marginally older, more likely to be male, and more deprived, the authors said. “They were also more likely to be hypertensive, compared with individuals without severe COVID-19, and a greater proportion of individuals with severe COVID-19 had cardiovascular comorbidities.”

The majority of the effect of hypertension on development of severe COVID-19 was “direct,” they said. However, a modest proportion of the effect was mediated via cardiovascular comorbidities such as peripheral vascular disease, MI, coronary heart disease, arrhythmias, and stroke. Of note, those with a history of stroke had a 47% higher risk of severe COVID-19 and those with a history of other cardiovascular comorbidities had a 30% higher risk of severe COVID-19, the authors commented.
 

J-shaped relationship

Of the total of 6,517 (40%) individuals who had a diagnosis of essential hypertension at baseline, 67% were treated (41% with monotherapy, 59% with combination therapy), and 33% were untreated.

There were similar numbers of severe COVID-19 in each medication group: ACE inhibitors, 34%; angiotensin receptor blockers (ARBs), 36%; and “other” medications 34%.

In hypertensive individuals receiving antihypertensive medications, there was a “J-shaped relationship” between the level of blood pressure and risk of severe COVID-19 when using a systolic blood pressure level of 120-129 mm Hg as a reference – 150-159 mm Hg versus 120-129 mm Hg (OR 1.91; 95% CI, 1.44-2.53), > 180+ mm Hg versus 120-129 mm Hg (OR 1.93; 95% CI, 1.06-3.51).

The authors commented that there was no evidence of a higher risk of severe COVID-19 until systolic blood pressure “exceeded 150 mm Hg.”

They said it was an interesting finding that “very well-controlled” systolic blood pressure < 120 mm Hg was associated with a 40% (OR, 1.40; 95% CI, 1.11-1.78) greater odds of severe COVID-19. “This may be due to reverse causality, where low systolic blood pressure levels may indicate poorer health, such that the occurrence of severe COVID-19 may be related to underlying disease rather than the level of SBP per se,” they suggested.

The J-shaped association observed remained after multiple adjustments, including presence of known cardiovascular comorbidities, which suggested a possible “real effect” of low SBP on severe COVID-19, “at least in treated hypertensive individuals.”

Their analyses also identified that, compared with a “normal” diastolic blood pressure (80-90 mm Hg), having a diastolic blood pressure higher than 90 mm Hg was associated with higher odds of severe COVID-19.

The association between hypertension and COVID-19 was “amplified” if the individuals were treated and their BP remained uncontrolled, the authors pointed out.

There did not appear to be any difference in the risk of severe COVID-19 between individuals taking ACE inhibitors and those taking ARBs or other antihypertensive medications, the authors said.
 

Better understanding of underlying mechanisms needed

Individuals with hypertension who tested positive for COVID-19 had “over twice” the risk of developing severe COVID-19, compared with nonhypertensive individuals, the authors said.

They highlighted that their findings also suggest that there are “further effects” influencing the severity of COVID-19 beyond a “dichotomous” diagnosis of hypertension.

“Individuals with a higher-than-target systolic blood pressure may be less healthy, less active, suffering more severe hypertension, or have developed drug-resistant hypertension, all suggesting that the effects of hypertension have already had detrimental physiological effects on the cardiovascular system, which in turn may offer some explanation for the higher risk of severe COVID-19 with uncontrolled SBP,” they explained.

“Hypertension is an important risk factor for COVID-19,” reiterated the authors, who emphasized that a better understanding of the underlying mechanisms driving this increased risk is warranted in case of “more severe strains or other viruses” in the future.

The authors have declared no competing interests.

A version of this article first appeared on Medscape UK.

U.K. researchers have established that hypertension is associated with a 22% greater risk of severe COVID-19, with the odds of severe COVID-19 unaffected by medication type.

Hypertension “appears to be one of the commonest comorbidities in COVID-19 patients”, explained the authors of a new study, published in PLOS ONE. The authors highlighted that previous research had shown that hypertension was more prevalent in severe and fatal cases compared with all cases of COVID-19.

They pointed out, however, that whether hypertensive individuals have a higher risk of severe COVID-19, compared with nonhypertensives, and whether the absolute level of systolic blood pressure or the type of antihypertensive medication is related to this risk, remained “unclear.”

To try to answer these questions, the research team, led by University of Cambridge researchers, analyzed data from 16,134 individuals who tested positive for COVID-19 (mean age 65.3 years, 47% male, 90% white), 40% were diagnosed with essential hypertension at the analysis baseline – 22% of whom had developed severe COVID-19.

Systolic blood pressure (SBP) was categorized by 10–mm Hg ranges, starting from < 120 mm Hg up to 180+ mm Hg, with the reference category defined as 120-129 mm Hg, based on data from the SPRINT study, which demonstrated that intensive SBP lowering to below 120 mm Hg, as compared with the traditional threshold of 140 mm Hg, was beneficial. Diastolic blood pressure was categorized by 10–mm Hg ranges, starting from < 60 mm Hg up to 100+ mm Hg with 80-90 mm Hg being the reference category.

In their analyses the researchers adjusted for age, sex, body mass index, ethnicity, smoking status, diabetes status, socioeconomic status, and inflammation (C-reactive protein [CRP]), as these were proposed as potential confounders. To assess the direct effect of hypertension on COVID-19, they also adjusted for intermediate variables, including cardiovascular comorbidities and stroke, on the causal pathway between hypertension and severe COVID-19.
 

Majority of effect of hypertension on severe COVID-19 was direct

The unadjusted odds ratio of the association between hypertension and severe COVID-19 was 2.33 (95% confidence interval, 2.16-2.51), the authors emphasized. They found that, after adjusting for all confounding variables, hypertension was associated with 22% higher odds of severe COVID-19 (OR, 1.22; 95% CI, 1.12-1.33), compared with normotension.

Individuals with severe COVID-19 were marginally older, more likely to be male, and more deprived, the authors said. “They were also more likely to be hypertensive, compared with individuals without severe COVID-19, and a greater proportion of individuals with severe COVID-19 had cardiovascular comorbidities.”

The majority of the effect of hypertension on development of severe COVID-19 was “direct,” they said. However, a modest proportion of the effect was mediated via cardiovascular comorbidities such as peripheral vascular disease, MI, coronary heart disease, arrhythmias, and stroke. Of note, those with a history of stroke had a 47% higher risk of severe COVID-19 and those with a history of other cardiovascular comorbidities had a 30% higher risk of severe COVID-19, the authors commented.
 

J-shaped relationship

Of the total of 6,517 (40%) individuals who had a diagnosis of essential hypertension at baseline, 67% were treated (41% with monotherapy, 59% with combination therapy), and 33% were untreated.

There were similar numbers of severe COVID-19 in each medication group: ACE inhibitors, 34%; angiotensin receptor blockers (ARBs), 36%; and “other” medications 34%.

In hypertensive individuals receiving antihypertensive medications, there was a “J-shaped relationship” between the level of blood pressure and risk of severe COVID-19 when using a systolic blood pressure level of 120-129 mm Hg as a reference – 150-159 mm Hg versus 120-129 mm Hg (OR 1.91; 95% CI, 1.44-2.53), > 180+ mm Hg versus 120-129 mm Hg (OR 1.93; 95% CI, 1.06-3.51).

