Clinical Topics & News

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has received consulting fees from Accordant, Biogen, Bristol Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio and grant funding from Actelion, Alkermes, Bristol Myers Squibb, CorEvitas LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has received consulting fees from Accordant, Biogen, Bristol Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio and grant funding from Actelion, Alkermes, Bristol Myers Squibb, CorEvitas LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has received consulting fees from Accordant, Biogen, Bristol Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio and grant funding from Actelion, Alkermes, Bristol Myers Squibb, CorEvitas LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Giving a boost radiation dose to the tumor bed following breast-conserving surgery and whole breast irradiation (WBI) has been shown to be effective at reducing recurrence of invasive breast cancer, and now a multinational randomized trial has shown that it can do the same for patients with non–low-risk ductal carcinoma in situ (DCIS).

“The results provide the first randomized trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control,” wrote the authors, led by Boon H. Chua, PhD, from the University of New South Wales, Sydney.

Among 1,608 patients with DCIS with at least one clinical or pathological marker for increased risk of local recurrence, 5-year rates of freedom from local recurrence were 97.1% for patients assigned to received a tumor bed boost versus 92.7% for patients who did not receive a boost dose. This difference translated into a hazard ratio for recurrence with radiation boost of 0.47 (P < .001).

“Our results support the use of tumor-bed boost radiation after postoperative WBI in patients with non–low-risk DCIS to optimize local control, and the adoption of moderately hypofractionated whole breast irradiation in practice to improve the balance of local control, toxicity, and socioeconomic burdens of treatment,” the authors wrote in a study published in The Lancet.

The investigators, from cancer centers in Australia, Europe, and Canada, noted that the advent of screening mammography was followed by a substantial increase in the diagnosis of DCIS. They also noted that patients who undergo breast-conserving surgery for DCIS are at risk for local recurrence, and half of recurrences present as invasive disease.

In addition, they said, there were high recurrence rates in randomized clinical for patients with DCIS who received conventionally fractionated WBI without a tumor boost following surgery.

“Further, the inconvenience of a 5- to 6-week course of conventionally fractionated WBI decreased the quality of life of patients. Thus, tailoring radiation dose fractionation according to recurrence risk is a prominent controversy in the radiation treatment of DCIS,” they wrote.
 

Four-way trial

To see whether a tumor-bed boost following WBI and alternative WBI fractionation schedules could improve outcomes for patients with non–low-risk DCIS, the researchers enrolled patients and assigned them on an equal basis to one of four groups, in which they would receive either conventional or hypofractionated WBI with or without a tumor-bed boost.

The conventional WBI regimen consisted of a total of 50 Gy delivered over 25 fractions. The hypofractionated regimen consisted of a total dose of 42.5 Gy delivered in 16 fractions. Patients assigned to get a boost dose to the tumor bed received an additional 16 Gy in eight fractions after WBI.

Of the 1,608 patients enrolled who eligible for randomization, 803 received a boost dose and 805 did not. As noted before, the risk of recurrence at 5 years was significantly lower with boosting, with 5-year free-from-local-recurrence rates of 97.1%, compared with 92.7% for patients who did not get a tumor-bed boost.

There were no significant differences according to fractionation schedule, however: among all randomly assigned patients the rate of 5-year freedom from recurrence was 94.9% for both the conventionally fractionated and hypofractionated WBI groups.

Not surprisingly, patients who received the boost dose had higher rates of grade 2 or greater toxicities, including breast pain (14% vs. 10%; P = .03) and induration (14% vs. 6%; P < .001).

The study was supported by the National Health and Medical Research Council of Australia, Susan G. Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, and Canadian Cancer Trials Group. Dr. Chua disclosed grant support from the organizations and others.

Giving a boost radiation dose to the tumor bed following breast-conserving surgery and whole breast irradiation (WBI) has been shown to be effective at reducing recurrence of invasive breast cancer, and now a multinational randomized trial has shown that it can do the same for patients with non–low-risk ductal carcinoma in situ (DCIS).

“The results provide the first randomized trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control,” wrote the authors, led by Boon H. Chua, PhD, from the University of New South Wales, Sydney.

Among 1,608 patients with DCIS with at least one clinical or pathological marker for increased risk of local recurrence, 5-year rates of freedom from local recurrence were 97.1% for patients assigned to received a tumor bed boost versus 92.7% for patients who did not receive a boost dose. This difference translated into a hazard ratio for recurrence with radiation boost of 0.47 (P < .001).

“Our results support the use of tumor-bed boost radiation after postoperative WBI in patients with non–low-risk DCIS to optimize local control, and the adoption of moderately hypofractionated whole breast irradiation in practice to improve the balance of local control, toxicity, and socioeconomic burdens of treatment,” the authors wrote in a study published in The Lancet.

The investigators, from cancer centers in Australia, Europe, and Canada, noted that the advent of screening mammography was followed by a substantial increase in the diagnosis of DCIS. They also noted that patients who undergo breast-conserving surgery for DCIS are at risk for local recurrence, and half of recurrences present as invasive disease.

In addition, they said, there were high recurrence rates in randomized clinical for patients with DCIS who received conventionally fractionated WBI without a tumor boost following surgery.

“Further, the inconvenience of a 5- to 6-week course of conventionally fractionated WBI decreased the quality of life of patients. Thus, tailoring radiation dose fractionation according to recurrence risk is a prominent controversy in the radiation treatment of DCIS,” they wrote.
 

Four-way trial

To see whether a tumor-bed boost following WBI and alternative WBI fractionation schedules could improve outcomes for patients with non–low-risk DCIS, the researchers enrolled patients and assigned them on an equal basis to one of four groups, in which they would receive either conventional or hypofractionated WBI with or without a tumor-bed boost.

The conventional WBI regimen consisted of a total of 50 Gy delivered over 25 fractions. The hypofractionated regimen consisted of a total dose of 42.5 Gy delivered in 16 fractions. Patients assigned to get a boost dose to the tumor bed received an additional 16 Gy in eight fractions after WBI.

Of the 1,608 patients enrolled who eligible for randomization, 803 received a boost dose and 805 did not. As noted before, the risk of recurrence at 5 years was significantly lower with boosting, with 5-year free-from-local-recurrence rates of 97.1%, compared with 92.7% for patients who did not get a tumor-bed boost.

There were no significant differences according to fractionation schedule, however: among all randomly assigned patients the rate of 5-year freedom from recurrence was 94.9% for both the conventionally fractionated and hypofractionated WBI groups.

