Vascular

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

From Western University of Health Sciences College of Pharmacy, Department of Pharmacy Practice and Administration, Pomona, CA.

Abstract

• Objective: To review the current literature regarding the clinical effectiveness and cost-effectiveness of implementing hypertension team-based care (TBC) interventions in the outpatient setting, and discuss challenges to implementation.
• Methods: A literature review was conducted of meta-analyses, systematic reviews, and randomized controlled trials comparing TBC models to usual care for hypertension management.
• Results: Compared to usual care, TBC models have demonstrated greater blood pressure reductions and improved blood pressure control rates. Evidence was strongest for models involving nurses and pharmacists whose roles included medication management, patient education and counseling, coordination of care and follow-up, population health management, and performance measurement with quality improvement. Although TBC results in an increase in health care costs, the overall long-term benefits support the cost-effectiveness of these models over usual care. The most common barriers to TBC implementation include underutilization of technology, stakeholder engagement, and reimbursement issues.
• Conclusion: Hypertension TBC models have been shown to be clinically effective and cost-effective, but continued research comparing different models is warranted to determine which combination of health professionals and interventions is most impactful and cost-effective in practice. An implementation science approach, in which TBC models unique to each organization’s situation are created, will be useful to identify and overcome challenges and provide a solid foundation for sustainment.

Keywords: blood pressure; pharmacist; nurse; nurse practitioner; cost-effectiveness; team-based care.

Approximately 1 in 3 US adults—or about 100 million people—have high blood pressure, and only about half (48%) have their blood pressure under control.¹ Effective blood pressure management has been shown to decrease the incidence of stroke, heart attack, and heart failure.^2-4 The American College of Cardiology/American Heart Association (ACC/AHA) 2017 blood pressure guidelines recommended lower thresholds for diagnosing hypertension and initiating antihypertensive medication, and intensified the blood pressure goal to less than 130/80 mm Hg.⁵ Changing practice standards to more intensive blood pressure goals requires significant adjustments by clinicians and health care systems. In fact, new guideline uptake is often delayed, ignored, or sparsely applied.⁶ Due to this dramatic change in hypertension practice standards, the ACC/AHA guidelines support interdisciplinary team-based care (TBC) for hypertension management.^5,7 Additionally, the Centers for Disease Control and Prevention (CDC) and the Community Preventive Services Task Force (CPSTF) promote TBC to improve blood pressure control in their initiatives to prevent heart disease and stroke.^8,9

The National Academy of Medicine defines TBC as “the provision of health services to individuals, families, and/or their communities by at least 2 healthcare providers who work collaboratively with patients and their caregivers—to the extent preferred by each patient—to accomplish shared goals within and across settings to achieve coordinated, high-quality care.”¹⁰ Specific goals for TBC in hypertension treatment are listed in Table 1, and a checklist of key elements of TBC to consider before implementation are presented in Table 2.

TBC has been shown to have many advantages, including increased access to care due to expanded hours of operation and shorter wait times.¹¹ Team-based models also provide effective and efficient delivery of patient education, behavioral health care, and care coordination.^12-14 Patients are more likely to receive high-quality care when multiple providers, each with varied expertise, are on the health care team.^11,15 Furthermore, clinicians report improved professional job satisfaction related to their ability to practice in environments where they are encouraged to work at the top of their licenses.¹⁶ Consequently, TBC has been accepted as a vital part of the patient-centered medical home (PCMH) model.^17-19 Standards set by the National Committee for Quality Assurance (NCQA) include TBC as a requirement health systems must meet in order to achieve the highest level of PCMH recognition. While a team-based approach offers substantial benefits and is recognized as a marker of quality, implementation has presented various challenges, and the sustainability of these models in care settings has been questioned.²⁰

In this article, we review the current literature regarding the clinical effectiveness and cost-effectiveness of implementing hypertension TBC interventions in the outpatient setting. We also discuss the challenges and opportunities of implementing this strategy in health systems and community settings in the United States.

Evidence of Impact and Effectiveness

Various models of hypertension TBC have been shown to increase the proportion of individuals with controlled blood pressure and to lead to a reduction in both systolic (SBP) and diastolic blood pressure (DBP), resulting in a strong recommendation for TBC approaches by the 2017 ACC/AHA blood pressure guidelines.^5,21-25 There is great diversity in the types of hypertension treatment models studied, with few utilizing physician specialists and most utilizing nonphysician providers, such as community health workers, physician assistants, nurses, nurse practitioners, dietitians, social workers, and pharmacists.^22,26-29 These professionals share duties of hypertension management with primary care physicians to reduce the burden of responsibility for care on any single provider type. TBC is patient-centered, and typically includes interprofessional collaboration, treatment algorithms, adherence counseling, frequent follow-up, home blood pressure monitoring, and patient self-management education.

Numerous studies have supported implementation of TBC in recent years. A systematic review and meta-analysis of 100 trials of hypertension TBC involving 55,920 patients concluded that the most effective blood pressure–lowering strategies use multilevel, multicomponent approaches to address barriers to hypertension control. Nonphysician providers are often involved in measuring blood pressure, ordering and assessing laboratory tests, and titrating medications.³⁰ Compared with usual care, TBC with physician medication titration resulted in reductions in mean SBP and DBP (6.2 mm Hg and 2.7 mm Hg, respectively), while TBC with nonphysician medication titration also resulted in reductions in mean SBP and DBP (7.1 mm Hg and 3.1 mm Hg, respectively). Nurses and pharmacists are specifically mentioned by the 2017 ACC/AHA blood pressure guidelines as essential members of the hypertension treatment team.⁵ Randomized controlled trials (RCTs) and meta-analyses of TBC involving nurse or pharmacist interventions demonstrated greater reductions in SBP and/or greater attainment of blood pressure goals compared to usual care.^21,26,31,32 The literature supports the roles of nurses and pharmacists in hypertension management in all aspects of care, including medication management, patient education and counseling, coordination of care and follow-up, population health management, and performance measurement with quality improvement.³³

Nurses

Nurses are commonly part of TBC hypertension management programs. One meta-analysis and systematic review of international RCTs compared nurse, nurse prescriber (United Kingdom), and nurse practitioner interventions for hypertension with usual care. Interventions that included a stepped treatment algorithm and nurse prescribing showed greater reductions in SBP (8.2 mm Hg and 8.9 mm Hg, respectively) compared to usual care.³¹ Similarly, models that utilized telephone monitoring demonstrated greater achievement of blood pressure targets, while those that involved home monitoring showed significant reductions in blood pressure. Another international meta-analysis and systematic review of 11 nurse-led interventions in hypertensive patients with diabetes demonstrated a 5.8 mm Hg mean decrease in SBP compared to physician-led care. However, nurse-led care was not superior in achievement of study targets.³⁴

A recent meta-analysis and systematic review, performed by Shaw and colleagues, sought to determine whether nurse-led protocols are effective for outpatient management of adults with diabetes, hypertension, and hyperlipidemia. All of the included studies involved a registered nurse who titrated medications by following a protocol, and most were RCTs comparing the nurse protocols to usual care. Overall, mean SBP and DBP decreased by 3.86 mm Hg and 1.56 mm Hg, respectively, while blood glucose and lipid levels were also reduced compared to usual care.²⁴

Limited RCT data have been published since the Shaw et al meta-analysis. A single-blind RCT was performed in an urban community health care center in China among patients with uncontrolled blood pressure (SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg).³⁵ The study group received care via a nurse-led model, which included a delivery design system, decision support, clinical information system, and self-management support, and the control group received usual care. At 12 weeks, patients in the study group had significantly lower blood pressure than control patients, with mean SBP/DBP reduction of 14.37/7.43 mm Hg and 5.10/2.69 mm Hg, respectively (P < 0.01). Improved medication adherence and increased patient satisfaction were other benefits of the nurse-led model.

Nurse case managers (NCM) also play a critical role in hypertension management, coordinating health care services to meet patient health needs. Ogedegbe sought to evaluate the comparative effectiveness of home blood pressure telemonitoring (HBPTM)+NCM versus HBPTM alone on SBP reduction in black and Hispanic stroke survivors.^36,37 NCMs evaluated patient profiles, counseled patients on target lifestyle behaviors, and reviewed home blood pressure data. At 6 months, SBP declined by 13.63 mm Hg from baseline in the HBPTM+NCM group and 6.31 mm Hg in the HBPTM alone group (P < 0.0001). At 12 months, SBP in the HBPTM+NCM group declined by 14.76 mm Hg, while blood pressure in the HBPTM alone group declined by 5.53 mm Hg (P < 0.0001).

Pharmacists

Clinical pharmacists are also widely utilized in TBC models for hypertension management. Typical models involve pharmacists entering into collaborative practice agreements with physicians, leading to optimization of medications, avoidance of adverse drug events, and transitional care activities focusing on medication reconciliation and patient education in outpatient settings.^30,38 The largest and most recent meta-analysis of pharmacist interventions, conducted in 2014 by Santschi et al,²³ combined 2 previous systematic reviews to include a total of 39 RCTs with 14,224 patients.^32,39 Pharmacist interventions included patient education, recommendations to physicians, and medication management. Compared with usual care, pharmacist interventions showed greater reductions in SBP (7.6 mm Hg) and DBP (3.9 mm Hg).²³

Numerous studies substantiating the impact of pharmacist interventions on clinical outcomes have heavily influenced clinical practice and guideline development. Carter et al conducted a prospective, multi-state, cluster-randomized trial in 32 primary care clinics to evaluate whether clinics randomized to receive the pharmacist-physician collaborative care model (PPCCM) achieved better blood pressure outcomes versus clinics randomized to usual care.²⁵ Investigators enrolled 625 patients with uncontrolled hypertension, 50% of whom had a prior diagnosis of diabetes mellitus or chronic kidney disease. The primary outcome of blood pressure control at 9 months in the intervention clinics compared to the control clinics was 43% and 34%, respectively (P = 0.059). The difference in mean SBP/DBP between the intervention and control clinics for all patients at 9 months was −6.1/−2.9 mm Hg. In a post-hoc analysis of patients with chronic kidney disease and diabetes, the pharmacist-intervention group had a significantly greater mean SBP reduction and higher blood pressure control rates compared to usual care at 9 months.⁴⁰

A pre-specified secondary analysis from the Carter et al study determined that, in patients from racial minority groups, the mean SBP was 7.3 mm Hg lower in those who received the intervention compared to those in the control group (P = 0.0042).⁴¹ In patients with less than 12 years of education, those in the intervention group had a mean SBP 8.1 mm Hg lower than the SBP of those in the control group (P = 0.0001). Similar reductions in blood pressure occurred in patients with low income, Medicaid beneficiaries, or those without insurance. This study demonstrated that pharmacist interventions reduced racial and socioeconomic disparities in blood pressure treatment.