The authors commented that there was no evidence of a higher risk of severe COVID-19 until systolic blood pressure “exceeded 150 mm Hg.”

They said it was an interesting finding that “very well-controlled” systolic blood pressure < 120 mm Hg was associated with a 40% (OR, 1.40; 95% CI, 1.11-1.78) greater odds of severe COVID-19. “This may be due to reverse causality, where low systolic blood pressure levels may indicate poorer health, such that the occurrence of severe COVID-19 may be related to underlying disease rather than the level of SBP per se,” they suggested.

The J-shaped association observed remained after multiple adjustments, including presence of known cardiovascular comorbidities, which suggested a possible “real effect” of low SBP on severe COVID-19, “at least in treated hypertensive individuals.”

Their analyses also identified that, compared with a “normal” diastolic blood pressure (80-90 mm Hg), having a diastolic blood pressure higher than 90 mm Hg was associated with higher odds of severe COVID-19.

The association between hypertension and COVID-19 was “amplified” if the individuals were treated and their BP remained uncontrolled, the authors pointed out.

There did not appear to be any difference in the risk of severe COVID-19 between individuals taking ACE inhibitors and those taking ARBs or other antihypertensive medications, the authors said.
 

Better understanding of underlying mechanisms needed

Individuals with hypertension who tested positive for COVID-19 had “over twice” the risk of developing severe COVID-19, compared with nonhypertensive individuals, the authors said.

They highlighted that their findings also suggest that there are “further effects” influencing the severity of COVID-19 beyond a “dichotomous” diagnosis of hypertension.

“Individuals with a higher-than-target systolic blood pressure may be less healthy, less active, suffering more severe hypertension, or have developed drug-resistant hypertension, all suggesting that the effects of hypertension have already had detrimental physiological effects on the cardiovascular system, which in turn may offer some explanation for the higher risk of severe COVID-19 with uncontrolled SBP,” they explained.

“Hypertension is an important risk factor for COVID-19,” reiterated the authors, who emphasized that a better understanding of the underlying mechanisms driving this increased risk is warranted in case of “more severe strains or other viruses” in the future.

The authors have declared no competing interests.

A version of this article first appeared on Medscape UK.

U.K. researchers have established that hypertension is associated with a 22% greater risk of severe COVID-19, with the odds of severe COVID-19 unaffected by medication type.

Hypertension “appears to be one of the commonest comorbidities in COVID-19 patients”, explained the authors of a new study, published in PLOS ONE. The authors highlighted that previous research had shown that hypertension was more prevalent in severe and fatal cases compared with all cases of COVID-19.

They pointed out, however, that whether hypertensive individuals have a higher risk of severe COVID-19, compared with nonhypertensives, and whether the absolute level of systolic blood pressure or the type of antihypertensive medication is related to this risk, remained “unclear.”

To try to answer these questions, the research team, led by University of Cambridge researchers, analyzed data from 16,134 individuals who tested positive for COVID-19 (mean age 65.3 years, 47% male, 90% white), 40% were diagnosed with essential hypertension at the analysis baseline – 22% of whom had developed severe COVID-19.

Systolic blood pressure (SBP) was categorized by 10–mm Hg ranges, starting from < 120 mm Hg up to 180+ mm Hg, with the reference category defined as 120-129 mm Hg, based on data from the SPRINT study, which demonstrated that intensive SBP lowering to below 120 mm Hg, as compared with the traditional threshold of 140 mm Hg, was beneficial. Diastolic blood pressure was categorized by 10–mm Hg ranges, starting from < 60 mm Hg up to 100+ mm Hg with 80-90 mm Hg being the reference category.

In their analyses the researchers adjusted for age, sex, body mass index, ethnicity, smoking status, diabetes status, socioeconomic status, and inflammation (C-reactive protein [CRP]), as these were proposed as potential confounders. To assess the direct effect of hypertension on COVID-19, they also adjusted for intermediate variables, including cardiovascular comorbidities and stroke, on the causal pathway between hypertension and severe COVID-19.
 

Majority of effect of hypertension on severe COVID-19 was direct

The unadjusted odds ratio of the association between hypertension and severe COVID-19 was 2.33 (95% confidence interval, 2.16-2.51), the authors emphasized. They found that, after adjusting for all confounding variables, hypertension was associated with 22% higher odds of severe COVID-19 (OR, 1.22; 95% CI, 1.12-1.33), compared with normotension.

Individuals with severe COVID-19 were marginally older, more likely to be male, and more deprived, the authors said. “They were also more likely to be hypertensive, compared with individuals without severe COVID-19, and a greater proportion of individuals with severe COVID-19 had cardiovascular comorbidities.”

The majority of the effect of hypertension on development of severe COVID-19 was “direct,” they said. However, a modest proportion of the effect was mediated via cardiovascular comorbidities such as peripheral vascular disease, MI, coronary heart disease, arrhythmias, and stroke. Of note, those with a history of stroke had a 47% higher risk of severe COVID-19 and those with a history of other cardiovascular comorbidities had a 30% higher risk of severe COVID-19, the authors commented.
 

J-shaped relationship

Of the total of 6,517 (40%) individuals who had a diagnosis of essential hypertension at baseline, 67% were treated (41% with monotherapy, 59% with combination therapy), and 33% were untreated.

There were similar numbers of severe COVID-19 in each medication group: ACE inhibitors, 34%; angiotensin receptor blockers (ARBs), 36%; and “other” medications 34%.

In hypertensive individuals receiving antihypertensive medications, there was a “J-shaped relationship” between the level of blood pressure and risk of severe COVID-19 when using a systolic blood pressure level of 120-129 mm Hg as a reference – 150-159 mm Hg versus 120-129 mm Hg (OR 1.91; 95% CI, 1.44-2.53), > 180+ mm Hg versus 120-129 mm Hg (OR 1.93; 95% CI, 1.06-3.51).

The authors commented that there was no evidence of a higher risk of severe COVID-19 until systolic blood pressure “exceeded 150 mm Hg.”

They said it was an interesting finding that “very well-controlled” systolic blood pressure < 120 mm Hg was associated with a 40% (OR, 1.40; 95% CI, 1.11-1.78) greater odds of severe COVID-19. “This may be due to reverse causality, where low systolic blood pressure levels may indicate poorer health, such that the occurrence of severe COVID-19 may be related to underlying disease rather than the level of SBP per se,” they suggested.

The J-shaped association observed remained after multiple adjustments, including presence of known cardiovascular comorbidities, which suggested a possible “real effect” of low SBP on severe COVID-19, “at least in treated hypertensive individuals.”

Their analyses also identified that, compared with a “normal” diastolic blood pressure (80-90 mm Hg), having a diastolic blood pressure higher than 90 mm Hg was associated with higher odds of severe COVID-19.

The association between hypertension and COVID-19 was “amplified” if the individuals were treated and their BP remained uncontrolled, the authors pointed out.

There did not appear to be any difference in the risk of severe COVID-19 between individuals taking ACE inhibitors and those taking ARBs or other antihypertensive medications, the authors said.
 

Better understanding of underlying mechanisms needed

Individuals with hypertension who tested positive for COVID-19 had “over twice” the risk of developing severe COVID-19, compared with nonhypertensive individuals, the authors said.

They highlighted that their findings also suggest that there are “further effects” influencing the severity of COVID-19 beyond a “dichotomous” diagnosis of hypertension.