Not surprisingly, patients who received the boost dose had higher rates of grade 2 or greater toxicities, including breast pain (14% vs. 10%; P = .03) and induration (14% vs. 6%; P < .001).

The study was supported by the National Health and Medical Research Council of Australia, Susan G. Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, and Canadian Cancer Trials Group. Dr. Chua disclosed grant support from the organizations and others.

Giving a boost radiation dose to the tumor bed following breast-conserving surgery and whole breast irradiation (WBI) has been shown to be effective at reducing recurrence of invasive breast cancer, and now a multinational randomized trial has shown that it can do the same for patients with non–low-risk ductal carcinoma in situ (DCIS).

“The results provide the first randomized trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control,” wrote the authors, led by Boon H. Chua, PhD, from the University of New South Wales, Sydney.

Among 1,608 patients with DCIS with at least one clinical or pathological marker for increased risk of local recurrence, 5-year rates of freedom from local recurrence were 97.1% for patients assigned to received a tumor bed boost versus 92.7% for patients who did not receive a boost dose. This difference translated into a hazard ratio for recurrence with radiation boost of 0.47 (P < .001).

“Our results support the use of tumor-bed boost radiation after postoperative WBI in patients with non–low-risk DCIS to optimize local control, and the adoption of moderately hypofractionated whole breast irradiation in practice to improve the balance of local control, toxicity, and socioeconomic burdens of treatment,” the authors wrote in a study published in The Lancet.

The investigators, from cancer centers in Australia, Europe, and Canada, noted that the advent of screening mammography was followed by a substantial increase in the diagnosis of DCIS. They also noted that patients who undergo breast-conserving surgery for DCIS are at risk for local recurrence, and half of recurrences present as invasive disease.

In addition, they said, there were high recurrence rates in randomized clinical for patients with DCIS who received conventionally fractionated WBI without a tumor boost following surgery.

“Further, the inconvenience of a 5- to 6-week course of conventionally fractionated WBI decreased the quality of life of patients. Thus, tailoring radiation dose fractionation according to recurrence risk is a prominent controversy in the radiation treatment of DCIS,” they wrote.
 

Four-way trial

To see whether a tumor-bed boost following WBI and alternative WBI fractionation schedules could improve outcomes for patients with non–low-risk DCIS, the researchers enrolled patients and assigned them on an equal basis to one of four groups, in which they would receive either conventional or hypofractionated WBI with or without a tumor-bed boost.

The conventional WBI regimen consisted of a total of 50 Gy delivered over 25 fractions. The hypofractionated regimen consisted of a total dose of 42.5 Gy delivered in 16 fractions. Patients assigned to get a boost dose to the tumor bed received an additional 16 Gy in eight fractions after WBI.

Of the 1,608 patients enrolled who eligible for randomization, 803 received a boost dose and 805 did not. As noted before, the risk of recurrence at 5 years was significantly lower with boosting, with 5-year free-from-local-recurrence rates of 97.1%, compared with 92.7% for patients who did not get a tumor-bed boost.

There were no significant differences according to fractionation schedule, however: among all randomly assigned patients the rate of 5-year freedom from recurrence was 94.9% for both the conventionally fractionated and hypofractionated WBI groups.

Not surprisingly, patients who received the boost dose had higher rates of grade 2 or greater toxicities, including breast pain (14% vs. 10%; P = .03) and induration (14% vs. 6%; P < .001).

The study was supported by the National Health and Medical Research Council of Australia, Susan G. Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, and Canadian Cancer Trials Group. Dr. Chua disclosed grant support from the organizations and others.

Endoscopic ultrasound (EUS)–guided through-the-needle biopsies (TTNBs) of pancreatic cystic lesions are sufficient for accurate molecular analysis, which offers a superior alternative to cyst fluid obtained via fine-needle aspiration, based on a prospective study.

For highest diagnostic clarity, next-generation sequencing (NGS) of TTNBs can be paired with histology, lead author Charlotte Vestrup Rift, MD, PhD, of Copenhagen University Hospital, and colleagues reported.

“The diagnostic algorithm for the management of [pancreatic cystic lesions] includes endoscopic ultrasound examination with aspiration of cyst fluid for cytology,” the investigators wrote in Gastrointestinal Endoscopy. “However, the reported sensitivity of cytology is low [at 54%]. A new microforceps, introduced through a 19-gauge needle, has proven useful for procurement of [TTNBs] that represent both the epithelial and stromal component of the cyst wall. TTNBs have a high sensitivity of 86% for the diagnosis of mucinous cysts.”

Dr. Rift and colleagues evaluated the impact of introducing NGS to the diagnostic process. They noted that concomitant mutations in GNAS and KRAS are diagnostic for intraductal papillary mucinous neoplasms (IPMNs), while other mutations have been linked with progression to cancer.

The study involved 101 patients with pancreatic cystic lesions larger than 15 mm in diameter, mean age of 68 years, among whom 91 had residual TTNBs available after microscopic analysis. These samples underwent a 51-gene NGS panel that included the “most prevalent hot-spot mutations.” Diagnoses were sorted into four categories: neoplastic cyst, mucinous cyst, IPMN, or serous cystic neoplasm.

The primary endpoint was diagnostic yield, both for molecular analysis of TTNBs and for molecular analysis plus histopathology of TTNBs. Sensitivity and specificity of NGS were also determined using histopathology as the gold standard.

Relying on NGS alone, diagnostic yields were 44.5% and 27.7% for detecting a mucinous cyst and determining type of cyst, respectively. These yields rose to 73.3% and 70.3%, respectively, when NGS was used with microscopic evaluation. Continuing with this combined approach, sensitivity and specificity were 83.7% and 81.8%, respectively, for the diagnosis of a mucinous cyst. Sensitivity and specificity were higher still, at 87.2% and 84.6%, respectively, for identifying IPMNs.

The adverse-event rate was 9.9%, with a risk of postprocedure acute pancreatitis of 8.9 % and procedure-associated intracystic bleeding of 3%, according to the authors.

Limitations of the study include the relatively small sample size and the single-center design.

“TTNB-NGS is not sufficient as a stand-alone diagnostic tool as of yet but has a high diagnostic yield when combined with microscopic evaluation and subtyping by immunohistochemistry,” the investigators concluded. “The advantage of EUS-TTNB over EUS–[fine-needle aspiration] is the ability to perform detailed cyst subtyping and the high technical success rate of the procedure. ... However, the procedure comes with a risk of adverse events and thus should be offered to patients where the value of an exact diagnosis outweighs the risks.”