Other studies of pharmacist interventions in underserved populations have yielded positive results. In a retrospective review of uninsured patients, blood pressure control rates in a pharmacist-driven primary care clinic ranked in the 90th percentile of NCQA benchmarks, and was superior to the 2013 reported mean for commercial insurers.⁴² Similarly, another retrospective cohort study of a PPCCM on time to goal blood pressure in uninsured patients with hypertension showed the median time to blood pressure goal was 36 days in the PPCCM cohort versus 259 days in usual care cohorts (P < 0.001).⁴³ A post-hoc analysis revealed the mean time-in-therapeutic blood pressure range was 46.2% ± 24.3% in the PPCCM group and 24.8% ± 27.4% in the usual care group (P < 0.0001). The blood pressure control rates at 12 months were 89% in the PPCCM group compared with 50% in the usual care group (P < 0.0001).⁴⁴

Tsuyuki et al conducted the RxACTION study, a multicenter RCT evaluating the effectiveness of enhanced pharmacist care versus usual care in 23 Canadian community pharmacies and outpatient clinics following a 6-month intervention.⁴⁵ Enhanced pharmacy services included pharmacist assessment of and counseling about cardiovascular disease risk and blood pressure control, review of current antihypertensive medications, and prescribing/titrating drug therapy, as needed, through independent prescriptive authority. Compared to the usual care group (n = 67), the intervention group had a reduction in SBP of 6.6 mm Hg (P = 0.006) and in DBP of 3.2 mm Hg (P = 0.01). This study expanded the pharmacists’ scope of practice, showing evidence for enhancing pharmacist roles on the hypertension care team. Tsuyuki et al also conducted the RxEACH randomized trial, which evaluated community pharmacist cardiovascular risk reduction interventions and showed an improvement in SBP and DBP, with reported results comparable to RxACTION.⁴⁶

Victor et al conducted the landmark Black Barbershop Study, a cluster RCT involving 319 non-Hispanic black male patients with hypertension from 52 black-owned barbershops.^47,48 Barbershops were assigned to 1 of 2 groups. The control group consisted of barbers who encouraged lifestyle modifications and made referrals to primary care providers. The intervention group had pharmacists who met regularly with participants at the barbershops and measured blood pressure, encouraged lifestyle changes, and prescribed drug therapy under collaborative practice agreements with physicians. Both groups demonstrated improvements in blood pressure outcomes, but the intervention group showed greater improvement in SBP and achievement of blood pressure goals compared to the control group. The results in the intervention group proved sustainable over the course of a year, even after the frequency of pharmacists’ visits was reduced. At 6 months, the mean SBP fell by 27.0 mm Hg (to 125.8 mm Hg) in the intervention group, as compared to a 9.3 mm Hg (to 145.4 mm Hg) reduction in the control group (P < 0.001), and blood pressure less than 130/80 mm Hg was achieved among 63.6% of the participants in the intervention group versus 11.7% in the control group (P < 0.001).

This community-level trial brought pharmacists to the barbershop and made them an essential part of the health care team through the endorsement of the barber, who the participants trusted and with whom they had a relationship. Long-standing issues related to distrust of the medical profession by this population were addressed, and trusted community barbershops were utilized as safe spaces for health care delivery. Health care professionals should consider utilizing community locations that other minority populations perceive as social centers and safe places, to reduce health disparities and barriers to care. However, models that bring care to patients need further economic and feasibility evaluations.

Other Health Care Professionals and Future Studies

In addition to models led by nurses and pharmacists, studies have also assessed models of TBC incorporating other health care professionals, including registered dietitians, medical assistants, community health workers, and health coaches (NCT02674464).^49,50 Ongoing studies are also looking at the impact of TBC on underserved communities (NCT02674464, NCT03504124). Involving a variety of health care professionals with different communities and populations in TBC studies is warranted to determine the optimal settings in which to utilize different skill sets.

The Impress Study involves nurses who are assessing lifestyle risk and developing an action plan according to a standardized procedure, which may be advantageous given the degree of heterogeneity found in other TBC models.⁵¹ There are also studies underway or recently published that compare different components of TBC in order to determine which combination of TBC elements is preferred. Some of these have shown the benefits of using clinical decision-support systems (through a guideline-based treatment protocol) or training programs with ongoing support.^52,53 Continued research comparing different TBC models is needed to determine which combination of health professionals and interventions is most impactful in practice.

Cost-Effectiveness

According to the CDC, TBC in hypertension management has proven to be cost-effective.⁵⁴ Systematic reviews and meta-analyses assessing the cost-effectiveness of TBC in hypertension management have been conducted.^{26,27,29,55-58} While the general consensus supports this approach as being cost-effective, these determinations are based on studies that are widely heterogeneous. In each of these studies, different types of costs are taken into account when determining cost-effectiveness. The range of costs can be quite wide, depending on how they are calculated, making it difficult to determine the true cost-effectiveness of different TBC models.

Intervention cost is represented by the amount of money spent to implement and maintain the intervention beyond the cost of usual care or the cost without the intervention. For TBC, intervention cost consists of personnel resources such as provider time, patient time, and non-personnel resources, including rent and utilities. Studies show that intervention costs for TBC can range from $35 to $1350 per person per year (mean, $618; median, $428).^27,56 One analysis, based on 20 studies comparing TBC to usual care, calculated an intervention cost of $284 per person per year,⁵⁵ while another study showed an intervention cost of $525 per enrollee per year.⁵⁶ Intervention cost can vary by the type of provider that is used, the amount of time spent per patient, and the setting where services are provided. Overall, the intervention cost of implementing TBC for hypertension management is consistently higher than the cost of usual care.

Health care cost is another factor to consider. It is the difference in the cost of health care products and services that are utilized in the process of TBC, as compared to care that is provided in the absence of TBC. Health care costs include the costs associated with hospitalizations, outpatient visits, emergency room visits, and medications. One study estimated a median health care cost of hypertension TBC of $65 per person per year.⁵⁵ Overall, studies evaluating the impact of TBC for hypertension management on health care costs were mixed, with some showing that TBC resulted in an increase in health care cost, and others showing a savings compared to usual care.⁵⁸ The variability in health care costs was due to the different number of health care components and comorbidities of the patients included in the studies. Also, study duration affected the estimated health care costs of TBC. Most studies did not assess long-term health care cost savings that could be achieved from prolonged blood pressure control.⁵⁸ When considering both intervention and health care cost, Jacob et al estimated that TBC increased overall net cost by a median value of $329 per person per year.⁵⁵ While some studies did attribute an overall reduction in health care costs to TBC for hypertension management, on average, team-based models increased health care costs compared to usual care.^{27,29,55,58,59}

However, health care costs do not take into account the long-term reductions in morbidity and mortality or increased quality-adjusted life years (QALY) that result from improved blood pressure control attributed to TBC. In most cost-effectiveness studies, an intervention is considered to be cost-effective if the cost per QALY gained is less than the accepted threshold of $50,000.⁵⁵ One study estimated that the cost per QALY of TBC in hypertension management is $4763,^55,60 while another study estimated a median cost per QALY of $9716 to $13,992.⁵⁵ A systematic review of 34 international studies estimated the median cost per QALY to be $13,986, ranging from $6683 to $58,610.⁵⁷ The wide range in cost can be attributed to the variability in interventions, health outcomes used to measure effectiveness, and the settings and countries where the studies were conducted. In another study, a TBC intervention involving pharmacists resulted in a cost per QALY of $26,800.⁶¹ The intervention was found to be cost-effective for higher-risk patients, defined as those having diabetes, a smoking history, dyslipidemia, or obesity. For patients who did not have these risk factors, the cost per QALY increased to $43,330.⁶¹ Thus, the patient population should be considered before implementing a TBC model. Furthermore, the increased use of technology, allowing for more efficient provision of services and communication between providers, could reduce intervention costs and lead to increased cost efficacy in these models.

The variation in the models used for TBC makes it difficult to draw conclusions on the cost-effectiveness of these interventions. Although it is apparent that TBC in general is cost-effective, more studies are needed comparing different team-based models to determine which specific ones are most cost-effective.

Challenges to Implementation of Team-Based Care

Recognizing and addressing the challenges inherent to a TBC approach is important to the sustainability of such a model within various settings and institutions. Numerous studies conducted on team-based models have identified common challenges that appear to be consistent across multiple settings. These challenges can be categorized as financial, provider-specific, and technology.

Financial Barriers

Although studies have demonstrated the cost-effectiveness of controlling hypertension and preventing serious complications, health systems are still confronted with the challenge of covering the cost for TBC implementation and maintenance.²⁹ The 2 main financial barriers for TBC services are stakeholder engagement and reimbursement for services. According to Kennelty et al, stakeholder engagement is key to the sustainability of the service.²⁷ However, decisions by stakeholders on cost are influenced by many factors, which include available funds, perceived value, and estimates for return on investment. Additionally, interventions must align with the organization’s mission and vision and be feasible to implement, and organizations must have the capacity for administrative support.²⁹ These various financial decisions may greatly influence the sustainability of a TBC model.