“Individuals with a higher-than-target systolic blood pressure may be less healthy, less active, suffering more severe hypertension, or have developed drug-resistant hypertension, all suggesting that the effects of hypertension have already had detrimental physiological effects on the cardiovascular system, which in turn may offer some explanation for the higher risk of severe COVID-19 with uncontrolled SBP,” they explained.

“Hypertension is an important risk factor for COVID-19,” reiterated the authors, who emphasized that a better understanding of the underlying mechanisms driving this increased risk is warranted in case of “more severe strains or other viruses” in the future.

The authors have declared no competing interests.

A version of this article first appeared on Medscape UK.

CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.

The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.

After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).

The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).

Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.

The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
 

Threading the needle

For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.

What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.

“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.

Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.

Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
 

‘A bright future’

“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.

She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.

“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”

Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.

Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.

Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.

Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.

At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.

The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m² reduced the likelihood of hyperkalemia and other adverse events.

Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.

The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.

The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.

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

CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.

The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.

After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).

The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).

Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.

The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
 

Threading the needle

For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.

What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.

“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.

Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.

Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
 

‘A bright future’

“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.

She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.

“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”

Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.

Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.

Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.

Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.

At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.

The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m² reduced the likelihood of hyperkalemia and other adverse events.

Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.

The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.

The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.

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

CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.

The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.

After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).

The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).

Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.

The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
 

Threading the needle

For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.

What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.

“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.

Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.

Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
 

‘A bright future’

“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.

She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.

“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”

Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.

Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.

Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.

Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.

At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.

The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m² reduced the likelihood of hyperkalemia and other adverse events.

Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.

The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.

The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.

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

CHICAGO – Renal denervation, relative to a sham procedure, was linked with statistically significant reductions in blood pressure in the newly completed SPYRAL HTN–ON MED trial, but several factors are likely to have worked in concert to prevent the study from meeting its primary endpoint.

Of these differences, probably none was more important than the substantially higher proportion of patients in the sham group that received additional BP-lowering medications over the course of the study, David E. Kandzari, MD, reported at the American Heart Association scientific sessions.

Ted Bosworth/MDedge News

The SPYRAL HTN–ON MED pivotal trial followed the previously completed SPYRAL HTN–ON MED pilot study, which did show a significant BP-lowering effect on antihypertensive medications followed radiofrequency denervation. In a recent update of the pilot study, the effect was persistent out to 3 years.

In the SPYRAL HTN–ON MED program, patients on their second screening visit were required to have a systolic pressure of between 140 and 170 mm Hg on 24-hour ambulatory BP monitoring (ABPM) while taking up to three antihypertensive medications. Patients who entered the study were randomized to renal denervation or sham control while maintaining their baseline antihypertensive therapies.

The previously reported pilot study comprised 80 patients. The expansion pivotal trial added 257 more patients for a total cohort of 337 patients. The primary efficacy endpoint was based on a Bayesian analysis of change in 24-hour systolic ABPM at 6 months for those in the experimental arm versus those on medications alone. Participants from both the pilot and pivotal trials were included.

The prespecified definition of success for renal denervation was a 97.5% threshold for probability of superiority on the basis of this Bayesian analysis. However, the Bayesian analysis was distorted by differences in the pilot and expansion cohorts, which complicated the superiority calculation. As a result, the analysis only yielded a 51% probability of superiority, a level substantially below the predefined threshold.

Despite differences seen in BP control in favor of renal denervation, several factors were identified that likely contributed to the missed primary endpoint. One stood out.

“Significant differences in medication prescriptions were disproportionate in favor of the sham group,” reported Dr. Kandzari, chief of Piedmont Heart Institute, Atlanta. He said these differences, which were a violation of the protocol mandate, led to a “bias toward the null” for the primary outcome.

The failure to meet the primary outcome was particularly disappointing in the wake of the favorable pilot study and the SPYRAL HTN–OFF MED pivotal trial, which were both positive.

In the pilot study, which did not have a medication imbalance, a 7.3–mm Hg reduction (P = .004) in 24-hour ABPM was seen at 6 months. Relative reductions in office-based systolic pressure reductions for renal denervation versus sham were 6.6 mm Hg (P = .03) and 4.0 mm Hg (P = .03) for the pilot and expansions groups, respectively.

On the basis of a Win ratio derived from a hierarchical analysis of ABMP and medication burden reduction, the 1.50 advantage (P = .005) for the renal denervation arm in the newly completed SPYRAL HTN–ON MED trial was also compelling.

At study entry, the median number of medications was 1.9 in both the renal denervation and sham arms. At the end of 6 months, the median number of medications was unchanged in the experimental arm but rose to 2.1 (P = .01) in the sham group. Similarly, there was little change in the medication burden from the start to the end of the trial in the denervation group (2.8 vs. 3.0), but a statistically significant change in the sham group (2.9 vs. 3.5; P = .04).

Furthermore, the net percentage change of patients receiving medications favoring BP reduction over the course of the study did not differ between the experimental and control arms of the pilot cohort, but was more than 10 times higher among controls in the expansion group (1.9% vs. 21.8%; P < .0001).

Medication changes over the course of the SPYRAL HTN–ON MED trial were even greater in some specific subgroups. Among Black participants, for example, 14.2% of those randomized to renal denervation and 54.6% of those randomized to the sham group increased their antihypertensive therapies over the course of the study.

The COVID-19 epidemic is suspected of playing another role in the negative results, according to Dr. Kandzari. After a brief pause in enrollment, the SPYRAL HTN–ON MED trial was resumed, but approximately 80% of the expansion cohort data were collected during this period. When compared, variances in office and 24-hour ABPM were observed for participants who were or were not evaluated during COVID.

“Significant differences in 24-hour ABPM patterns pre- and during COVID may reflect changes in patient behavior and lifestyle,” Dr. Kandzari speculated.

The data from this study differ from essentially all of the other studies in the SPYRAL HTN program as well as several other sham-controlled studies with renal denervation, according to Dr. Kandzari.

Ted Bosworth/MDedge News

The AHA-invited discussant, Ajay J. Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, largely agreed that several variables appeared to conspire against a positive result in this trial, but he zeroed in on the imbalance of antihypertensive medications.

“Any trial that attempts to show a difference between renal denervation and a sham procedure must insure that antihypertensive medications are the same in the two arms. They cannot be different,” he said.

As an active investigator in the field of renal denervation, Dr. Kirtane thinks the evidence does support a benefit from renal denervation, but he believes data are still needed to determine which patients are candidates.

“Renal denervation is not going to be a replacement for previous established therapies, but it will be an adjunct,” he predicted. The preponderance of evidence supports clinically meaningful reductions in BP with this approach, “but we need to determine who to consider [for this therapy] and to have realistic expectations about the degree of benefit.”

Dr. Kandzari reported financial relationships with Abbott Vascular, Ablative Solutions, Biotronik, Boston Scientific, CSI, Medtronic Cardiovascular, OrbusNeich, and Teleflex. Dr. Kirtane reported financial relationships with Abbott Vascular, Abiomed, Boston Scientific, Cardiovascular Systems, Cathworks, Chiesi, Medtronic, Opens, Philipps, Regeneron, ReCor Medical, Siemens, Spectranetics, and Zoll.
 