“Molecular subtyping is emerging as a useful clinical test for diagnosing pancreatic cysts,” said Margaret Geraldine Keane, MBBS, MSc, of Johns Hopkins Medicine, Baltimore, although she noted that NGS remains expensive and sporadically available, “which limits its clinical utility and incorporation into diagnostic algorithms for pancreatic cysts. In the future, as the cost of sequencing reduces, and availability improves, this may change.”

For now, Dr. Keane advised physicians to reserve molecular subtyping for cases in which “accurate cyst subtyping will change management ... or when other tests have not provided a clear diagnosis.”

She said the present study is valuable because better diagnostic tests are badly needed for patients with pancreatic cysts, considering the high rate of surgical overtreatment.

“Having more diagnostic tests, such as those described in this publication [to be used on their own or in combination] to decide which patients need surgery, is important,” Dr. Keane said who was not involved in the study.

Better diagnostic tests could also improve outcomes for patients with pancreatic cancer, she said, noting a 5-year survival rate of 10%.

“This outcome is in large part attributable to the late stage at which the majority of patients are diagnosed,” Dr. Keane said. “If patients can be diagnosed earlier, survival dramatically improves. Improvements in diagnostic tests for premalignant pancreatic cystic lesions are therefore vital.”

The study was supported by Rigshospitalets Research Foundation, The Novo Nordisk Foundation, The Danish Cancer Society, and others, although they did not have a role in conducting the study or preparing the manuscript. One investigator disclosed a relationship with MediGlobe. The other investigators reported no conflicts of interest. Dr. Keane disclosed no conflicts of interest.

Endoscopic ultrasound (EUS)–guided through-the-needle biopsies (TTNBs) of pancreatic cystic lesions are sufficient for accurate molecular analysis, which offers a superior alternative to cyst fluid obtained via fine-needle aspiration, based on a prospective study.

For highest diagnostic clarity, next-generation sequencing (NGS) of TTNBs can be paired with histology, lead author Charlotte Vestrup Rift, MD, PhD, of Copenhagen University Hospital, and colleagues reported.

“The diagnostic algorithm for the management of [pancreatic cystic lesions] includes endoscopic ultrasound examination with aspiration of cyst fluid for cytology,” the investigators wrote in Gastrointestinal Endoscopy. “However, the reported sensitivity of cytology is low [at 54%]. A new microforceps, introduced through a 19-gauge needle, has proven useful for procurement of [TTNBs] that represent both the epithelial and stromal component of the cyst wall. TTNBs have a high sensitivity of 86% for the diagnosis of mucinous cysts.”

Dr. Rift and colleagues evaluated the impact of introducing NGS to the diagnostic process. They noted that concomitant mutations in GNAS and KRAS are diagnostic for intraductal papillary mucinous neoplasms (IPMNs), while other mutations have been linked with progression to cancer.

The study involved 101 patients with pancreatic cystic lesions larger than 15 mm in diameter, mean age of 68 years, among whom 91 had residual TTNBs available after microscopic analysis. These samples underwent a 51-gene NGS panel that included the “most prevalent hot-spot mutations.” Diagnoses were sorted into four categories: neoplastic cyst, mucinous cyst, IPMN, or serous cystic neoplasm.

The primary endpoint was diagnostic yield, both for molecular analysis of TTNBs and for molecular analysis plus histopathology of TTNBs. Sensitivity and specificity of NGS were also determined using histopathology as the gold standard.

Relying on NGS alone, diagnostic yields were 44.5% and 27.7% for detecting a mucinous cyst and determining type of cyst, respectively. These yields rose to 73.3% and 70.3%, respectively, when NGS was used with microscopic evaluation. Continuing with this combined approach, sensitivity and specificity were 83.7% and 81.8%, respectively, for the diagnosis of a mucinous cyst. Sensitivity and specificity were higher still, at 87.2% and 84.6%, respectively, for identifying IPMNs.

The adverse-event rate was 9.9%, with a risk of postprocedure acute pancreatitis of 8.9 % and procedure-associated intracystic bleeding of 3%, according to the authors.

Limitations of the study include the relatively small sample size and the single-center design.

“TTNB-NGS is not sufficient as a stand-alone diagnostic tool as of yet but has a high diagnostic yield when combined with microscopic evaluation and subtyping by immunohistochemistry,” the investigators concluded. “The advantage of EUS-TTNB over EUS–[fine-needle aspiration] is the ability to perform detailed cyst subtyping and the high technical success rate of the procedure. ... However, the procedure comes with a risk of adverse events and thus should be offered to patients where the value of an exact diagnosis outweighs the risks.”

“Molecular subtyping is emerging as a useful clinical test for diagnosing pancreatic cysts,” said Margaret Geraldine Keane, MBBS, MSc, of Johns Hopkins Medicine, Baltimore, although she noted that NGS remains expensive and sporadically available, “which limits its clinical utility and incorporation into diagnostic algorithms for pancreatic cysts. In the future, as the cost of sequencing reduces, and availability improves, this may change.”

For now, Dr. Keane advised physicians to reserve molecular subtyping for cases in which “accurate cyst subtyping will change management ... or when other tests have not provided a clear diagnosis.”

She said the present study is valuable because better diagnostic tests are badly needed for patients with pancreatic cysts, considering the high rate of surgical overtreatment.

“Having more diagnostic tests, such as those described in this publication [to be used on their own or in combination] to decide which patients need surgery, is important,” Dr. Keane said who was not involved in the study.

Better diagnostic tests could also improve outcomes for patients with pancreatic cancer, she said, noting a 5-year survival rate of 10%.

“This outcome is in large part attributable to the late stage at which the majority of patients are diagnosed,” Dr. Keane said. “If patients can be diagnosed earlier, survival dramatically improves. Improvements in diagnostic tests for premalignant pancreatic cystic lesions are therefore vital.”

The study was supported by Rigshospitalets Research Foundation, The Novo Nordisk Foundation, The Danish Cancer Society, and others, although they did not have a role in conducting the study or preparing the manuscript. One investigator disclosed a relationship with MediGlobe. The other investigators reported no conflicts of interest. Dr. Keane disclosed no conflicts of interest.

Endoscopic ultrasound (EUS)–guided through-the-needle biopsies (TTNBs) of pancreatic cystic lesions are sufficient for accurate molecular analysis, which offers a superior alternative to cyst fluid obtained via fine-needle aspiration, based on a prospective study.

For highest diagnostic clarity, next-generation sequencing (NGS) of TTNBs can be paired with histology, lead author Charlotte Vestrup Rift, MD, PhD, of Copenhagen University Hospital, and colleagues reported.