The reimbursement challenges for individual providers are an additional barrier to the sustainability of the service. In the United States, most providers are reimbursed via fee-for-service payment plans, but these plans do not reimburse all clinical providers because they are not all recognized as licensed providers.^62,63 For example, pharmacists are not recognized by the Centers for Medicare & Medicaid Services as licensed health care providers, which limits their ability to be reimbursed for clinical services provided outside of a traditional dispensing role. Furthermore, state laws determine the services nonphysician providers can offer and how they are recognized for reimbursement by tertiary payers. For instance, pharmacist roles, such as ordering labs and modifying or prescribing medication regimens, vary greatly between states.^7,63,64

Financial barriers are a major challenge facing the sustainability of a TBC hypertension service, so including all stakeholders in the decision-making process may improve the organization’s ability to sustain the service.

Provider-Specific Barriers

Notable barriers that are attributed to providers include lack of knowledge, lack of time, lack of initiative to change blood pressure medications, and inability to reach intensive blood pressure goals set in guidelines.²⁹ Studies such as the SPRINT trial have significantly impacted clinical guideline cut-offs for blood pressure, but reaching the intensive blood pressure goals from clinical trials is difficult to emulate in clinical practice.⁶⁵ In a typical clinical setting, providers may lack the confidence to make adjustments in therapy based on a single blood pressure measurement, and clinical inertia, defined as failure of health care providers to modify therapy when indicated,⁶⁶ may contribute to the inability to achieve blood pressure goals. Many factors contribute to clinical inertia, including lack of knowledge, time, or clinical protocols on how to modify therapy, causing providers to delay clinical decisions. Implementing site-specific protocols and utilizing hypertension specialist health care professionals in TBC can address the barriers contributing to clinical inertia.

Technology Barriers

A common barrier in a variety of services, but especially prevalent in a TBC service, is access to an electronic health record (EHR) for all providers treating the patient. Some providers who are not directly tied to the same clinical site as the patient’s primary care provider may not have adequate access to the full EHR. For example, pharmacists who are managing hypertension in a TBC model in a community pharmacy may have access only to health information from prescription records. Patient interviews may not provide the pharmacist with adequate information about laboratory results, vitals, and other medical information and history for the patient, making it difficult for the pharmacist to make a proper recommendation for treatment.²⁷ Depending on the setting, communication between providers may be a barrier in achieving optimal outcomes, especially when providers do not have access to a shared medical record.

In addition, patients often lack access to technology used to manage hypertension. Many new technologies exist that aid patients in managing their blood pressure, such as smart phone applications to track blood pressure readings and alarms to remind patients to take their medications. Studies have shown that telemonitoring of blood pressure measurements and management of hypertension, especially in combination with TBC, is effective and reduces costs compared to usual care.⁶⁷ However, the lack of equal access to the various technologies available may inhibit the success of a TBC hypertension program. Patients may lack access, knowledge, or financial means to utilize the various methods available for managing their hypertension electronically.²⁹

Conclusion

Incorporating nonphysician providers into the health care team for the treatment of hypertension has proven to be more effective than usual care and has been recognized by recent guidelines as a best practice approach to achieving blood pressure goals. Multiple studies have demonstrated that TBC utilizing nurses and pharmacists can improve blood pressure management. While adding members to the team increases health care costs, the long-term benefits of achieving optimal blood pressure goals contribute to the overall cost-effectiveness of TBC strategies over usual care. However, comparisons between different TBC models are warranted to determine which combination of health care professionals and/or interventions is most effective. Cost-analysis estimates are difficult to compare due to widely varied methodology and variance in the models that have been employed. Studies must consider pathways to overcoming reimbursement issues, provider-specific challenges, and technology barriers. Follow-up and monitoring after initiation of drug therapy for hypertension control should include systematic strategies to help improve blood pressure, including use of home blood pressure monitoring, TBC, and telehealth strategies. Future implementation science approaches to hypertension TBC models within specific clinic settings will be useful to identify and overcome challenges and will help to determine the populations who will benefit most, allowing for greater success in sustaining TBC models.

Corresponding author: Shawn R. Smith, PharmD, 309 E. 2nd Street, Pomona, CA 91766; [email protected].

Financial disclosures: None.

From Western University of Health Sciences College of Pharmacy, Department of Pharmacy Practice and Administration, Pomona, CA.

Abstract

• Objective: To review the current literature regarding the clinical effectiveness and cost-effectiveness of implementing hypertension team-based care (TBC) interventions in the outpatient setting, and discuss challenges to implementation.
• Methods: A literature review was conducted of meta-analyses, systematic reviews, and randomized controlled trials comparing TBC models to usual care for hypertension management.
• Results: Compared to usual care, TBC models have demonstrated greater blood pressure reductions and improved blood pressure control rates. Evidence was strongest for models involving nurses and pharmacists whose roles included medication management, patient education and counseling, coordination of care and follow-up, population health management, and performance measurement with quality improvement. Although TBC results in an increase in health care costs, the overall long-term benefits support the cost-effectiveness of these models over usual care. The most common barriers to TBC implementation include underutilization of technology, stakeholder engagement, and reimbursement issues.
• Conclusion: Hypertension TBC models have been shown to be clinically effective and cost-effective, but continued research comparing different models is warranted to determine which combination of health professionals and interventions is most impactful and cost-effective in practice. An implementation science approach, in which TBC models unique to each organization’s situation are created, will be useful to identify and overcome challenges and provide a solid foundation for sustainment.

Keywords: blood pressure; pharmacist; nurse; nurse practitioner; cost-effectiveness; team-based care.

Approximately 1 in 3 US adults—or about 100 million people—have high blood pressure, and only about half (48%) have their blood pressure under control.¹ Effective blood pressure management has been shown to decrease the incidence of stroke, heart attack, and heart failure.^2-4 The American College of Cardiology/American Heart Association (ACC/AHA) 2017 blood pressure guidelines recommended lower thresholds for diagnosing hypertension and initiating antihypertensive medication, and intensified the blood pressure goal to less than 130/80 mm Hg.⁵ Changing practice standards to more intensive blood pressure goals requires significant adjustments by clinicians and health care systems. In fact, new guideline uptake is often delayed, ignored, or sparsely applied.⁶ Due to this dramatic change in hypertension practice standards, the ACC/AHA guidelines support interdisciplinary team-based care (TBC) for hypertension management.^5,7 Additionally, the Centers for Disease Control and Prevention (CDC) and the Community Preventive Services Task Force (CPSTF) promote TBC to improve blood pressure control in their initiatives to prevent heart disease and stroke.^8,9

The National Academy of Medicine defines TBC as “the provision of health services to individuals, families, and/or their communities by at least 2 healthcare providers who work collaboratively with patients and their caregivers—to the extent preferred by each patient—to accomplish shared goals within and across settings to achieve coordinated, high-quality care.”¹⁰ Specific goals for TBC in hypertension treatment are listed in Table 1, and a checklist of key elements of TBC to consider before implementation are presented in Table 2.

TBC has been shown to have many advantages, including increased access to care due to expanded hours of operation and shorter wait times.¹¹ Team-based models also provide effective and efficient delivery of patient education, behavioral health care, and care coordination.^12-14 Patients are more likely to receive high-quality care when multiple providers, each with varied expertise, are on the health care team.^11,15 Furthermore, clinicians report improved professional job satisfaction related to their ability to practice in environments where they are encouraged to work at the top of their licenses.¹⁶ Consequently, TBC has been accepted as a vital part of the patient-centered medical home (PCMH) model.^17-19 Standards set by the National Committee for Quality Assurance (NCQA) include TBC as a requirement health systems must meet in order to achieve the highest level of PCMH recognition. While a team-based approach offers substantial benefits and is recognized as a marker of quality, implementation has presented various challenges, and the sustainability of these models in care settings has been questioned.²⁰

In this article, we review the current literature regarding the clinical effectiveness and cost-effectiveness of implementing hypertension TBC interventions in the outpatient setting. We also discuss the challenges and opportunities of implementing this strategy in health systems and community settings in the United States.

Evidence of Impact and Effectiveness

Various models of hypertension TBC have been shown to increase the proportion of individuals with controlled blood pressure and to lead to a reduction in both systolic (SBP) and diastolic blood pressure (DBP), resulting in a strong recommendation for TBC approaches by the 2017 ACC/AHA blood pressure guidelines.^5,21-25 There is great diversity in the types of hypertension treatment models studied, with few utilizing physician specialists and most utilizing nonphysician providers, such as community health workers, physician assistants, nurses, nurse practitioners, dietitians, social workers, and pharmacists.^22,26-29 These professionals share duties of hypertension management with primary care physicians to reduce the burden of responsibility for care on any single provider type. TBC is patient-centered, and typically includes interprofessional collaboration, treatment algorithms, adherence counseling, frequent follow-up, home blood pressure monitoring, and patient self-management education.