CHICAGO – Renal denervation, relative to a sham procedure, was linked with statistically significant reductions in blood pressure in the newly completed SPYRAL HTN–ON MED trial, but several factors are likely to have worked in concert to prevent the study from meeting its primary endpoint.

Of these differences, probably none was more important than the substantially higher proportion of patients in the sham group that received additional BP-lowering medications over the course of the study, David E. Kandzari, MD, reported at the American Heart Association scientific sessions.

Ted Bosworth/MDedge News

The SPYRAL HTN–ON MED pivotal trial followed the previously completed SPYRAL HTN–ON MED pilot study, which did show a significant BP-lowering effect on antihypertensive medications followed radiofrequency denervation. In a recent update of the pilot study, the effect was persistent out to 3 years.

In the SPYRAL HTN–ON MED program, patients on their second screening visit were required to have a systolic pressure of between 140 and 170 mm Hg on 24-hour ambulatory BP monitoring (ABPM) while taking up to three antihypertensive medications. Patients who entered the study were randomized to renal denervation or sham control while maintaining their baseline antihypertensive therapies.

The previously reported pilot study comprised 80 patients. The expansion pivotal trial added 257 more patients for a total cohort of 337 patients. The primary efficacy endpoint was based on a Bayesian analysis of change in 24-hour systolic ABPM at 6 months for those in the experimental arm versus those on medications alone. Participants from both the pilot and pivotal trials were included.

The prespecified definition of success for renal denervation was a 97.5% threshold for probability of superiority on the basis of this Bayesian analysis. However, the Bayesian analysis was distorted by differences in the pilot and expansion cohorts, which complicated the superiority calculation. As a result, the analysis only yielded a 51% probability of superiority, a level substantially below the predefined threshold.

Despite differences seen in BP control in favor of renal denervation, several factors were identified that likely contributed to the missed primary endpoint. One stood out.

“Significant differences in medication prescriptions were disproportionate in favor of the sham group,” reported Dr. Kandzari, chief of Piedmont Heart Institute, Atlanta. He said these differences, which were a violation of the protocol mandate, led to a “bias toward the null” for the primary outcome.

The failure to meet the primary outcome was particularly disappointing in the wake of the favorable pilot study and the SPYRAL HTN–OFF MED pivotal trial, which were both positive.

In the pilot study, which did not have a medication imbalance, a 7.3–mm Hg reduction (P = .004) in 24-hour ABPM was seen at 6 months. Relative reductions in office-based systolic pressure reductions for renal denervation versus sham were 6.6 mm Hg (P = .03) and 4.0 mm Hg (P = .03) for the pilot and expansions groups, respectively.

On the basis of a Win ratio derived from a hierarchical analysis of ABMP and medication burden reduction, the 1.50 advantage (P = .005) for the renal denervation arm in the newly completed SPYRAL HTN–ON MED trial was also compelling.

At study entry, the median number of medications was 1.9 in both the renal denervation and sham arms. At the end of 6 months, the median number of medications was unchanged in the experimental arm but rose to 2.1 (P = .01) in the sham group. Similarly, there was little change in the medication burden from the start to the end of the trial in the denervation group (2.8 vs. 3.0), but a statistically significant change in the sham group (2.9 vs. 3.5; P = .04).

Furthermore, the net percentage change of patients receiving medications favoring BP reduction over the course of the study did not differ between the experimental and control arms of the pilot cohort, but was more than 10 times higher among controls in the expansion group (1.9% vs. 21.8%; P < .0001).

Medication changes over the course of the SPYRAL HTN–ON MED trial were even greater in some specific subgroups. Among Black participants, for example, 14.2% of those randomized to renal denervation and 54.6% of those randomized to the sham group increased their antihypertensive therapies over the course of the study.

The COVID-19 epidemic is suspected of playing another role in the negative results, according to Dr. Kandzari. After a brief pause in enrollment, the SPYRAL HTN–ON MED trial was resumed, but approximately 80% of the expansion cohort data were collected during this period. When compared, variances in office and 24-hour ABPM were observed for participants who were or were not evaluated during COVID.

“Significant differences in 24-hour ABPM patterns pre- and during COVID may reflect changes in patient behavior and lifestyle,” Dr. Kandzari speculated.

The data from this study differ from essentially all of the other studies in the SPYRAL HTN program as well as several other sham-controlled studies with renal denervation, according to Dr. Kandzari.

Ted Bosworth/MDedge News

The AHA-invited discussant, Ajay J. Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, largely agreed that several variables appeared to conspire against a positive result in this trial, but he zeroed in on the imbalance of antihypertensive medications.

“Any trial that attempts to show a difference between renal denervation and a sham procedure must insure that antihypertensive medications are the same in the two arms. They cannot be different,” he said.

As an active investigator in the field of renal denervation, Dr. Kirtane thinks the evidence does support a benefit from renal denervation, but he believes data are still needed to determine which patients are candidates.

“Renal denervation is not going to be a replacement for previous established therapies, but it will be an adjunct,” he predicted. The preponderance of evidence supports clinically meaningful reductions in BP with this approach, “but we need to determine who to consider [for this therapy] and to have realistic expectations about the degree of benefit.”

Dr. Kandzari reported financial relationships with Abbott Vascular, Ablative Solutions, Biotronik, Boston Scientific, CSI, Medtronic Cardiovascular, OrbusNeich, and Teleflex. Dr. Kirtane reported financial relationships with Abbott Vascular, Abiomed, Boston Scientific, Cardiovascular Systems, Cathworks, Chiesi, Medtronic, Opens, Philipps, Regeneron, ReCor Medical, Siemens, Spectranetics, and Zoll.
 

CHICAGO – Renal denervation, relative to a sham procedure, was linked with statistically significant reductions in blood pressure in the newly completed SPYRAL HTN–ON MED trial, but several factors are likely to have worked in concert to prevent the study from meeting its primary endpoint.

Of these differences, probably none was more important than the substantially higher proportion of patients in the sham group that received additional BP-lowering medications over the course of the study, David E. Kandzari, MD, reported at the American Heart Association scientific sessions.

Ted Bosworth/MDedge News

The SPYRAL HTN–ON MED pivotal trial followed the previously completed SPYRAL HTN–ON MED pilot study, which did show a significant BP-lowering effect on antihypertensive medications followed radiofrequency denervation. In a recent update of the pilot study, the effect was persistent out to 3 years.

In the SPYRAL HTN–ON MED program, patients on their second screening visit were required to have a systolic pressure of between 140 and 170 mm Hg on 24-hour ambulatory BP monitoring (ABPM) while taking up to three antihypertensive medications. Patients who entered the study were randomized to renal denervation or sham control while maintaining their baseline antihypertensive therapies.

The previously reported pilot study comprised 80 patients. The expansion pivotal trial added 257 more patients for a total cohort of 337 patients. The primary efficacy endpoint was based on a Bayesian analysis of change in 24-hour systolic ABPM at 6 months for those in the experimental arm versus those on medications alone. Participants from both the pilot and pivotal trials were included.

The prespecified definition of success for renal denervation was a 97.5% threshold for probability of superiority on the basis of this Bayesian analysis. However, the Bayesian analysis was distorted by differences in the pilot and expansion cohorts, which complicated the superiority calculation. As a result, the analysis only yielded a 51% probability of superiority, a level substantially below the predefined threshold.