“The diagnostic algorithm for the management of [pancreatic cystic lesions] includes endoscopic ultrasound examination with aspiration of cyst fluid for cytology,” the investigators wrote in Gastrointestinal Endoscopy. “However, the reported sensitivity of cytology is low [at 54%]. A new microforceps, introduced through a 19-gauge needle, has proven useful for procurement of [TTNBs] that represent both the epithelial and stromal component of the cyst wall. TTNBs have a high sensitivity of 86% for the diagnosis of mucinous cysts.”

Dr. Rift and colleagues evaluated the impact of introducing NGS to the diagnostic process. They noted that concomitant mutations in GNAS and KRAS are diagnostic for intraductal papillary mucinous neoplasms (IPMNs), while other mutations have been linked with progression to cancer.

The study involved 101 patients with pancreatic cystic lesions larger than 15 mm in diameter, mean age of 68 years, among whom 91 had residual TTNBs available after microscopic analysis. These samples underwent a 51-gene NGS panel that included the “most prevalent hot-spot mutations.” Diagnoses were sorted into four categories: neoplastic cyst, mucinous cyst, IPMN, or serous cystic neoplasm.

The primary endpoint was diagnostic yield, both for molecular analysis of TTNBs and for molecular analysis plus histopathology of TTNBs. Sensitivity and specificity of NGS were also determined using histopathology as the gold standard.

Relying on NGS alone, diagnostic yields were 44.5% and 27.7% for detecting a mucinous cyst and determining type of cyst, respectively. These yields rose to 73.3% and 70.3%, respectively, when NGS was used with microscopic evaluation. Continuing with this combined approach, sensitivity and specificity were 83.7% and 81.8%, respectively, for the diagnosis of a mucinous cyst. Sensitivity and specificity were higher still, at 87.2% and 84.6%, respectively, for identifying IPMNs.

The adverse-event rate was 9.9%, with a risk of postprocedure acute pancreatitis of 8.9 % and procedure-associated intracystic bleeding of 3%, according to the authors.

Limitations of the study include the relatively small sample size and the single-center design.

“TTNB-NGS is not sufficient as a stand-alone diagnostic tool as of yet but has a high diagnostic yield when combined with microscopic evaluation and subtyping by immunohistochemistry,” the investigators concluded. “The advantage of EUS-TTNB over EUS–[fine-needle aspiration] is the ability to perform detailed cyst subtyping and the high technical success rate of the procedure. ... However, the procedure comes with a risk of adverse events and thus should be offered to patients where the value of an exact diagnosis outweighs the risks.”

“Molecular subtyping is emerging as a useful clinical test for diagnosing pancreatic cysts,” said Margaret Geraldine Keane, MBBS, MSc, of Johns Hopkins Medicine, Baltimore, although she noted that NGS remains expensive and sporadically available, “which limits its clinical utility and incorporation into diagnostic algorithms for pancreatic cysts. In the future, as the cost of sequencing reduces, and availability improves, this may change.”

For now, Dr. Keane advised physicians to reserve molecular subtyping for cases in which “accurate cyst subtyping will change management ... or when other tests have not provided a clear diagnosis.”

She said the present study is valuable because better diagnostic tests are badly needed for patients with pancreatic cysts, considering the high rate of surgical overtreatment.

“Having more diagnostic tests, such as those described in this publication [to be used on their own or in combination] to decide which patients need surgery, is important,” Dr. Keane said who was not involved in the study.

Better diagnostic tests could also improve outcomes for patients with pancreatic cancer, she said, noting a 5-year survival rate of 10%.

“This outcome is in large part attributable to the late stage at which the majority of patients are diagnosed,” Dr. Keane said. “If patients can be diagnosed earlier, survival dramatically improves. Improvements in diagnostic tests for premalignant pancreatic cystic lesions are therefore vital.”

The study was supported by Rigshospitalets Research Foundation, The Novo Nordisk Foundation, The Danish Cancer Society, and others, although they did not have a role in conducting the study or preparing the manuscript. One investigator disclosed a relationship with MediGlobe. The other investigators reported no conflicts of interest. Dr. Keane disclosed no conflicts of interest.

An international team of researchers have developed a “molecular map” of chronic lymphocytic leukemia (CLL) and used it to refine genetic subtypes and variations that appear to be linked to clinical outcomes.

Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.

“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.

According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.

For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.

“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”

In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”

The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.

The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”

Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”

While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”

In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”

The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
 

An international team of researchers have developed a “molecular map” of chronic lymphocytic leukemia (CLL) and used it to refine genetic subtypes and variations that appear to be linked to clinical outcomes.

Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.

“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.

According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.

For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.

“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”

In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”

The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.

The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”

Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”

While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”

In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”

The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
 

An international team of researchers have developed a “molecular map” of chronic lymphocytic leukemia (CLL) and used it to refine genetic subtypes and variations that appear to be linked to clinical outcomes.

Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.

“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.

According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.

For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.

“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”

In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”

The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.

The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”

Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”

While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”

In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”

The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
 

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

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

MDedge News/Mitchel L. Zoler

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

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

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

A lower threshold for albuminuria?

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

MDedge News/Mitchel L. Zoler

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

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

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

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

More albuminuria measurement needed in primary care

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

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

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

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

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

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

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

MDedge News/Mitchel L. Zoler

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

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

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

A lower threshold for albuminuria?

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

MDedge News/Mitchel L. Zoler

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

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

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

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

More albuminuria measurement needed in primary care

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

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

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

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

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

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

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

MDedge News/Mitchel L. Zoler

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

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

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

A lower threshold for albuminuria?

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

MDedge News/Mitchel L. Zoler

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

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

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

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

More albuminuria measurement needed in primary care

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

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

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

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

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

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

In June, Rebecca A. Shatsky, MD, a medical oncologist, turned to Twitter for advice: “What do you do/say when a patient won’t believe you that they have #CANCER. As an oncologist this comes up every now and then and proves very difficult, looking to hear how others have dealt and what works best to help patients here.”

About a dozen people weighed in, offering various thoughts on how to approach these thorny situations. One oncologist suggested revisiting the conversation a few days later, after the patient has more time to process; others suggested sharing the pathology report or images with their patient.

Another person simply noted that “if a [patient] doesn’t want to believe they have cancer, no amount of evidence will change that.”

Based on the initial responses, “it appears there is a paucity of answers sadly,” wrote Dr. Shatsky, a breast cancer specialist at University of California, San Diego.

But for Dr. Shatsky, these incidents spoke to another alarming trend: a rampant mistrust of the medical community that is “becoming MORE common instead of less.”
 