Numerous studies have supported implementation of TBC in recent years. A systematic review and meta-analysis of 100 trials of hypertension TBC involving 55,920 patients concluded that the most effective blood pressure–lowering strategies use multilevel, multicomponent approaches to address barriers to hypertension control. Nonphysician providers are often involved in measuring blood pressure, ordering and assessing laboratory tests, and titrating medications.³⁰ Compared with usual care, TBC with physician medication titration resulted in reductions in mean SBP and DBP (6.2 mm Hg and 2.7 mm Hg, respectively), while TBC with nonphysician medication titration also resulted in reductions in mean SBP and DBP (7.1 mm Hg and 3.1 mm Hg, respectively). Nurses and pharmacists are specifically mentioned by the 2017 ACC/AHA blood pressure guidelines as essential members of the hypertension treatment team.⁵ Randomized controlled trials (RCTs) and meta-analyses of TBC involving nurse or pharmacist interventions demonstrated greater reductions in SBP and/or greater attainment of blood pressure goals compared to usual care.^21,26,31,32 The literature supports the roles of nurses and pharmacists in hypertension management in all aspects of care, including medication management, patient education and counseling, coordination of care and follow-up, population health management, and performance measurement with quality improvement.³³

Nurses

Nurses are commonly part of TBC hypertension management programs. One meta-analysis and systematic review of international RCTs compared nurse, nurse prescriber (United Kingdom), and nurse practitioner interventions for hypertension with usual care. Interventions that included a stepped treatment algorithm and nurse prescribing showed greater reductions in SBP (8.2 mm Hg and 8.9 mm Hg, respectively) compared to usual care.³¹ Similarly, models that utilized telephone monitoring demonstrated greater achievement of blood pressure targets, while those that involved home monitoring showed significant reductions in blood pressure. Another international meta-analysis and systematic review of 11 nurse-led interventions in hypertensive patients with diabetes demonstrated a 5.8 mm Hg mean decrease in SBP compared to physician-led care. However, nurse-led care was not superior in achievement of study targets.³⁴

A recent meta-analysis and systematic review, performed by Shaw and colleagues, sought to determine whether nurse-led protocols are effective for outpatient management of adults with diabetes, hypertension, and hyperlipidemia. All of the included studies involved a registered nurse who titrated medications by following a protocol, and most were RCTs comparing the nurse protocols to usual care. Overall, mean SBP and DBP decreased by 3.86 mm Hg and 1.56 mm Hg, respectively, while blood glucose and lipid levels were also reduced compared to usual care.²⁴

Limited RCT data have been published since the Shaw et al meta-analysis. A single-blind RCT was performed in an urban community health care center in China among patients with uncontrolled blood pressure (SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg).³⁵ The study group received care via a nurse-led model, which included a delivery design system, decision support, clinical information system, and self-management support, and the control group received usual care. At 12 weeks, patients in the study group had significantly lower blood pressure than control patients, with mean SBP/DBP reduction of 14.37/7.43 mm Hg and 5.10/2.69 mm Hg, respectively (P < 0.01). Improved medication adherence and increased patient satisfaction were other benefits of the nurse-led model.

Nurse case managers (NCM) also play a critical role in hypertension management, coordinating health care services to meet patient health needs. Ogedegbe sought to evaluate the comparative effectiveness of home blood pressure telemonitoring (HBPTM)+NCM versus HBPTM alone on SBP reduction in black and Hispanic stroke survivors.^36,37 NCMs evaluated patient profiles, counseled patients on target lifestyle behaviors, and reviewed home blood pressure data. At 6 months, SBP declined by 13.63 mm Hg from baseline in the HBPTM+NCM group and 6.31 mm Hg in the HBPTM alone group (P < 0.0001). At 12 months, SBP in the HBPTM+NCM group declined by 14.76 mm Hg, while blood pressure in the HBPTM alone group declined by 5.53 mm Hg (P < 0.0001).

Pharmacists

Clinical pharmacists are also widely utilized in TBC models for hypertension management. Typical models involve pharmacists entering into collaborative practice agreements with physicians, leading to optimization of medications, avoidance of adverse drug events, and transitional care activities focusing on medication reconciliation and patient education in outpatient settings.^30,38 The largest and most recent meta-analysis of pharmacist interventions, conducted in 2014 by Santschi et al,²³ combined 2 previous systematic reviews to include a total of 39 RCTs with 14,224 patients.^32,39 Pharmacist interventions included patient education, recommendations to physicians, and medication management. Compared with usual care, pharmacist interventions showed greater reductions in SBP (7.6 mm Hg) and DBP (3.9 mm Hg).²³

Numerous studies substantiating the impact of pharmacist interventions on clinical outcomes have heavily influenced clinical practice and guideline development. Carter et al conducted a prospective, multi-state, cluster-randomized trial in 32 primary care clinics to evaluate whether clinics randomized to receive the pharmacist-physician collaborative care model (PPCCM) achieved better blood pressure outcomes versus clinics randomized to usual care.²⁵ Investigators enrolled 625 patients with uncontrolled hypertension, 50% of whom had a prior diagnosis of diabetes mellitus or chronic kidney disease. The primary outcome of blood pressure control at 9 months in the intervention clinics compared to the control clinics was 43% and 34%, respectively (P = 0.059). The difference in mean SBP/DBP between the intervention and control clinics for all patients at 9 months was −6.1/−2.9 mm Hg. In a post-hoc analysis of patients with chronic kidney disease and diabetes, the pharmacist-intervention group had a significantly greater mean SBP reduction and higher blood pressure control rates compared to usual care at 9 months.⁴⁰

A pre-specified secondary analysis from the Carter et al study determined that, in patients from racial minority groups, the mean SBP was 7.3 mm Hg lower in those who received the intervention compared to those in the control group (P = 0.0042).⁴¹ In patients with less than 12 years of education, those in the intervention group had a mean SBP 8.1 mm Hg lower than the SBP of those in the control group (P = 0.0001). Similar reductions in blood pressure occurred in patients with low income, Medicaid beneficiaries, or those without insurance. This study demonstrated that pharmacist interventions reduced racial and socioeconomic disparities in blood pressure treatment.

Other studies of pharmacist interventions in underserved populations have yielded positive results. In a retrospective review of uninsured patients, blood pressure control rates in a pharmacist-driven primary care clinic ranked in the 90th percentile of NCQA benchmarks, and was superior to the 2013 reported mean for commercial insurers.⁴² Similarly, another retrospective cohort study of a PPCCM on time to goal blood pressure in uninsured patients with hypertension showed the median time to blood pressure goal was 36 days in the PPCCM cohort versus 259 days in usual care cohorts (P < 0.001).⁴³ A post-hoc analysis revealed the mean time-in-therapeutic blood pressure range was 46.2% ± 24.3% in the PPCCM group and 24.8% ± 27.4% in the usual care group (P < 0.0001). The blood pressure control rates at 12 months were 89% in the PPCCM group compared with 50% in the usual care group (P < 0.0001).⁴⁴

Tsuyuki et al conducted the RxACTION study, a multicenter RCT evaluating the effectiveness of enhanced pharmacist care versus usual care in 23 Canadian community pharmacies and outpatient clinics following a 6-month intervention.⁴⁵ Enhanced pharmacy services included pharmacist assessment of and counseling about cardiovascular disease risk and blood pressure control, review of current antihypertensive medications, and prescribing/titrating drug therapy, as needed, through independent prescriptive authority. Compared to the usual care group (n = 67), the intervention group had a reduction in SBP of 6.6 mm Hg (P = 0.006) and in DBP of 3.2 mm Hg (P = 0.01). This study expanded the pharmacists’ scope of practice, showing evidence for enhancing pharmacist roles on the hypertension care team. Tsuyuki et al also conducted the RxEACH randomized trial, which evaluated community pharmacist cardiovascular risk reduction interventions and showed an improvement in SBP and DBP, with reported results comparable to RxACTION.⁴⁶

Victor et al conducted the landmark Black Barbershop Study, a cluster RCT involving 319 non-Hispanic black male patients with hypertension from 52 black-owned barbershops.^47,48 Barbershops were assigned to 1 of 2 groups. The control group consisted of barbers who encouraged lifestyle modifications and made referrals to primary care providers. The intervention group had pharmacists who met regularly with participants at the barbershops and measured blood pressure, encouraged lifestyle changes, and prescribed drug therapy under collaborative practice agreements with physicians. Both groups demonstrated improvements in blood pressure outcomes, but the intervention group showed greater improvement in SBP and achievement of blood pressure goals compared to the control group. The results in the intervention group proved sustainable over the course of a year, even after the frequency of pharmacists’ visits was reduced. At 6 months, the mean SBP fell by 27.0 mm Hg (to 125.8 mm Hg) in the intervention group, as compared to a 9.3 mm Hg (to 145.4 mm Hg) reduction in the control group (P < 0.001), and blood pressure less than 130/80 mm Hg was achieved among 63.6% of the participants in the intervention group versus 11.7% in the control group (P < 0.001).

This community-level trial brought pharmacists to the barbershop and made them an essential part of the health care team through the endorsement of the barber, who the participants trusted and with whom they had a relationship. Long-standing issues related to distrust of the medical profession by this population were addressed, and trusted community barbershops were utilized as safe spaces for health care delivery. Health care professionals should consider utilizing community locations that other minority populations perceive as social centers and safe places, to reduce health disparities and barriers to care. However, models that bring care to patients need further economic and feasibility evaluations.

Other Health Care Professionals and Future Studies

In addition to models led by nurses and pharmacists, studies have also assessed models of TBC incorporating other health care professionals, including registered dietitians, medical assistants, community health workers, and health coaches (NCT02674464).^49,50 Ongoing studies are also looking at the impact of TBC on underserved communities (NCT02674464, NCT03504124). Involving a variety of health care professionals with different communities and populations in TBC studies is warranted to determine the optimal settings in which to utilize different skill sets.

The Impress Study involves nurses who are assessing lifestyle risk and developing an action plan according to a standardized procedure, which may be advantageous given the degree of heterogeneity found in other TBC models.⁵¹ There are also studies underway or recently published that compare different components of TBC in order to determine which combination of TBC elements is preferred. Some of these have shown the benefits of using clinical decision-support systems (through a guideline-based treatment protocol) or training programs with ongoing support.^52,53 Continued research comparing different TBC models is needed to determine which combination of health professionals and interventions is most impactful in practice.