Despite differences seen in BP control in favor of renal denervation, several factors were identified that likely contributed to the missed primary endpoint. One stood out.

“Significant differences in medication prescriptions were disproportionate in favor of the sham group,” reported Dr. Kandzari, chief of Piedmont Heart Institute, Atlanta. He said these differences, which were a violation of the protocol mandate, led to a “bias toward the null” for the primary outcome.

The failure to meet the primary outcome was particularly disappointing in the wake of the favorable pilot study and the SPYRAL HTN–OFF MED pivotal trial, which were both positive.

In the pilot study, which did not have a medication imbalance, a 7.3–mm Hg reduction (P = .004) in 24-hour ABPM was seen at 6 months. Relative reductions in office-based systolic pressure reductions for renal denervation versus sham were 6.6 mm Hg (P = .03) and 4.0 mm Hg (P = .03) for the pilot and expansions groups, respectively.

On the basis of a Win ratio derived from a hierarchical analysis of ABMP and medication burden reduction, the 1.50 advantage (P = .005) for the renal denervation arm in the newly completed SPYRAL HTN–ON MED trial was also compelling.

At study entry, the median number of medications was 1.9 in both the renal denervation and sham arms. At the end of 6 months, the median number of medications was unchanged in the experimental arm but rose to 2.1 (P = .01) in the sham group. Similarly, there was little change in the medication burden from the start to the end of the trial in the denervation group (2.8 vs. 3.0), but a statistically significant change in the sham group (2.9 vs. 3.5; P = .04).

Furthermore, the net percentage change of patients receiving medications favoring BP reduction over the course of the study did not differ between the experimental and control arms of the pilot cohort, but was more than 10 times higher among controls in the expansion group (1.9% vs. 21.8%; P < .0001).

Medication changes over the course of the SPYRAL HTN–ON MED trial were even greater in some specific subgroups. Among Black participants, for example, 14.2% of those randomized to renal denervation and 54.6% of those randomized to the sham group increased their antihypertensive therapies over the course of the study.

The COVID-19 epidemic is suspected of playing another role in the negative results, according to Dr. Kandzari. After a brief pause in enrollment, the SPYRAL HTN–ON MED trial was resumed, but approximately 80% of the expansion cohort data were collected during this period. When compared, variances in office and 24-hour ABPM were observed for participants who were or were not evaluated during COVID.

“Significant differences in 24-hour ABPM patterns pre- and during COVID may reflect changes in patient behavior and lifestyle,” Dr. Kandzari speculated.

The data from this study differ from essentially all of the other studies in the SPYRAL HTN program as well as several other sham-controlled studies with renal denervation, according to Dr. Kandzari.

Ted Bosworth/MDedge News

The AHA-invited discussant, Ajay J. Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, largely agreed that several variables appeared to conspire against a positive result in this trial, but he zeroed in on the imbalance of antihypertensive medications.

“Any trial that attempts to show a difference between renal denervation and a sham procedure must insure that antihypertensive medications are the same in the two arms. They cannot be different,” he said.

As an active investigator in the field of renal denervation, Dr. Kirtane thinks the evidence does support a benefit from renal denervation, but he believes data are still needed to determine which patients are candidates.

“Renal denervation is not going to be a replacement for previous established therapies, but it will be an adjunct,” he predicted. The preponderance of evidence supports clinically meaningful reductions in BP with this approach, “but we need to determine who to consider [for this therapy] and to have realistic expectations about the degree of benefit.”

Dr. Kandzari reported financial relationships with Abbott Vascular, Ablative Solutions, Biotronik, Boston Scientific, CSI, Medtronic Cardiovascular, OrbusNeich, and Teleflex. Dr. Kirtane reported financial relationships with Abbott Vascular, Abiomed, Boston Scientific, Cardiovascular Systems, Cathworks, Chiesi, Medtronic, Opens, Philipps, Regeneron, ReCor Medical, Siemens, Spectranetics, and Zoll.
 

CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

Bullous pemphigoid (BP) is the most common autoimmune bullous disease. It most frequently occurs in elderly patients and is associated with various predisposing factors, including HLA genes, comorbidities, aging, and trigger factors such as drugs, trauma, radiation, chemotherapy, and infections. The autoimmune reaction is mediated by a dysregulation of T cells in which IgG and IgE autoantibodies form against hemidesmosomal proteins (BP180 and BP230). These autoantibodies induce neutrophil activation, recruitment, and degradation in the basement membrane of the skin.

Typically, patients present with intense pruritus followed by an urticarial or eczematous eruption. Tense blisters and bullae occur commonly on the trunk and extremities. Drug-associated bullous pemphigoid (DABP) is a common manifestation of the disease with histologic and immunologic features similar to those of the idiopathic version. Eruptions can be triggered by systemic or topical medications, and incidence of these reactions may be related to a genetic predisposition for the disease.

Some research suggests that drug-induced changes to the antigenic properties of the epidermal basement membrane result in an augmented immune response, while others point to structural modification in these zones that stimulate the immune system. Thiol- and phenol-based drugs have been largely implicated in the development of DABP because they are capable of structural modification and disruption of the dermo-epidermal junction in the basement membrane.

DABP often presents with patients taking multiple medications. Some of the most common medications are gliptins, PD-1 inhibitors, diuretics, antibiotics, anti-inflammatory drugs, and ACE-inhibitors, and other cardiovascular drugs. DABP may present with mucosal eruptions unlike its idiopathic counterpart that is mostly contained to the skin.

On this patient, two punch biopsies were taken. Histopathology revealed an eosinophil-rich subepidermal blister with a smooth epidermal undersurface consistent with bullous pemphigoid. Direct immunofluorescence was positive with a deposition of IgG and C3 at the epidermal side of salt split basement membrane zone.

Treatment for BP includes high potency topical and systemic steroids. Tetracyclines and niacinamide have been reported to improve the condition. Treatment is tailored to allow for cutaneous healing and control pruritus, but the physician must be mindful of the patient’s comorbidities and capacity for self-care. Prognosis is often better for DABP as withdrawal of the medication greatly accelerates clearance of the lesions. Worse prognosis is related to increased number of comorbidities and older age. Our patient’s BP is controlled currently with topical steroids and oral doxycycline.

This case and photo were submitted by Lucas Shapiro, BS, Nova Southeastern University College of Osteopathic Medicine, Tampa, and Dr. Bilu Martin.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Miyamoto D et al. An Bras Dermatol. 2019 Mar-Apr;94(2):133-46.

2. Moro et al. Biomolecules. 2020 Oct 10;10(10):1432.

3. Verheyden M et al. Acta Derm Venereol. 2020 Aug 17;100(15):adv00224.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease. It most frequently occurs in elderly patients and is associated with various predisposing factors, including HLA genes, comorbidities, aging, and trigger factors such as drugs, trauma, radiation, chemotherapy, and infections. The autoimmune reaction is mediated by a dysregulation of T cells in which IgG and IgE autoantibodies form against hemidesmosomal proteins (BP180 and BP230). These autoantibodies induce neutrophil activation, recruitment, and degradation in the basement membrane of the skin.

Typically, patients present with intense pruritus followed by an urticarial or eczematous eruption. Tense blisters and bullae occur commonly on the trunk and extremities. Drug-associated bullous pemphigoid (DABP) is a common manifestation of the disease with histologic and immunologic features similar to those of the idiopathic version. Eruptions can be triggered by systemic or topical medications, and incidence of these reactions may be related to a genetic predisposition for the disease.