‘Erosion of trust’

Overall, experts say that situations like the one Dr. Shatsky described – patients who don’t believe their cancer diagnosis – occur infrequently.

But denial comes in many forms, and complete disbelief is probably the most extreme. Patients may also downplay the severity of their disease, shy away from hearing bad news, or refuse standard treatment or their doctor’s advice.

Like Dr. Shatsky, these experts say they are also seeing a troubling increase in patients who don’t believe their physicians or don’t trust their recommendations.

“I think there’s an erosion of trust in expertise, in general,” said Ronald M. Epstein, MD, professor of family medicine and psychiatry & oncology at the University of Rochester (N.Y.). “People distrust science more than they did maybe 20 or 30 years ago, or at least that seems to be the case.”

Denial and distrust in cancer care are not new. These responses – along with wishful thinking, distraction, and minimization – are long-established responses among oncology patients. In 1972, Avery D. Weisman, MD, a psychiatrist at Harvard Medical School, Boston, wrote his book “On Dying and Denying,” and ever since, denial and similar responses have been explored in the oncology literature.

Much of this research has focused on the latter stages of illness, but denial can be present at diagnosis as well. One study of patients with breast cancer, carried out nearly 30 years ago, suggested that denial of diagnosis generally occurs early in a patient’s course of illness and decreases over time, but may arise again in the terminal phase of cancer. Another analysis, evaluating this phenomenon across 13 studies, found that the prevalence of denial at diagnosis ranged from 4% to as high as 47%. 

An oncologist delivers somewhere between 10,000 to 30,000 episodes of bad news over the course of a career, so there’s always a chance that a patient will respond in a way that’s on the “spectrum of disbelief,” said Paul Helft, MD, professor of medicine and recently retired director of the ethics center at Indiana University, Indianapolis.

Diane Meier, MD, said denial and disbelief are natural, protective responses to difficult or frightening news.

When patients exhibit denial, Dr. Meier advises patience and time. Physicians can also ask the patient if there’s a person they trust – a family member or faith leader, for example – who could speak on their behalf about possible next steps.

“The main thing is not to find ourselves in opposition to the patient ... or threaten them with what will happen if they don’t listen to us,” said Dr. Meier, a professor of geriatrics and palliative medicine at the Icahn School of Medicine at Mount Sinai, New York.

And physicians should be careful when they feel themselves wanting to argue with or lecture a patient.

“The minute we feel that urge coming on, that’s a signal to us to stop and realize that something is going on inside the patient that we don’t understand,” she said. “Forcing information on a person who is signaling in every way that they don’t want it and can’t handle it is not a recipe for trust or a high-quality relationship.”
 

Refusing expert advice

Jennifer Lycette, MD, has encountered a growing number of patients who don’t believe their disease should be treated the way she or other oncologists recommend. Some patients remain adamant about sticking with alternative medicine or doing nothing, despite growing sicker.

“I’ve even had situations where the tumor might be visible, like growing through the skin, and people still double down that whatever they’re doing is working,” said Dr. Lycette, a hematologist and medical oncologist at the Providence Seaside Cancer Center in Seaside, Ore.

She encourages these patients to get a second opinion and tries to keep an open mind about alternative approaches. If she’s not familiar with something a patient is considering, she’ll research it with them.

But she makes sure to point out any risks associated with these approaches. While some alternative therapies can support patients through standard treatment, she strongly cautions patients against using these therapies in place of standard treatment.

“The bottom line is to keep the lines of communication open,” she said.

Like Dr. Lycette, Dr. Helft has been encountering more patients with alternative health beliefs who rely on people outside of the medical system for elements of their care.

In the past, he used to tell these patients that science is incomplete, and physicians don’t know everything. But he’s changed his tune.

“I’ve taken to just telling them what I believe, which is that the majority of things that they hear and are being sold are almost certainly ineffective and a waste of money,” he said. “I’ve come to accept that people are adults, and they make their own decisions, and sometimes they make decisions that are not the ones that I would make or want them to make.”
 

Delivering bad news

Dr. Helft often sees patients seeking a second or third opinion on their cancer. These patients may not all be in denial about having cancer, but they typically don’t want to hear bad news, which can make treatment a challenge.

To handle these scenarios, Dr. Helft has developed a system of responses for engaging with patients. He borrows an approach described in 2008 where he acknowledges a patient’s emotional distress and tries to understand why they may not want to know more.

For instance, he might tell a patient: “I have formulated an opinion about your situation, but it sounds as if you have heard many negative descriptions previously. I don’t want to burden you with one more if you don’t feel prepared to talk about it.”

Trying to understand why a patient is resistant to hearing about their condition may also help build trust. “If you could help me understand your thinking about why you would rather not talk about prognosis, it will help me know more about how to discuss other serious issues,” is one approach highlighted in the 2008 guide.

Behind the scenes, Dr. Helft will privately assess how much information about a patient’s prognosis is salient to their decision making, especially if the patient appears to misunderstand their prognosis or if there are various options for treatment over the long-term. 

Dr. Helft will also ask patients how much they want to know. Do they want to discuss no options? A few? All and in detail?

This approach implicitly recognizes that the information is highly stressful but avoids being overly blunt, he notes. It can also help steer patients on the right treatment track and minimize poor decision making.

Samantha Winemaker, MD, a palliative care physician in Hamilton, Ont., finds patients often go through an adjustment period after learning about a new diagnosis. The reaction tends to range from needing time to accept the diagnosis as real to jumping in to understand as much as possible.

Dr. Winemaker, who cohosts “The Waiting Room Revolution” podcast that focuses on helping people deal with a serious illness, encourages physicians to be realistic with patients about their prognosis and deliver news with a dose of gentle truth from the start.

“We should invite patients ‘into the know’ as early as possible, while maintaining hope,” she said.

She calls this approach of balancing hope and reality “walking two roads” and said it extends throughout the illness journey. This way, patients are less likely to be surprised if things make a turn for the worse.

“We should never wait until the 11th hour to give someone bad news,” she said.
 

‘We all want to hope’

Dr. Epstein has listened to hundreds of hours of discussion between doctors and patients as part of his research on communication. He often hears doctors initiate difficult conversations by lecturing a patient.

Many physicians mistakenly believe that, if they say something authoritatively, patients will believe it, he said. But the opposite often happens – patients shut down and instinctively distrust the physician.

Dr. Epstein teaches doctors to establish trust before providing difficult information. Even when a patient expresses outlandish ideas about their illness, treat them with dignity and respect, he advised. “If people don’t feel respected, you don’t have a leg to stand on and there’s no point in trying to convince them.”