Cost-Effectiveness

According to the CDC, TBC in hypertension management has proven to be cost-effective.⁵⁴ Systematic reviews and meta-analyses assessing the cost-effectiveness of TBC in hypertension management have been conducted.^{26,27,29,55-58} While the general consensus supports this approach as being cost-effective, these determinations are based on studies that are widely heterogeneous. In each of these studies, different types of costs are taken into account when determining cost-effectiveness. The range of costs can be quite wide, depending on how they are calculated, making it difficult to determine the true cost-effectiveness of different TBC models.

Intervention cost is represented by the amount of money spent to implement and maintain the intervention beyond the cost of usual care or the cost without the intervention. For TBC, intervention cost consists of personnel resources such as provider time, patient time, and non-personnel resources, including rent and utilities. Studies show that intervention costs for TBC can range from $35 to $1350 per person per year (mean, $618; median, $428).^27,56 One analysis, based on 20 studies comparing TBC to usual care, calculated an intervention cost of $284 per person per year,⁵⁵ while another study showed an intervention cost of $525 per enrollee per year.⁵⁶ Intervention cost can vary by the type of provider that is used, the amount of time spent per patient, and the setting where services are provided. Overall, the intervention cost of implementing TBC for hypertension management is consistently higher than the cost of usual care.

Health care cost is another factor to consider. It is the difference in the cost of health care products and services that are utilized in the process of TBC, as compared to care that is provided in the absence of TBC. Health care costs include the costs associated with hospitalizations, outpatient visits, emergency room visits, and medications. One study estimated a median health care cost of hypertension TBC of $65 per person per year.⁵⁵ Overall, studies evaluating the impact of TBC for hypertension management on health care costs were mixed, with some showing that TBC resulted in an increase in health care cost, and others showing a savings compared to usual care.⁵⁸ The variability in health care costs was due to the different number of health care components and comorbidities of the patients included in the studies. Also, study duration affected the estimated health care costs of TBC. Most studies did not assess long-term health care cost savings that could be achieved from prolonged blood pressure control.⁵⁸ When considering both intervention and health care cost, Jacob et al estimated that TBC increased overall net cost by a median value of $329 per person per year.⁵⁵ While some studies did attribute an overall reduction in health care costs to TBC for hypertension management, on average, team-based models increased health care costs compared to usual care.^{27,29,55,58,59}

However, health care costs do not take into account the long-term reductions in morbidity and mortality or increased quality-adjusted life years (QALY) that result from improved blood pressure control attributed to TBC. In most cost-effectiveness studies, an intervention is considered to be cost-effective if the cost per QALY gained is less than the accepted threshold of $50,000.⁵⁵ One study estimated that the cost per QALY of TBC in hypertension management is $4763,^55,60 while another study estimated a median cost per QALY of $9716 to $13,992.⁵⁵ A systematic review of 34 international studies estimated the median cost per QALY to be $13,986, ranging from $6683 to $58,610.⁵⁷ The wide range in cost can be attributed to the variability in interventions, health outcomes used to measure effectiveness, and the settings and countries where the studies were conducted. In another study, a TBC intervention involving pharmacists resulted in a cost per QALY of $26,800.⁶¹ The intervention was found to be cost-effective for higher-risk patients, defined as those having diabetes, a smoking history, dyslipidemia, or obesity. For patients who did not have these risk factors, the cost per QALY increased to $43,330.⁶¹ Thus, the patient population should be considered before implementing a TBC model. Furthermore, the increased use of technology, allowing for more efficient provision of services and communication between providers, could reduce intervention costs and lead to increased cost efficacy in these models.

The variation in the models used for TBC makes it difficult to draw conclusions on the cost-effectiveness of these interventions. Although it is apparent that TBC in general is cost-effective, more studies are needed comparing different team-based models to determine which specific ones are most cost-effective.

Challenges to Implementation of Team-Based Care

Recognizing and addressing the challenges inherent to a TBC approach is important to the sustainability of such a model within various settings and institutions. Numerous studies conducted on team-based models have identified common challenges that appear to be consistent across multiple settings. These challenges can be categorized as financial, provider-specific, and technology.

Financial Barriers

Although studies have demonstrated the cost-effectiveness of controlling hypertension and preventing serious complications, health systems are still confronted with the challenge of covering the cost for TBC implementation and maintenance.²⁹ The 2 main financial barriers for TBC services are stakeholder engagement and reimbursement for services. According to Kennelty et al, stakeholder engagement is key to the sustainability of the service.²⁷ However, decisions by stakeholders on cost are influenced by many factors, which include available funds, perceived value, and estimates for return on investment. Additionally, interventions must align with the organization’s mission and vision and be feasible to implement, and organizations must have the capacity for administrative support.²⁹ These various financial decisions may greatly influence the sustainability of a TBC model.

The reimbursement challenges for individual providers are an additional barrier to the sustainability of the service. In the United States, most providers are reimbursed via fee-for-service payment plans, but these plans do not reimburse all clinical providers because they are not all recognized as licensed providers.^62,63 For example, pharmacists are not recognized by the Centers for Medicare & Medicaid Services as licensed health care providers, which limits their ability to be reimbursed for clinical services provided outside of a traditional dispensing role. Furthermore, state laws determine the services nonphysician providers can offer and how they are recognized for reimbursement by tertiary payers. For instance, pharmacist roles, such as ordering labs and modifying or prescribing medication regimens, vary greatly between states.^7,63,64

Financial barriers are a major challenge facing the sustainability of a TBC hypertension service, so including all stakeholders in the decision-making process may improve the organization’s ability to sustain the service.

Provider-Specific Barriers

Notable barriers that are attributed to providers include lack of knowledge, lack of time, lack of initiative to change blood pressure medications, and inability to reach intensive blood pressure goals set in guidelines.²⁹ Studies such as the SPRINT trial have significantly impacted clinical guideline cut-offs for blood pressure, but reaching the intensive blood pressure goals from clinical trials is difficult to emulate in clinical practice.⁶⁵ In a typical clinical setting, providers may lack the confidence to make adjustments in therapy based on a single blood pressure measurement, and clinical inertia, defined as failure of health care providers to modify therapy when indicated,⁶⁶ may contribute to the inability to achieve blood pressure goals. Many factors contribute to clinical inertia, including lack of knowledge, time, or clinical protocols on how to modify therapy, causing providers to delay clinical decisions. Implementing site-specific protocols and utilizing hypertension specialist health care professionals in TBC can address the barriers contributing to clinical inertia.

Technology Barriers

A common barrier in a variety of services, but especially prevalent in a TBC service, is access to an electronic health record (EHR) for all providers treating the patient. Some providers who are not directly tied to the same clinical site as the patient’s primary care provider may not have adequate access to the full EHR. For example, pharmacists who are managing hypertension in a TBC model in a community pharmacy may have access only to health information from prescription records. Patient interviews may not provide the pharmacist with adequate information about laboratory results, vitals, and other medical information and history for the patient, making it difficult for the pharmacist to make a proper recommendation for treatment.²⁷ Depending on the setting, communication between providers may be a barrier in achieving optimal outcomes, especially when providers do not have access to a shared medical record.

In addition, patients often lack access to technology used to manage hypertension. Many new technologies exist that aid patients in managing their blood pressure, such as smart phone applications to track blood pressure readings and alarms to remind patients to take their medications. Studies have shown that telemonitoring of blood pressure measurements and management of hypertension, especially in combination with TBC, is effective and reduces costs compared to usual care.⁶⁷ However, the lack of equal access to the various technologies available may inhibit the success of a TBC hypertension program. Patients may lack access, knowledge, or financial means to utilize the various methods available for managing their hypertension electronically.²⁹

Conclusion

Incorporating nonphysician providers into the health care team for the treatment of hypertension has proven to be more effective than usual care and has been recognized by recent guidelines as a best practice approach to achieving blood pressure goals. Multiple studies have demonstrated that TBC utilizing nurses and pharmacists can improve blood pressure management. While adding members to the team increases health care costs, the long-term benefits of achieving optimal blood pressure goals contribute to the overall cost-effectiveness of TBC strategies over usual care. However, comparisons between different TBC models are warranted to determine which combination of health care professionals and/or interventions is most effective. Cost-analysis estimates are difficult to compare due to widely varied methodology and variance in the models that have been employed. Studies must consider pathways to overcoming reimbursement issues, provider-specific challenges, and technology barriers. Follow-up and monitoring after initiation of drug therapy for hypertension control should include systematic strategies to help improve blood pressure, including use of home blood pressure monitoring, TBC, and telehealth strategies. Future implementation science approaches to hypertension TBC models within specific clinic settings will be useful to identify and overcome challenges and will help to determine the populations who will benefit most, allowing for greater success in sustaining TBC models.

Corresponding author: Shawn R. Smith, PharmD, 309 E. 2nd Street, Pomona, CA 91766; [email protected].

Financial disclosures: None.

From Western University of Health Sciences College of Pharmacy, Department of Pharmacy Practice and Administration, Pomona, CA.

Abstract

• Objective: To review the current literature regarding the clinical effectiveness and cost-effectiveness of implementing hypertension team-based care (TBC) interventions in the outpatient setting, and discuss challenges to implementation.
• Methods: A literature review was conducted of meta-analyses, systematic reviews, and randomized controlled trials comparing TBC models to usual care for hypertension management.
• Results: Compared to usual care, TBC models have demonstrated greater blood pressure reductions and improved blood pressure control rates. Evidence was strongest for models involving nurses and pharmacists whose roles included medication management, patient education and counseling, coordination of care and follow-up, population health management, and performance measurement with quality improvement. Although TBC results in an increase in health care costs, the overall long-term benefits support the cost-effectiveness of these models over usual care. The most common barriers to TBC implementation include underutilization of technology, stakeholder engagement, and reimbursement issues.
• Conclusion: Hypertension TBC models have been shown to be clinically effective and cost-effective, but continued research comparing different models is warranted to determine which combination of health professionals and interventions is most impactful and cost-effective in practice. An implementation science approach, in which TBC models unique to each organization’s situation are created, will be useful to identify and overcome challenges and provide a solid foundation for sustainment.