Some research suggests that drug-induced changes to the antigenic properties of the epidermal basement membrane result in an augmented immune response, while others point to structural modification in these zones that stimulate the immune system. Thiol- and phenol-based drugs have been largely implicated in the development of DABP because they are capable of structural modification and disruption of the dermo-epidermal junction in the basement membrane.

DABP often presents with patients taking multiple medications. Some of the most common medications are gliptins, PD-1 inhibitors, diuretics, antibiotics, anti-inflammatory drugs, and ACE-inhibitors, and other cardiovascular drugs. DABP may present with mucosal eruptions unlike its idiopathic counterpart that is mostly contained to the skin.

On this patient, two punch biopsies were taken. Histopathology revealed an eosinophil-rich subepidermal blister with a smooth epidermal undersurface consistent with bullous pemphigoid. Direct immunofluorescence was positive with a deposition of IgG and C3 at the epidermal side of salt split basement membrane zone.

Treatment for BP includes high potency topical and systemic steroids. Tetracyclines and niacinamide have been reported to improve the condition. Treatment is tailored to allow for cutaneous healing and control pruritus, but the physician must be mindful of the patient’s comorbidities and capacity for self-care. Prognosis is often better for DABP as withdrawal of the medication greatly accelerates clearance of the lesions. Worse prognosis is related to increased number of comorbidities and older age. Our patient’s BP is controlled currently with topical steroids and oral doxycycline.

This case and photo were submitted by Lucas Shapiro, BS, Nova Southeastern University College of Osteopathic Medicine, Tampa, and Dr. Bilu Martin.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Miyamoto D et al. An Bras Dermatol. 2019 Mar-Apr;94(2):133-46.

2. Moro et al. Biomolecules. 2020 Oct 10;10(10):1432.

3. Verheyden M et al. Acta Derm Venereol. 2020 Aug 17;100(15):adv00224.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease. It most frequently occurs in elderly patients and is associated with various predisposing factors, including HLA genes, comorbidities, aging, and trigger factors such as drugs, trauma, radiation, chemotherapy, and infections. The autoimmune reaction is mediated by a dysregulation of T cells in which IgG and IgE autoantibodies form against hemidesmosomal proteins (BP180 and BP230). These autoantibodies induce neutrophil activation, recruitment, and degradation in the basement membrane of the skin.

Typically, patients present with intense pruritus followed by an urticarial or eczematous eruption. Tense blisters and bullae occur commonly on the trunk and extremities. Drug-associated bullous pemphigoid (DABP) is a common manifestation of the disease with histologic and immunologic features similar to those of the idiopathic version. Eruptions can be triggered by systemic or topical medications, and incidence of these reactions may be related to a genetic predisposition for the disease.

Some research suggests that drug-induced changes to the antigenic properties of the epidermal basement membrane result in an augmented immune response, while others point to structural modification in these zones that stimulate the immune system. Thiol- and phenol-based drugs have been largely implicated in the development of DABP because they are capable of structural modification and disruption of the dermo-epidermal junction in the basement membrane.

DABP often presents with patients taking multiple medications. Some of the most common medications are gliptins, PD-1 inhibitors, diuretics, antibiotics, anti-inflammatory drugs, and ACE-inhibitors, and other cardiovascular drugs. DABP may present with mucosal eruptions unlike its idiopathic counterpart that is mostly contained to the skin.

On this patient, two punch biopsies were taken. Histopathology revealed an eosinophil-rich subepidermal blister with a smooth epidermal undersurface consistent with bullous pemphigoid. Direct immunofluorescence was positive with a deposition of IgG and C3 at the epidermal side of salt split basement membrane zone.

Treatment for BP includes high potency topical and systemic steroids. Tetracyclines and niacinamide have been reported to improve the condition. Treatment is tailored to allow for cutaneous healing and control pruritus, but the physician must be mindful of the patient’s comorbidities and capacity for self-care. Prognosis is often better for DABP as withdrawal of the medication greatly accelerates clearance of the lesions. Worse prognosis is related to increased number of comorbidities and older age. Our patient’s BP is controlled currently with topical steroids and oral doxycycline.

This case and photo were submitted by Lucas Shapiro, BS, Nova Southeastern University College of Osteopathic Medicine, Tampa, and Dr. Bilu Martin.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Miyamoto D et al. An Bras Dermatol. 2019 Mar-Apr;94(2):133-46.

2. Moro et al. Biomolecules. 2020 Oct 10;10(10):1432.

3. Verheyden M et al. Acta Derm Venereol. 2020 Aug 17;100(15):adv00224.

That a bustling medical conference can have global reach as it unfolds is one of the COVID pandemic’s many lessons for science. Hybrid meetings such as the American Heart Association scientific sessions, getting underway Nov. 5 in Chicago and cyberspace, are one of its legacies.

The conference is set to recapture the magic of the in-person Scientific Sessions last experienced in Philadelphia in 2019. But planners are mindful of a special responsibility to younger clinicians and scientists who entered the field knowing only the virtual format and who may not know “what it’s like in a room when major science is presented or to present posters and have people come by for conversations,” Manesh R. Patel, MD, chair of the AHA 2022 Scientific Sessions program committee, told this news organization.

Still, the pandemic has underlined the value of live streaming for the great many who can’t attend in person, Dr. Patel said. At AHA 2022, virtual access doesn’t mean only late breaking and featured presentations; more than 70 full sessions will be streamed from Friday through Monday.

Overall, the conference has more than 800 sessions on the schedule, about a third are panels or invited lectures and two-thirds are original reports on the latest research. At the core of the research offerings, 78 studies and analyses are slated across 18 Late-Breaking Science (LBS) and Featured Science (FS) sessions from Saturday through Monday. At least 30 presentations and abstracts will enter the peer-reviewed literature right away with their simultaneous online publication, Dr. Patel said.

More a meet-and-greet than a presentation, the Puppy Snuggles Booth will make a return appearance in Chicago after earning rave reviews at the 2019 Sessions in Philadelphia. All are invited to take a breather from their schedules to pet, cuddle, and play with a passel of pups, all in need of homes and available for adoption. The experience’s favorable effect on blood pressure is almost guaranteed.
 

LBS and FS highlights

“It’s an amazing year for Late Breaking Science and Featured Science at the Scientific Sessions,” Dr. Patel said of the presentations selected for special attention after a rigorous review process. “We have science that is as broad and as deep as we’ve seen in years.”

Saturday’s two LBS sessions kick off the series with studies looking at agents long available in heart failure and hypertension but lacking solid supporting evidence, “pretty large randomized trials that are, we think, going to affect clinical practice as soon as they are presented,” Dr. Patel said.

They include TRANSFORM-HF, a comparison of the loop diuretics furosemide and torsemide in patients hospitalized with heart failure. And the Diuretic Comparison Project (DCP), with more than 13,000 patients with hypertension assigned to the diuretics chlorthalidone or hydrochlorothiazide, “is going to immediately impact how people think about blood pressure management,” Dr. Patel said.

Other highlights in the hypertension arena include the CRHCP trial, the MB-BP study, the Rich Life Project, and the polypill efficacy and safety trial QUARTET-USA, all in Sunday’s LBS-4; and the FRESH, PRECISION, and BrigHTN trials, all in LBS-9 on Monday.