Patients and physicians often leave conversations with discordant views of what’s ahead. In one study, two-thirds of patients held wildly different views on their prognosis, compared with their doctors, and most had no idea they were at odds with their physician.

In the past, Dr. Epstein has tried to close the gap between his understanding of a patient’s prognosis and the patient’s. But more recently he has become less convinced of the need to do so.

“What I try to do now is focus more on the uncertainty there,” he said. He uses phrases like: “Given that we don’t know how long you will live, I just need to know what you would want me to do if things took a turn for the worse” or “I’m worried that if you don’t have the surgery, you might experience more pain in the future.”

He urged doctors to pay attention to their word choices. Use care with the phrase “response rate” – patients sometimes mistake this to mean that they are being cured. And, instead of telling patients they “must” do something, he says that he worries about consequences for them if they don’t.

He asks patients what they’re hearing from other people in their lives or online. Sometimes patients say that people close to them are encouraging them to stop medical treatment or pursue alternative therapies. When that happens, Dr. Epstein asks to meet with that person to talk to them about his concerns for their loved one.

He also acknowledges calculated uncertainty often exists in medicine. That, he says, leaves open the potential for exceptional circumstances.

“And we all want to hope,” Dr. Epstein said.

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

In June, Rebecca A. Shatsky, MD, a medical oncologist, turned to Twitter for advice: “What do you do/say when a patient won’t believe you that they have #CANCER. As an oncologist this comes up every now and then and proves very difficult, looking to hear how others have dealt and what works best to help patients here.”

About a dozen people weighed in, offering various thoughts on how to approach these thorny situations. One oncologist suggested revisiting the conversation a few days later, after the patient has more time to process; others suggested sharing the pathology report or images with their patient.

Another person simply noted that “if a [patient] doesn’t want to believe they have cancer, no amount of evidence will change that.”

Based on the initial responses, “it appears there is a paucity of answers sadly,” wrote Dr. Shatsky, a breast cancer specialist at University of California, San Diego.

But for Dr. Shatsky, these incidents spoke to another alarming trend: a rampant mistrust of the medical community that is “becoming MORE common instead of less.”
 

‘Erosion of trust’

Overall, experts say that situations like the one Dr. Shatsky described – patients who don’t believe their cancer diagnosis – occur infrequently.

But denial comes in many forms, and complete disbelief is probably the most extreme. Patients may also downplay the severity of their disease, shy away from hearing bad news, or refuse standard treatment or their doctor’s advice.

Like Dr. Shatsky, these experts say they are also seeing a troubling increase in patients who don’t believe their physicians or don’t trust their recommendations.

“I think there’s an erosion of trust in expertise, in general,” said Ronald M. Epstein, MD, professor of family medicine and psychiatry & oncology at the University of Rochester (N.Y.). “People distrust science more than they did maybe 20 or 30 years ago, or at least that seems to be the case.”

Denial and distrust in cancer care are not new. These responses – along with wishful thinking, distraction, and minimization – are long-established responses among oncology patients. In 1972, Avery D. Weisman, MD, a psychiatrist at Harvard Medical School, Boston, wrote his book “On Dying and Denying,” and ever since, denial and similar responses have been explored in the oncology literature.

Much of this research has focused on the latter stages of illness, but denial can be present at diagnosis as well. One study of patients with breast cancer, carried out nearly 30 years ago, suggested that denial of diagnosis generally occurs early in a patient’s course of illness and decreases over time, but may arise again in the terminal phase of cancer. Another analysis, evaluating this phenomenon across 13 studies, found that the prevalence of denial at diagnosis ranged from 4% to as high as 47%. 

An oncologist delivers somewhere between 10,000 to 30,000 episodes of bad news over the course of a career, so there’s always a chance that a patient will respond in a way that’s on the “spectrum of disbelief,” said Paul Helft, MD, professor of medicine and recently retired director of the ethics center at Indiana University, Indianapolis.

Diane Meier, MD, said denial and disbelief are natural, protective responses to difficult or frightening news.

When patients exhibit denial, Dr. Meier advises patience and time. Physicians can also ask the patient if there’s a person they trust – a family member or faith leader, for example – who could speak on their behalf about possible next steps.

“The main thing is not to find ourselves in opposition to the patient ... or threaten them with what will happen if they don’t listen to us,” said Dr. Meier, a professor of geriatrics and palliative medicine at the Icahn School of Medicine at Mount Sinai, New York.

And physicians should be careful when they feel themselves wanting to argue with or lecture a patient.

“The minute we feel that urge coming on, that’s a signal to us to stop and realize that something is going on inside the patient that we don’t understand,” she said. “Forcing information on a person who is signaling in every way that they don’t want it and can’t handle it is not a recipe for trust or a high-quality relationship.”
 

Refusing expert advice

Jennifer Lycette, MD, has encountered a growing number of patients who don’t believe their disease should be treated the way she or other oncologists recommend. Some patients remain adamant about sticking with alternative medicine or doing nothing, despite growing sicker.

“I’ve even had situations where the tumor might be visible, like growing through the skin, and people still double down that whatever they’re doing is working,” said Dr. Lycette, a hematologist and medical oncologist at the Providence Seaside Cancer Center in Seaside, Ore.

She encourages these patients to get a second opinion and tries to keep an open mind about alternative approaches. If she’s not familiar with something a patient is considering, she’ll research it with them.

But she makes sure to point out any risks associated with these approaches. While some alternative therapies can support patients through standard treatment, she strongly cautions patients against using these therapies in place of standard treatment.

“The bottom line is to keep the lines of communication open,” she said.

Like Dr. Lycette, Dr. Helft has been encountering more patients with alternative health beliefs who rely on people outside of the medical system for elements of their care.

In the past, he used to tell these patients that science is incomplete, and physicians don’t know everything. But he’s changed his tune.

“I’ve taken to just telling them what I believe, which is that the majority of things that they hear and are being sold are almost certainly ineffective and a waste of money,” he said. “I’ve come to accept that people are adults, and they make their own decisions, and sometimes they make decisions that are not the ones that I would make or want them to make.”
 

Delivering bad news

Dr. Helft often sees patients seeking a second or third opinion on their cancer. These patients may not all be in denial about having cancer, but they typically don’t want to hear bad news, which can make treatment a challenge.

To handle these scenarios, Dr. Helft has developed a system of responses for engaging with patients. He borrows an approach described in 2008 where he acknowledges a patient’s emotional distress and tries to understand why they may not want to know more.