Keywords: blood pressure; pharmacist; nurse; nurse practitioner; cost-effectiveness; team-based care.

Approximately 1 in 3 US adults—or about 100 million people—have high blood pressure, and only about half (48%) have their blood pressure under control.¹ Effective blood pressure management has been shown to decrease the incidence of stroke, heart attack, and heart failure.^2-4 The American College of Cardiology/American Heart Association (ACC/AHA) 2017 blood pressure guidelines recommended lower thresholds for diagnosing hypertension and initiating antihypertensive medication, and intensified the blood pressure goal to less than 130/80 mm Hg.⁵ Changing practice standards to more intensive blood pressure goals requires significant adjustments by clinicians and health care systems. In fact, new guideline uptake is often delayed, ignored, or sparsely applied.⁶ Due to this dramatic change in hypertension practice standards, the ACC/AHA guidelines support interdisciplinary team-based care (TBC) for hypertension management.^5,7 Additionally, the Centers for Disease Control and Prevention (CDC) and the Community Preventive Services Task Force (CPSTF) promote TBC to improve blood pressure control in their initiatives to prevent heart disease and stroke.^8,9

The National Academy of Medicine defines TBC as “the provision of health services to individuals, families, and/or their communities by at least 2 healthcare providers who work collaboratively with patients and their caregivers—to the extent preferred by each patient—to accomplish shared goals within and across settings to achieve coordinated, high-quality care.”¹⁰ Specific goals for TBC in hypertension treatment are listed in Table 1, and a checklist of key elements of TBC to consider before implementation are presented in Table 2.

TBC has been shown to have many advantages, including increased access to care due to expanded hours of operation and shorter wait times.¹¹ Team-based models also provide effective and efficient delivery of patient education, behavioral health care, and care coordination.^12-14 Patients are more likely to receive high-quality care when multiple providers, each with varied expertise, are on the health care team.^11,15 Furthermore, clinicians report improved professional job satisfaction related to their ability to practice in environments where they are encouraged to work at the top of their licenses.¹⁶ Consequently, TBC has been accepted as a vital part of the patient-centered medical home (PCMH) model.^17-19 Standards set by the National Committee for Quality Assurance (NCQA) include TBC as a requirement health systems must meet in order to achieve the highest level of PCMH recognition. While a team-based approach offers substantial benefits and is recognized as a marker of quality, implementation has presented various challenges, and the sustainability of these models in care settings has been questioned.²⁰

In this article, we review the current literature regarding the clinical effectiveness and cost-effectiveness of implementing hypertension TBC interventions in the outpatient setting. We also discuss the challenges and opportunities of implementing this strategy in health systems and community settings in the United States.

Evidence of Impact and Effectiveness

Various models of hypertension TBC have been shown to increase the proportion of individuals with controlled blood pressure and to lead to a reduction in both systolic (SBP) and diastolic blood pressure (DBP), resulting in a strong recommendation for TBC approaches by the 2017 ACC/AHA blood pressure guidelines.^5,21-25 There is great diversity in the types of hypertension treatment models studied, with few utilizing physician specialists and most utilizing nonphysician providers, such as community health workers, physician assistants, nurses, nurse practitioners, dietitians, social workers, and pharmacists.^22,26-29 These professionals share duties of hypertension management with primary care physicians to reduce the burden of responsibility for care on any single provider type. TBC is patient-centered, and typically includes interprofessional collaboration, treatment algorithms, adherence counseling, frequent follow-up, home blood pressure monitoring, and patient self-management education.

Numerous studies have supported implementation of TBC in recent years. A systematic review and meta-analysis of 100 trials of hypertension TBC involving 55,920 patients concluded that the most effective blood pressure–lowering strategies use multilevel, multicomponent approaches to address barriers to hypertension control. Nonphysician providers are often involved in measuring blood pressure, ordering and assessing laboratory tests, and titrating medications.³⁰ Compared with usual care, TBC with physician medication titration resulted in reductions in mean SBP and DBP (6.2 mm Hg and 2.7 mm Hg, respectively), while TBC with nonphysician medication titration also resulted in reductions in mean SBP and DBP (7.1 mm Hg and 3.1 mm Hg, respectively). Nurses and pharmacists are specifically mentioned by the 2017 ACC/AHA blood pressure guidelines as essential members of the hypertension treatment team.⁵ Randomized controlled trials (RCTs) and meta-analyses of TBC involving nurse or pharmacist interventions demonstrated greater reductions in SBP and/or greater attainment of blood pressure goals compared to usual care.^21,26,31,32 The literature supports the roles of nurses and pharmacists in hypertension management in all aspects of care, including medication management, patient education and counseling, coordination of care and follow-up, population health management, and performance measurement with quality improvement.³³

Nurses

Nurses are commonly part of TBC hypertension management programs. One meta-analysis and systematic review of international RCTs compared nurse, nurse prescriber (United Kingdom), and nurse practitioner interventions for hypertension with usual care. Interventions that included a stepped treatment algorithm and nurse prescribing showed greater reductions in SBP (8.2 mm Hg and 8.9 mm Hg, respectively) compared to usual care.³¹ Similarly, models that utilized telephone monitoring demonstrated greater achievement of blood pressure targets, while those that involved home monitoring showed significant reductions in blood pressure. Another international meta-analysis and systematic review of 11 nurse-led interventions in hypertensive patients with diabetes demonstrated a 5.8 mm Hg mean decrease in SBP compared to physician-led care. However, nurse-led care was not superior in achievement of study targets.³⁴

A recent meta-analysis and systematic review, performed by Shaw and colleagues, sought to determine whether nurse-led protocols are effective for outpatient management of adults with diabetes, hypertension, and hyperlipidemia. All of the included studies involved a registered nurse who titrated medications by following a protocol, and most were RCTs comparing the nurse protocols to usual care. Overall, mean SBP and DBP decreased by 3.86 mm Hg and 1.56 mm Hg, respectively, while blood glucose and lipid levels were also reduced compared to usual care.²⁴

Limited RCT data have been published since the Shaw et al meta-analysis. A single-blind RCT was performed in an urban community health care center in China among patients with uncontrolled blood pressure (SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg).³⁵ The study group received care via a nurse-led model, which included a delivery design system, decision support, clinical information system, and self-management support, and the control group received usual care. At 12 weeks, patients in the study group had significantly lower blood pressure than control patients, with mean SBP/DBP reduction of 14.37/7.43 mm Hg and 5.10/2.69 mm Hg, respectively (P < 0.01). Improved medication adherence and increased patient satisfaction were other benefits of the nurse-led model.

Nurse case managers (NCM) also play a critical role in hypertension management, coordinating health care services to meet patient health needs. Ogedegbe sought to evaluate the comparative effectiveness of home blood pressure telemonitoring (HBPTM)+NCM versus HBPTM alone on SBP reduction in black and Hispanic stroke survivors.^36,37 NCMs evaluated patient profiles, counseled patients on target lifestyle behaviors, and reviewed home blood pressure data. At 6 months, SBP declined by 13.63 mm Hg from baseline in the HBPTM+NCM group and 6.31 mm Hg in the HBPTM alone group (P < 0.0001). At 12 months, SBP in the HBPTM+NCM group declined by 14.76 mm Hg, while blood pressure in the HBPTM alone group declined by 5.53 mm Hg (P < 0.0001).

Pharmacists

Clinical pharmacists are also widely utilized in TBC models for hypertension management. Typical models involve pharmacists entering into collaborative practice agreements with physicians, leading to optimization of medications, avoidance of adverse drug events, and transitional care activities focusing on medication reconciliation and patient education in outpatient settings.^30,38 The largest and most recent meta-analysis of pharmacist interventions, conducted in 2014 by Santschi et al,²³ combined 2 previous systematic reviews to include a total of 39 RCTs with 14,224 patients.^32,39 Pharmacist interventions included patient education, recommendations to physicians, and medication management. Compared with usual care, pharmacist interventions showed greater reductions in SBP (7.6 mm Hg) and DBP (3.9 mm Hg).²³

Numerous studies substantiating the impact of pharmacist interventions on clinical outcomes have heavily influenced clinical practice and guideline development. Carter et al conducted a prospective, multi-state, cluster-randomized trial in 32 primary care clinics to evaluate whether clinics randomized to receive the pharmacist-physician collaborative care model (PPCCM) achieved better blood pressure outcomes versus clinics randomized to usual care.²⁵ Investigators enrolled 625 patients with uncontrolled hypertension, 50% of whom had a prior diagnosis of diabetes mellitus or chronic kidney disease. The primary outcome of blood pressure control at 9 months in the intervention clinics compared to the control clinics was 43% and 34%, respectively (P = 0.059). The difference in mean SBP/DBP between the intervention and control clinics for all patients at 9 months was −6.1/−2.9 mm Hg. In a post-hoc analysis of patients with chronic kidney disease and diabetes, the pharmacist-intervention group had a significantly greater mean SBP reduction and higher blood pressure control rates compared to usual care at 9 months.⁴⁰

A pre-specified secondary analysis from the Carter et al study determined that, in patients from racial minority groups, the mean SBP was 7.3 mm Hg lower in those who received the intervention compared to those in the control group (P = 0.0042).⁴¹ In patients with less than 12 years of education, those in the intervention group had a mean SBP 8.1 mm Hg lower than the SBP of those in the control group (P = 0.0001). Similar reductions in blood pressure occurred in patients with low income, Medicaid beneficiaries, or those without insurance. This study demonstrated that pharmacist interventions reduced racial and socioeconomic disparities in blood pressure treatment.