Other heart failure trials joining TRANSFORM-HF in the line-up include IRONMAN, which revisited IV iron therapy in iron-deficient patients, in LBS-2 on Saturday and, in FS-4 on Monday, BETA3LVH and STRONG-HF, the latter a timely randomized test of pre- and post-discharge biomarker-driven uptitration of guideline-directed heart failure meds.

STRONG-HF was halted early, the trial’s nonprofit sponsor announced only weeks ago, after patients following the intensive uptitration strategy versus usual care showed a reduced risk of death or heart failure readmission; few other details were given.

Several sessions will be devoted to a rare breed of randomized trial, one that tests the efficacy of traditional herbal meds or nonprescription supplements against proven medications. “These are going to get a lot of people’s interest, one can imagine, because they are on common questions that patients bring to the clinic every day,” Dr. Patel said.

Such studies include CTS-AMI, which explored the traditional Chinese herbal medicine tongxinluo in ST-segment elevation myocardial infarction, in LBS-3 on Sunday, and SPORT in Sunday’s LBS-5, a small randomized comparison of low-dose rosuvastatin, cinnamon, garlic, turmeric, an omega-3 fish-oil supplement, a plant sterol, red yeast rice, and placebo for any effects on LDL-C levels.

Other novel approaches to dyslipidemia management are to be covered in RESPECT-EPA and OCEAN(a)-DOSE, both in LBS-5 on Sunday, and all five presentations in Monday’s FS-9, including ARCHES-2, SHASTA-2, FOURIER-OLE, and ORION-3.

The interplay of antiplatelets and coronary interventions will be explored in presentations called OPTION, in LBS-6 on Sunday, and HOST-EXAM and TWILIGHT, in FS-6 on Monday.

Coronary and peripheral-vascular interventions are center stage in reports on RAPCO in LBS-3 and BRIGHT-4 in LBS-6, both on Sunday, and BEST-CLI in LBS-7 and the After-80 Study in FS-6, both on Monday.

Several Monday reports will cover comorbidities and complications associated with COVID-19, including PREVENT-HD in LBS-7, and PANAMO, FERMIN, COVID-NET, and a secondary analysis of the DELIVER trial in FS-5.
 

Rebroadcasts for the Pacific Rim

The sessions will also feature several evening rebroadcasts of earlier LBS sessions that meeting planners scored highly for scientific merit and potential clinical impact but also for their “regional pull,” primarily for our colleagues in Asia, Dr. Patel said.

The first two LBS sessions presented live during the day in Chicago will be rebroadcast that evening as, for example, Sunday morning and afternoon fare in Tokyo and Singapore. And LBS-5 live Sunday afternoon will rebroadcast that night as a Monday mid-morning session in, say, Hong Kong or Seoul.

This year’s AHA meeting spans the range of cardiovascular care, from precision therapies, such as gene editing or specific drugs, to broad strategies that consider, for example, social determinants of health, Dr. Patel said. “I think people, when they leave the Scientific Sessions, will feel very engaged in the larger conversation about how you impact very common conditions globally.”

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

That a bustling medical conference can have global reach as it unfolds is one of the COVID pandemic’s many lessons for science. Hybrid meetings such as the American Heart Association scientific sessions, getting underway Nov. 5 in Chicago and cyberspace, are one of its legacies.

The conference is set to recapture the magic of the in-person Scientific Sessions last experienced in Philadelphia in 2019. But planners are mindful of a special responsibility to younger clinicians and scientists who entered the field knowing only the virtual format and who may not know “what it’s like in a room when major science is presented or to present posters and have people come by for conversations,” Manesh R. Patel, MD, chair of the AHA 2022 Scientific Sessions program committee, told this news organization.

Still, the pandemic has underlined the value of live streaming for the great many who can’t attend in person, Dr. Patel said. At AHA 2022, virtual access doesn’t mean only late breaking and featured presentations; more than 70 full sessions will be streamed from Friday through Monday.

Overall, the conference has more than 800 sessions on the schedule, about a third are panels or invited lectures and two-thirds are original reports on the latest research. At the core of the research offerings, 78 studies and analyses are slated across 18 Late-Breaking Science (LBS) and Featured Science (FS) sessions from Saturday through Monday. At least 30 presentations and abstracts will enter the peer-reviewed literature right away with their simultaneous online publication, Dr. Patel said.

More a meet-and-greet than a presentation, the Puppy Snuggles Booth will make a return appearance in Chicago after earning rave reviews at the 2019 Sessions in Philadelphia. All are invited to take a breather from their schedules to pet, cuddle, and play with a passel of pups, all in need of homes and available for adoption. The experience’s favorable effect on blood pressure is almost guaranteed.
 

LBS and FS highlights

“It’s an amazing year for Late Breaking Science and Featured Science at the Scientific Sessions,” Dr. Patel said of the presentations selected for special attention after a rigorous review process. “We have science that is as broad and as deep as we’ve seen in years.”

Saturday’s two LBS sessions kick off the series with studies looking at agents long available in heart failure and hypertension but lacking solid supporting evidence, “pretty large randomized trials that are, we think, going to affect clinical practice as soon as they are presented,” Dr. Patel said.

They include TRANSFORM-HF, a comparison of the loop diuretics furosemide and torsemide in patients hospitalized with heart failure. And the Diuretic Comparison Project (DCP), with more than 13,000 patients with hypertension assigned to the diuretics chlorthalidone or hydrochlorothiazide, “is going to immediately impact how people think about blood pressure management,” Dr. Patel said.

Other highlights in the hypertension arena include the CRHCP trial, the MB-BP study, the Rich Life Project, and the polypill efficacy and safety trial QUARTET-USA, all in Sunday’s LBS-4; and the FRESH, PRECISION, and BrigHTN trials, all in LBS-9 on Monday.

Other heart failure trials joining TRANSFORM-HF in the line-up include IRONMAN, which revisited IV iron therapy in iron-deficient patients, in LBS-2 on Saturday and, in FS-4 on Monday, BETA3LVH and STRONG-HF, the latter a timely randomized test of pre- and post-discharge biomarker-driven uptitration of guideline-directed heart failure meds.

STRONG-HF was halted early, the trial’s nonprofit sponsor announced only weeks ago, after patients following the intensive uptitration strategy versus usual care showed a reduced risk of death or heart failure readmission; few other details were given.

Several sessions will be devoted to a rare breed of randomized trial, one that tests the efficacy of traditional herbal meds or nonprescription supplements against proven medications. “These are going to get a lot of people’s interest, one can imagine, because they are on common questions that patients bring to the clinic every day,” Dr. Patel said.

Such studies include CTS-AMI, which explored the traditional Chinese herbal medicine tongxinluo in ST-segment elevation myocardial infarction, in LBS-3 on Sunday, and SPORT in Sunday’s LBS-5, a small randomized comparison of low-dose rosuvastatin, cinnamon, garlic, turmeric, an omega-3 fish-oil supplement, a plant sterol, red yeast rice, and placebo for any effects on LDL-C levels.

Other novel approaches to dyslipidemia management are to be covered in RESPECT-EPA and OCEAN(a)-DOSE, both in LBS-5 on Sunday, and all five presentations in Monday’s FS-9, including ARCHES-2, SHASTA-2, FOURIER-OLE, and ORION-3.