For instance, he might tell a patient: “I have formulated an opinion about your situation, but it sounds as if you have heard many negative descriptions previously. I don’t want to burden you with one more if you don’t feel prepared to talk about it.”

Trying to understand why a patient is resistant to hearing about their condition may also help build trust. “If you could help me understand your thinking about why you would rather not talk about prognosis, it will help me know more about how to discuss other serious issues,” is one approach highlighted in the 2008 guide.

Behind the scenes, Dr. Helft will privately assess how much information about a patient’s prognosis is salient to their decision making, especially if the patient appears to misunderstand their prognosis or if there are various options for treatment over the long-term. 

Dr. Helft will also ask patients how much they want to know. Do they want to discuss no options? A few? All and in detail?

This approach implicitly recognizes that the information is highly stressful but avoids being overly blunt, he notes. It can also help steer patients on the right treatment track and minimize poor decision making.

Samantha Winemaker, MD, a palliative care physician in Hamilton, Ont., finds patients often go through an adjustment period after learning about a new diagnosis. The reaction tends to range from needing time to accept the diagnosis as real to jumping in to understand as much as possible.

Dr. Winemaker, who cohosts “The Waiting Room Revolution” podcast that focuses on helping people deal with a serious illness, encourages physicians to be realistic with patients about their prognosis and deliver news with a dose of gentle truth from the start.

“We should invite patients ‘into the know’ as early as possible, while maintaining hope,” she said.

She calls this approach of balancing hope and reality “walking two roads” and said it extends throughout the illness journey. This way, patients are less likely to be surprised if things make a turn for the worse.

“We should never wait until the 11th hour to give someone bad news,” she said.
 

‘We all want to hope’

Dr. Epstein has listened to hundreds of hours of discussion between doctors and patients as part of his research on communication. He often hears doctors initiate difficult conversations by lecturing a patient.

Many physicians mistakenly believe that, if they say something authoritatively, patients will believe it, he said. But the opposite often happens – patients shut down and instinctively distrust the physician.

Dr. Epstein teaches doctors to establish trust before providing difficult information. Even when a patient expresses outlandish ideas about their illness, treat them with dignity and respect, he advised. “If people don’t feel respected, you don’t have a leg to stand on and there’s no point in trying to convince them.”

Patients and physicians often leave conversations with discordant views of what’s ahead. In one study, two-thirds of patients held wildly different views on their prognosis, compared with their doctors, and most had no idea they were at odds with their physician.

In the past, Dr. Epstein has tried to close the gap between his understanding of a patient’s prognosis and the patient’s. But more recently he has become less convinced of the need to do so.

“What I try to do now is focus more on the uncertainty there,” he said. He uses phrases like: “Given that we don’t know how long you will live, I just need to know what you would want me to do if things took a turn for the worse” or “I’m worried that if you don’t have the surgery, you might experience more pain in the future.”

He urged doctors to pay attention to their word choices. Use care with the phrase “response rate” – patients sometimes mistake this to mean that they are being cured. And, instead of telling patients they “must” do something, he says that he worries about consequences for them if they don’t.

He asks patients what they’re hearing from other people in their lives or online. Sometimes patients say that people close to them are encouraging them to stop medical treatment or pursue alternative therapies. When that happens, Dr. Epstein asks to meet with that person to talk to them about his concerns for their loved one.

He also acknowledges calculated uncertainty often exists in medicine. That, he says, leaves open the potential for exceptional circumstances.

“And we all want to hope,” Dr. Epstein said.

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

In June, Rebecca A. Shatsky, MD, a medical oncologist, turned to Twitter for advice: “What do you do/say when a patient won’t believe you that they have #CANCER. As an oncologist this comes up every now and then and proves very difficult, looking to hear how others have dealt and what works best to help patients here.”

About a dozen people weighed in, offering various thoughts on how to approach these thorny situations. One oncologist suggested revisiting the conversation a few days later, after the patient has more time to process; others suggested sharing the pathology report or images with their patient.

Another person simply noted that “if a [patient] doesn’t want to believe they have cancer, no amount of evidence will change that.”

Based on the initial responses, “it appears there is a paucity of answers sadly,” wrote Dr. Shatsky, a breast cancer specialist at University of California, San Diego.

But for Dr. Shatsky, these incidents spoke to another alarming trend: a rampant mistrust of the medical community that is “becoming MORE common instead of less.”
 

‘Erosion of trust’

Overall, experts say that situations like the one Dr. Shatsky described – patients who don’t believe their cancer diagnosis – occur infrequently.

But denial comes in many forms, and complete disbelief is probably the most extreme. Patients may also downplay the severity of their disease, shy away from hearing bad news, or refuse standard treatment or their doctor’s advice.

Like Dr. Shatsky, these experts say they are also seeing a troubling increase in patients who don’t believe their physicians or don’t trust their recommendations.

“I think there’s an erosion of trust in expertise, in general,” said Ronald M. Epstein, MD, professor of family medicine and psychiatry & oncology at the University of Rochester (N.Y.). “People distrust science more than they did maybe 20 or 30 years ago, or at least that seems to be the case.”

Denial and distrust in cancer care are not new. These responses – along with wishful thinking, distraction, and minimization – are long-established responses among oncology patients. In 1972, Avery D. Weisman, MD, a psychiatrist at Harvard Medical School, Boston, wrote his book “On Dying and Denying,” and ever since, denial and similar responses have been explored in the oncology literature.

Much of this research has focused on the latter stages of illness, but denial can be present at diagnosis as well. One study of patients with breast cancer, carried out nearly 30 years ago, suggested that denial of diagnosis generally occurs early in a patient’s course of illness and decreases over time, but may arise again in the terminal phase of cancer. Another analysis, evaluating this phenomenon across 13 studies, found that the prevalence of denial at diagnosis ranged from 4% to as high as 47%. 

An oncologist delivers somewhere between 10,000 to 30,000 episodes of bad news over the course of a career, so there’s always a chance that a patient will respond in a way that’s on the “spectrum of disbelief,” said Paul Helft, MD, professor of medicine and recently retired director of the ethics center at Indiana University, Indianapolis.

Diane Meier, MD, said denial and disbelief are natural, protective responses to difficult or frightening news.

When patients exhibit denial, Dr. Meier advises patience and time. Physicians can also ask the patient if there’s a person they trust – a family member or faith leader, for example – who could speak on their behalf about possible next steps.

“The main thing is not to find ourselves in opposition to the patient ... or threaten them with what will happen if they don’t listen to us,” said Dr. Meier, a professor of geriatrics and palliative medicine at the Icahn School of Medicine at Mount Sinai, New York.