Other studies of pharmacist interventions in underserved populations have yielded positive results. In a retrospective review of uninsured patients, blood pressure control rates in a pharmacist-driven primary care clinic ranked in the 90th percentile of NCQA benchmarks, and was superior to the 2013 reported mean for commercial insurers.⁴² Similarly, another retrospective cohort study of a PPCCM on time to goal blood pressure in uninsured patients with hypertension showed the median time to blood pressure goal was 36 days in the PPCCM cohort versus 259 days in usual care cohorts (P < 0.001).⁴³ A post-hoc analysis revealed the mean time-in-therapeutic blood pressure range was 46.2% ± 24.3% in the PPCCM group and 24.8% ± 27.4% in the usual care group (P < 0.0001). The blood pressure control rates at 12 months were 89% in the PPCCM group compared with 50% in the usual care group (P < 0.0001).⁴⁴

Tsuyuki et al conducted the RxACTION study, a multicenter RCT evaluating the effectiveness of enhanced pharmacist care versus usual care in 23 Canadian community pharmacies and outpatient clinics following a 6-month intervention.⁴⁵ Enhanced pharmacy services included pharmacist assessment of and counseling about cardiovascular disease risk and blood pressure control, review of current antihypertensive medications, and prescribing/titrating drug therapy, as needed, through independent prescriptive authority. Compared to the usual care group (n = 67), the intervention group had a reduction in SBP of 6.6 mm Hg (P = 0.006) and in DBP of 3.2 mm Hg (P = 0.01). This study expanded the pharmacists’ scope of practice, showing evidence for enhancing pharmacist roles on the hypertension care team. Tsuyuki et al also conducted the RxEACH randomized trial, which evaluated community pharmacist cardiovascular risk reduction interventions and showed an improvement in SBP and DBP, with reported results comparable to RxACTION.⁴⁶

Victor et al conducted the landmark Black Barbershop Study, a cluster RCT involving 319 non-Hispanic black male patients with hypertension from 52 black-owned barbershops.^47,48 Barbershops were assigned to 1 of 2 groups. The control group consisted of barbers who encouraged lifestyle modifications and made referrals to primary care providers. The intervention group had pharmacists who met regularly with participants at the barbershops and measured blood pressure, encouraged lifestyle changes, and prescribed drug therapy under collaborative practice agreements with physicians. Both groups demonstrated improvements in blood pressure outcomes, but the intervention group showed greater improvement in SBP and achievement of blood pressure goals compared to the control group. The results in the intervention group proved sustainable over the course of a year, even after the frequency of pharmacists’ visits was reduced. At 6 months, the mean SBP fell by 27.0 mm Hg (to 125.8 mm Hg) in the intervention group, as compared to a 9.3 mm Hg (to 145.4 mm Hg) reduction in the control group (P < 0.001), and blood pressure less than 130/80 mm Hg was achieved among 63.6% of the participants in the intervention group versus 11.7% in the control group (P < 0.001).

This community-level trial brought pharmacists to the barbershop and made them an essential part of the health care team through the endorsement of the barber, who the participants trusted and with whom they had a relationship. Long-standing issues related to distrust of the medical profession by this population were addressed, and trusted community barbershops were utilized as safe spaces for health care delivery. Health care professionals should consider utilizing community locations that other minority populations perceive as social centers and safe places, to reduce health disparities and barriers to care. However, models that bring care to patients need further economic and feasibility evaluations.

Other Health Care Professionals and Future Studies

In addition to models led by nurses and pharmacists, studies have also assessed models of TBC incorporating other health care professionals, including registered dietitians, medical assistants, community health workers, and health coaches (NCT02674464).^49,50 Ongoing studies are also looking at the impact of TBC on underserved communities (NCT02674464, NCT03504124). Involving a variety of health care professionals with different communities and populations in TBC studies is warranted to determine the optimal settings in which to utilize different skill sets.

The Impress Study involves nurses who are assessing lifestyle risk and developing an action plan according to a standardized procedure, which may be advantageous given the degree of heterogeneity found in other TBC models.⁵¹ There are also studies underway or recently published that compare different components of TBC in order to determine which combination of TBC elements is preferred. Some of these have shown the benefits of using clinical decision-support systems (through a guideline-based treatment protocol) or training programs with ongoing support.^52,53 Continued research comparing different TBC models is needed to determine which combination of health professionals and interventions is most impactful in practice.

Cost-Effectiveness

According to the CDC, TBC in hypertension management has proven to be cost-effective.⁵⁴ Systematic reviews and meta-analyses assessing the cost-effectiveness of TBC in hypertension management have been conducted.^{26,27,29,55-58} While the general consensus supports this approach as being cost-effective, these determinations are based on studies that are widely heterogeneous. In each of these studies, different types of costs are taken into account when determining cost-effectiveness. The range of costs can be quite wide, depending on how they are calculated, making it difficult to determine the true cost-effectiveness of different TBC models.

Intervention cost is represented by the amount of money spent to implement and maintain the intervention beyond the cost of usual care or the cost without the intervention. For TBC, intervention cost consists of personnel resources such as provider time, patient time, and non-personnel resources, including rent and utilities. Studies show that intervention costs for TBC can range from $35 to $1350 per person per year (mean, $618; median, $428).^27,56 One analysis, based on 20 studies comparing TBC to usual care, calculated an intervention cost of $284 per person per year,⁵⁵ while another study showed an intervention cost of $525 per enrollee per year.⁵⁶ Intervention cost can vary by the type of provider that is used, the amount of time spent per patient, and the setting where services are provided. Overall, the intervention cost of implementing TBC for hypertension management is consistently higher than the cost of usual care.

Health care cost is another factor to consider. It is the difference in the cost of health care products and services that are utilized in the process of TBC, as compared to care that is provided in the absence of TBC. Health care costs include the costs associated with hospitalizations, outpatient visits, emergency room visits, and medications. One study estimated a median health care cost of hypertension TBC of $65 per person per year.⁵⁵ Overall, studies evaluating the impact of TBC for hypertension management on health care costs were mixed, with some showing that TBC resulted in an increase in health care cost, and others showing a savings compared to usual care.⁵⁸ The variability in health care costs was due to the different number of health care components and comorbidities of the patients included in the studies. Also, study duration affected the estimated health care costs of TBC. Most studies did not assess long-term health care cost savings that could be achieved from prolonged blood pressure control.⁵⁸ When considering both intervention and health care cost, Jacob et al estimated that TBC increased overall net cost by a median value of $329 per person per year.⁵⁵ While some studies did attribute an overall reduction in health care costs to TBC for hypertension management, on average, team-based models increased health care costs compared to usual care.^{27,29,55,58,59}

However, health care costs do not take into account the long-term reductions in morbidity and mortality or increased quality-adjusted life years (QALY) that result from improved blood pressure control attributed to TBC. In most cost-effectiveness studies, an intervention is considered to be cost-effective if the cost per QALY gained is less than the accepted threshold of $50,000.⁵⁵ One study estimated that the cost per QALY of TBC in hypertension management is $4763,^55,60 while another study estimated a median cost per QALY of $9716 to $13,992.⁵⁵ A systematic review of 34 international studies estimated the median cost per QALY to be $13,986, ranging from $6683 to $58,610.⁵⁷ The wide range in cost can be attributed to the variability in interventions, health outcomes used to measure effectiveness, and the settings and countries where the studies were conducted. In another study, a TBC intervention involving pharmacists resulted in a cost per QALY of $26,800.⁶¹ The intervention was found to be cost-effective for higher-risk patients, defined as those having diabetes, a smoking history, dyslipidemia, or obesity. For patients who did not have these risk factors, the cost per QALY increased to $43,330.⁶¹ Thus, the patient population should be considered before implementing a TBC model. Furthermore, the increased use of technology, allowing for more efficient provision of services and communication between providers, could reduce intervention costs and lead to increased cost efficacy in these models.

The variation in the models used for TBC makes it difficult to draw conclusions on the cost-effectiveness of these interventions. Although it is apparent that TBC in general is cost-effective, more studies are needed comparing different team-based models to determine which specific ones are most cost-effective.

Challenges to Implementation of Team-Based Care

Recognizing and addressing the challenges inherent to a TBC approach is important to the sustainability of such a model within various settings and institutions. Numerous studies conducted on team-based models have identified common challenges that appear to be consistent across multiple settings. These challenges can be categorized as financial, provider-specific, and technology.

Financial Barriers

Although studies have demonstrated the cost-effectiveness of controlling hypertension and preventing serious complications, health systems are still confronted with the challenge of covering the cost for TBC implementation and maintenance.²⁹ The 2 main financial barriers for TBC services are stakeholder engagement and reimbursement for services. According to Kennelty et al, stakeholder engagement is key to the sustainability of the service.²⁷ However, decisions by stakeholders on cost are influenced by many factors, which include available funds, perceived value, and estimates for return on investment. Additionally, interventions must align with the organization’s mission and vision and be feasible to implement, and organizations must have the capacity for administrative support.²⁹ These various financial decisions may greatly influence the sustainability of a TBC model.

The reimbursement challenges for individual providers are an additional barrier to the sustainability of the service. In the United States, most providers are reimbursed via fee-for-service payment plans, but these plans do not reimburse all clinical providers because they are not all recognized as licensed providers.^62,63 For example, pharmacists are not recognized by the Centers for Medicare & Medicaid Services as licensed health care providers, which limits their ability to be reimbursed for clinical services provided outside of a traditional dispensing role. Furthermore, state laws determine the services nonphysician providers can offer and how they are recognized for reimbursement by tertiary payers. For instance, pharmacist roles, such as ordering labs and modifying or prescribing medication regimens, vary greatly between states.^7,63,64

Financial barriers are a major challenge facing the sustainability of a TBC hypertension service, so including all stakeholders in the decision-making process may improve the organization’s ability to sustain the service.