The interplay of antiplatelets and coronary interventions will be explored in presentations called OPTION, in LBS-6 on Sunday, and HOST-EXAM and TWILIGHT, in FS-6 on Monday.

Coronary and peripheral-vascular interventions are center stage in reports on RAPCO in LBS-3 and BRIGHT-4 in LBS-6, both on Sunday, and BEST-CLI in LBS-7 and the After-80 Study in FS-6, both on Monday.

Several Monday reports will cover comorbidities and complications associated with COVID-19, including PREVENT-HD in LBS-7, and PANAMO, FERMIN, COVID-NET, and a secondary analysis of the DELIVER trial in FS-5.
 

Rebroadcasts for the Pacific Rim

The sessions will also feature several evening rebroadcasts of earlier LBS sessions that meeting planners scored highly for scientific merit and potential clinical impact but also for their “regional pull,” primarily for our colleagues in Asia, Dr. Patel said.

The first two LBS sessions presented live during the day in Chicago will be rebroadcast that evening as, for example, Sunday morning and afternoon fare in Tokyo and Singapore. And LBS-5 live Sunday afternoon will rebroadcast that night as a Monday mid-morning session in, say, Hong Kong or Seoul.

This year’s AHA meeting spans the range of cardiovascular care, from precision therapies, such as gene editing or specific drugs, to broad strategies that consider, for example, social determinants of health, Dr. Patel said. “I think people, when they leave the Scientific Sessions, will feel very engaged in the larger conversation about how you impact very common conditions globally.”

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

That a bustling medical conference can have global reach as it unfolds is one of the COVID pandemic’s many lessons for science. Hybrid meetings such as the American Heart Association scientific sessions, getting underway Nov. 5 in Chicago and cyberspace, are one of its legacies.

The conference is set to recapture the magic of the in-person Scientific Sessions last experienced in Philadelphia in 2019. But planners are mindful of a special responsibility to younger clinicians and scientists who entered the field knowing only the virtual format and who may not know “what it’s like in a room when major science is presented or to present posters and have people come by for conversations,” Manesh R. Patel, MD, chair of the AHA 2022 Scientific Sessions program committee, told this news organization.

Still, the pandemic has underlined the value of live streaming for the great many who can’t attend in person, Dr. Patel said. At AHA 2022, virtual access doesn’t mean only late breaking and featured presentations; more than 70 full sessions will be streamed from Friday through Monday.

Overall, the conference has more than 800 sessions on the schedule, about a third are panels or invited lectures and two-thirds are original reports on the latest research. At the core of the research offerings, 78 studies and analyses are slated across 18 Late-Breaking Science (LBS) and Featured Science (FS) sessions from Saturday through Monday. At least 30 presentations and abstracts will enter the peer-reviewed literature right away with their simultaneous online publication, Dr. Patel said.

More a meet-and-greet than a presentation, the Puppy Snuggles Booth will make a return appearance in Chicago after earning rave reviews at the 2019 Sessions in Philadelphia. All are invited to take a breather from their schedules to pet, cuddle, and play with a passel of pups, all in need of homes and available for adoption. The experience’s favorable effect on blood pressure is almost guaranteed.
 

LBS and FS highlights

“It’s an amazing year for Late Breaking Science and Featured Science at the Scientific Sessions,” Dr. Patel said of the presentations selected for special attention after a rigorous review process. “We have science that is as broad and as deep as we’ve seen in years.”

Saturday’s two LBS sessions kick off the series with studies looking at agents long available in heart failure and hypertension but lacking solid supporting evidence, “pretty large randomized trials that are, we think, going to affect clinical practice as soon as they are presented,” Dr. Patel said.

They include TRANSFORM-HF, a comparison of the loop diuretics furosemide and torsemide in patients hospitalized with heart failure. And the Diuretic Comparison Project (DCP), with more than 13,000 patients with hypertension assigned to the diuretics chlorthalidone or hydrochlorothiazide, “is going to immediately impact how people think about blood pressure management,” Dr. Patel said.

Other highlights in the hypertension arena include the CRHCP trial, the MB-BP study, the Rich Life Project, and the polypill efficacy and safety trial QUARTET-USA, all in Sunday’s LBS-4; and the FRESH, PRECISION, and BrigHTN trials, all in LBS-9 on Monday.

Other heart failure trials joining TRANSFORM-HF in the line-up include IRONMAN, which revisited IV iron therapy in iron-deficient patients, in LBS-2 on Saturday and, in FS-4 on Monday, BETA3LVH and STRONG-HF, the latter a timely randomized test of pre- and post-discharge biomarker-driven uptitration of guideline-directed heart failure meds.

STRONG-HF was halted early, the trial’s nonprofit sponsor announced only weeks ago, after patients following the intensive uptitration strategy versus usual care showed a reduced risk of death or heart failure readmission; few other details were given.

Several sessions will be devoted to a rare breed of randomized trial, one that tests the efficacy of traditional herbal meds or nonprescription supplements against proven medications. “These are going to get a lot of people’s interest, one can imagine, because they are on common questions that patients bring to the clinic every day,” Dr. Patel said.

Such studies include CTS-AMI, which explored the traditional Chinese herbal medicine tongxinluo in ST-segment elevation myocardial infarction, in LBS-3 on Sunday, and SPORT in Sunday’s LBS-5, a small randomized comparison of low-dose rosuvastatin, cinnamon, garlic, turmeric, an omega-3 fish-oil supplement, a plant sterol, red yeast rice, and placebo for any effects on LDL-C levels.

Other novel approaches to dyslipidemia management are to be covered in RESPECT-EPA and OCEAN(a)-DOSE, both in LBS-5 on Sunday, and all five presentations in Monday’s FS-9, including ARCHES-2, SHASTA-2, FOURIER-OLE, and ORION-3.

The interplay of antiplatelets and coronary interventions will be explored in presentations called OPTION, in LBS-6 on Sunday, and HOST-EXAM and TWILIGHT, in FS-6 on Monday.

Coronary and peripheral-vascular interventions are center stage in reports on RAPCO in LBS-3 and BRIGHT-4 in LBS-6, both on Sunday, and BEST-CLI in LBS-7 and the After-80 Study in FS-6, both on Monday.

Several Monday reports will cover comorbidities and complications associated with COVID-19, including PREVENT-HD in LBS-7, and PANAMO, FERMIN, COVID-NET, and a secondary analysis of the DELIVER trial in FS-5.
 

Rebroadcasts for the Pacific Rim

The sessions will also feature several evening rebroadcasts of earlier LBS sessions that meeting planners scored highly for scientific merit and potential clinical impact but also for their “regional pull,” primarily for our colleagues in Asia, Dr. Patel said.

The first two LBS sessions presented live during the day in Chicago will be rebroadcast that evening as, for example, Sunday morning and afternoon fare in Tokyo and Singapore. And LBS-5 live Sunday afternoon will rebroadcast that night as a Monday mid-morning session in, say, Hong Kong or Seoul.

This year’s AHA meeting spans the range of cardiovascular care, from precision therapies, such as gene editing or specific drugs, to broad strategies that consider, for example, social determinants of health, Dr. Patel said. “I think people, when they leave the Scientific Sessions, will feel very engaged in the larger conversation about how you impact very common conditions globally.”

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