And physicians should be careful when they feel themselves wanting to argue with or lecture a patient.

“The minute we feel that urge coming on, that’s a signal to us to stop and realize that something is going on inside the patient that we don’t understand,” she said. “Forcing information on a person who is signaling in every way that they don’t want it and can’t handle it is not a recipe for trust or a high-quality relationship.”
 

Refusing expert advice

Jennifer Lycette, MD, has encountered a growing number of patients who don’t believe their disease should be treated the way she or other oncologists recommend. Some patients remain adamant about sticking with alternative medicine or doing nothing, despite growing sicker.

“I’ve even had situations where the tumor might be visible, like growing through the skin, and people still double down that whatever they’re doing is working,” said Dr. Lycette, a hematologist and medical oncologist at the Providence Seaside Cancer Center in Seaside, Ore.

She encourages these patients to get a second opinion and tries to keep an open mind about alternative approaches. If she’s not familiar with something a patient is considering, she’ll research it with them.

But she makes sure to point out any risks associated with these approaches. While some alternative therapies can support patients through standard treatment, she strongly cautions patients against using these therapies in place of standard treatment.

“The bottom line is to keep the lines of communication open,” she said.

Like Dr. Lycette, Dr. Helft has been encountering more patients with alternative health beliefs who rely on people outside of the medical system for elements of their care.

In the past, he used to tell these patients that science is incomplete, and physicians don’t know everything. But he’s changed his tune.

“I’ve taken to just telling them what I believe, which is that the majority of things that they hear and are being sold are almost certainly ineffective and a waste of money,” he said. “I’ve come to accept that people are adults, and they make their own decisions, and sometimes they make decisions that are not the ones that I would make or want them to make.”
 

Delivering bad news

Dr. Helft often sees patients seeking a second or third opinion on their cancer. These patients may not all be in denial about having cancer, but they typically don’t want to hear bad news, which can make treatment a challenge.

To handle these scenarios, Dr. Helft has developed a system of responses for engaging with patients. He borrows an approach described in 2008 where he acknowledges a patient’s emotional distress and tries to understand why they may not want to know more.

For instance, he might tell a patient: “I have formulated an opinion about your situation, but it sounds as if you have heard many negative descriptions previously. I don’t want to burden you with one more if you don’t feel prepared to talk about it.”

Trying to understand why a patient is resistant to hearing about their condition may also help build trust. “If you could help me understand your thinking about why you would rather not talk about prognosis, it will help me know more about how to discuss other serious issues,” is one approach highlighted in the 2008 guide.

Behind the scenes, Dr. Helft will privately assess how much information about a patient’s prognosis is salient to their decision making, especially if the patient appears to misunderstand their prognosis or if there are various options for treatment over the long-term. 

Dr. Helft will also ask patients how much they want to know. Do they want to discuss no options? A few? All and in detail?

This approach implicitly recognizes that the information is highly stressful but avoids being overly blunt, he notes. It can also help steer patients on the right treatment track and minimize poor decision making.

Samantha Winemaker, MD, a palliative care physician in Hamilton, Ont., finds patients often go through an adjustment period after learning about a new diagnosis. The reaction tends to range from needing time to accept the diagnosis as real to jumping in to understand as much as possible.

Dr. Winemaker, who cohosts “The Waiting Room Revolution” podcast that focuses on helping people deal with a serious illness, encourages physicians to be realistic with patients about their prognosis and deliver news with a dose of gentle truth from the start.

“We should invite patients ‘into the know’ as early as possible, while maintaining hope,” she said.

She calls this approach of balancing hope and reality “walking two roads” and said it extends throughout the illness journey. This way, patients are less likely to be surprised if things make a turn for the worse.

“We should never wait until the 11th hour to give someone bad news,” she said.
 

‘We all want to hope’

Dr. Epstein has listened to hundreds of hours of discussion between doctors and patients as part of his research on communication. He often hears doctors initiate difficult conversations by lecturing a patient.

Many physicians mistakenly believe that, if they say something authoritatively, patients will believe it, he said. But the opposite often happens – patients shut down and instinctively distrust the physician.

Dr. Epstein teaches doctors to establish trust before providing difficult information. Even when a patient expresses outlandish ideas about their illness, treat them with dignity and respect, he advised. “If people don’t feel respected, you don’t have a leg to stand on and there’s no point in trying to convince them.”

Patients and physicians often leave conversations with discordant views of what’s ahead. In one study, two-thirds of patients held wildly different views on their prognosis, compared with their doctors, and most had no idea they were at odds with their physician.

In the past, Dr. Epstein has tried to close the gap between his understanding of a patient’s prognosis and the patient’s. But more recently he has become less convinced of the need to do so.

“What I try to do now is focus more on the uncertainty there,” he said. He uses phrases like: “Given that we don’t know how long you will live, I just need to know what you would want me to do if things took a turn for the worse” or “I’m worried that if you don’t have the surgery, you might experience more pain in the future.”

He urged doctors to pay attention to their word choices. Use care with the phrase “response rate” – patients sometimes mistake this to mean that they are being cured. And, instead of telling patients they “must” do something, he says that he worries about consequences for them if they don’t.

He asks patients what they’re hearing from other people in their lives or online. Sometimes patients say that people close to them are encouraging them to stop medical treatment or pursue alternative therapies. When that happens, Dr. Epstein asks to meet with that person to talk to them about his concerns for their loved one.

He also acknowledges calculated uncertainty often exists in medicine. That, he says, leaves open the potential for exceptional circumstances.

“And we all want to hope,” Dr. Epstein said.

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

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.

Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.

The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”

Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.

It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.

Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.

“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.

Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.

“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”

Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.

Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.

The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”

Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.

Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.

At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”

“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”

According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”

Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.

If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.

“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.

The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.

Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.

Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.

While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.

White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.

White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.

Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.

Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.

The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.

Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.

But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.

Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.

“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”

The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.

Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.

Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.

But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.

“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”

It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.

“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.

Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.

The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”

Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.

It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.

Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.

“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.

Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.

“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”

Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.

Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.

The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”

Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.

Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.

At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”

“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”

According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”

Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.

If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.

“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.

The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.

Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.

Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.

While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.

White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.

White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.

Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.

Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.

The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.

Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.

But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.

Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.

“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”

The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.

Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.

Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.

But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.

“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”

It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.

“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.

Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.

The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”

Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.

It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.

Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.

“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.

Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.

“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”

Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.

Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.

The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”

Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.

Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.

At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”

“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”

According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”

Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.

If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.

“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.

The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.

Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.

Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.

While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.

White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.

White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.

Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.

Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.

The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.

Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.

But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.

Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.

“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”

The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.

Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.

Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.

But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.

“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”

It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.

“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.