Provider-Specific Barriers

Notable barriers that are attributed to providers include lack of knowledge, lack of time, lack of initiative to change blood pressure medications, and inability to reach intensive blood pressure goals set in guidelines.²⁹ Studies such as the SPRINT trial have significantly impacted clinical guideline cut-offs for blood pressure, but reaching the intensive blood pressure goals from clinical trials is difficult to emulate in clinical practice.⁶⁵ In a typical clinical setting, providers may lack the confidence to make adjustments in therapy based on a single blood pressure measurement, and clinical inertia, defined as failure of health care providers to modify therapy when indicated,⁶⁶ may contribute to the inability to achieve blood pressure goals. Many factors contribute to clinical inertia, including lack of knowledge, time, or clinical protocols on how to modify therapy, causing providers to delay clinical decisions. Implementing site-specific protocols and utilizing hypertension specialist health care professionals in TBC can address the barriers contributing to clinical inertia.

Technology Barriers

A common barrier in a variety of services, but especially prevalent in a TBC service, is access to an electronic health record (EHR) for all providers treating the patient. Some providers who are not directly tied to the same clinical site as the patient’s primary care provider may not have adequate access to the full EHR. For example, pharmacists who are managing hypertension in a TBC model in a community pharmacy may have access only to health information from prescription records. Patient interviews may not provide the pharmacist with adequate information about laboratory results, vitals, and other medical information and history for the patient, making it difficult for the pharmacist to make a proper recommendation for treatment.²⁷ Depending on the setting, communication between providers may be a barrier in achieving optimal outcomes, especially when providers do not have access to a shared medical record.

In addition, patients often lack access to technology used to manage hypertension. Many new technologies exist that aid patients in managing their blood pressure, such as smart phone applications to track blood pressure readings and alarms to remind patients to take their medications. Studies have shown that telemonitoring of blood pressure measurements and management of hypertension, especially in combination with TBC, is effective and reduces costs compared to usual care.⁶⁷ However, the lack of equal access to the various technologies available may inhibit the success of a TBC hypertension program. Patients may lack access, knowledge, or financial means to utilize the various methods available for managing their hypertension electronically.²⁹

Conclusion

Incorporating nonphysician providers into the health care team for the treatment of hypertension has proven to be more effective than usual care and has been recognized by recent guidelines as a best practice approach to achieving blood pressure goals. Multiple studies have demonstrated that TBC utilizing nurses and pharmacists can improve blood pressure management. While adding members to the team increases health care costs, the long-term benefits of achieving optimal blood pressure goals contribute to the overall cost-effectiveness of TBC strategies over usual care. However, comparisons between different TBC models are warranted to determine which combination of health care professionals and/or interventions is most effective. Cost-analysis estimates are difficult to compare due to widely varied methodology and variance in the models that have been employed. Studies must consider pathways to overcoming reimbursement issues, provider-specific challenges, and technology barriers. Follow-up and monitoring after initiation of drug therapy for hypertension control should include systematic strategies to help improve blood pressure, including use of home blood pressure monitoring, TBC, and telehealth strategies. Future implementation science approaches to hypertension TBC models within specific clinic settings will be useful to identify and overcome challenges and will help to determine the populations who will benefit most, allowing for greater success in sustaining TBC models.

Corresponding author: Shawn R. Smith, PharmD, 309 E. 2nd Street, Pomona, CA 91766; [email protected].

Financial disclosures: None.

A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.

The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.

“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”

“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.

Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.

VOYAGER PAD trial

The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).

Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.

“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.

[email protected]

SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.

A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.

The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.

“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”

“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.

Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.

VOYAGER PAD trial

The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).

Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.

“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.

[email protected]

SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.

A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.

The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.

“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”

“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.

Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.

VOYAGER PAD trial

The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).

Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.

“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.

[email protected]

SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.

LOS ANGELES – Carotid artery stenting in older, asymptomatic patients with severe carotid artery stenosis is, in general, as bad an idea as it has already proven to be in symptomatic patients, with a multifold increase in adverse short- and mid-term outcomes, compared with similar older, asymptomatic patients who underwent endarterectomy, according to a combined-study analysis with more than 2,500 patients.

Mitchel L. Zoler/MDedge News

The risk for poor outcomes in patients with severe but asymptomatic carotid artery disease who underwent carotid artery stenting (CAS), compared with patients who instead underwent carotid endarterectomy (CEA) “abruptly increased around age 75,” in an analysis that combined data from the two major, published, randomized trials that compared these two interventions in this patient population, Jenifer H. Voeks, PhD said at the International Stroke Conference sponsored by the American Heart Association.

These results “largely mirror” the findings from a similar combined analysis of data from four major, randomized trials that compared CEA and CAS in patients with symptomatic carotid disease, she noted (Lancet. 2016 Mar 26;387[10025]:1305-11). The new findings in an expanded population of asymptomatic patients derived from two separate studies showed that, in patients aged 70 years or less, “CAS appears to be a reasonable alternative to CEA, but above age 70, and certainly above age 75, age-related risk factors such as cerebrovascular anatomy and underlying cerebral pathology should be carefully considered before selecting patients for CAS,” said Dr. Voeks, a neurology researcher at the Medical University of South Carolina, Charleston. Many experts also believe that, for asymptomatic patients, intensive medical management may have returned as an alternative to either of these invasive approaches for treating severe carotid stenosis and has achieved a level of equipoise that led to the launch of CREST 2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial). CREST 2 is comparing CEA and CAS with medical management, and is scheduled to report results in 2021.

The data for this analysis in asymptomatic patients came from the first CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial; N Engl J Med. 2010 Jul 1;363[1]:11-23), which included 1,181 asymptomatic patients (nearly half the total enrollment, with symptomatic patients making up the balance) and had no age ceiling, as well as all 1,453 patients from the ACT 1 trial, which enrolled exclusively asymptomatic patients and limited enrollment to patients aged 79 years or less (N Engl J Med. 2016 Mar 17;374[11]: 1011-20). Because the maximum age of patients in ACT 1 was 79 years, for this analysis Dr. Voeks and associates only included the 1,091 asymptomatic CREST patients who also were within the same age ceiling. The resulting cohort of 2,544 included 1,637 patients who underwent CAS and 907 who underwent CEA (because of a 3:1 randomization ratio in ACT 1), creating the largest data set to compare CAS and CEA by age in asymptomatic patients, Dr. Voeks noted. When subdivided by age, 30% of the cohort was younger that 65 years, 54% were 65-74, and 16% were 75-79.

The primary outcome the researchers used for their analysis was the combined incidence of periprocedural stroke, MI, or death, plus the incidence of ipsilateral stroke during 4 years of follow-up post procedure. Among patients who underwent CAS, this outcome occurred in roughly 9% of patients aged 75-79 years and in about 3% of those younger than 65 years, a hazard ratio of 2.9 that was statistically significant. In contrast, the incidence of the primary outcome among patients aged 65-74 years was just 30% higher, compared with patients aged less than 65 years, a difference that was not statistically significant.

Patients who underwent CEA showed no similar relationship between age and outcome. The incidence of the primary outcome among the CEA patients was roughly the same, about 3.5%, regardless of their age.

A second analysis that considered age as a continuous variable showed a sharply spiked increase in the risk for CAS patients, compared with CEA patients once they reached about age 73-75 years. Until about age 72, the rate of the primary outcome was nearly the same regardless of whether patients underwent CAS or CEA, but the risk for adverse outcomes rose “steeply” starting at about age 75 so that by age 79 the rate of the primary outcome approached 300% higher among the CAS patients compared with CEA patients, Dr. Voeks said.

She cautioned that the analysis included just 115 total primary-outcome events, which makes the incidence rate estimates somewhat imprecise, and that the data reflect outcomes in patients who were treated more than a decade ago, but these data remain the only reported results from large randomized trials that compared CAS and CEA in asymptomatic patients.

Dr. Voeks reported no disclosures.

[email protected]

SOURCE: Voeks JH al. Stroke. 2020 Feb 12;51[suppl 1], Abstract 70.

LOS ANGELES – Carotid artery stenting in older, asymptomatic patients with severe carotid artery stenosis is, in general, as bad an idea as it has already proven to be in symptomatic patients, with a multifold increase in adverse short- and mid-term outcomes, compared with similar older, asymptomatic patients who underwent endarterectomy, according to a combined-study analysis with more than 2,500 patients.

Mitchel L. Zoler/MDedge News

The risk for poor outcomes in patients with severe but asymptomatic carotid artery disease who underwent carotid artery stenting (CAS), compared with patients who instead underwent carotid endarterectomy (CEA) “abruptly increased around age 75,” in an analysis that combined data from the two major, published, randomized trials that compared these two interventions in this patient population, Jenifer H. Voeks, PhD said at the International Stroke Conference sponsored by the American Heart Association.

These results “largely mirror” the findings from a similar combined analysis of data from four major, randomized trials that compared CEA and CAS in patients with symptomatic carotid disease, she noted (Lancet. 2016 Mar 26;387[10025]:1305-11). The new findings in an expanded population of asymptomatic patients derived from two separate studies showed that, in patients aged 70 years or less, “CAS appears to be a reasonable alternative to CEA, but above age 70, and certainly above age 75, age-related risk factors such as cerebrovascular anatomy and underlying cerebral pathology should be carefully considered before selecting patients for CAS,” said Dr. Voeks, a neurology researcher at the Medical University of South Carolina, Charleston. Many experts also believe that, for asymptomatic patients, intensive medical management may have returned as an alternative to either of these invasive approaches for treating severe carotid stenosis and has achieved a level of equipoise that led to the launch of CREST 2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial). CREST 2 is comparing CEA and CAS with medical management, and is scheduled to report results in 2021.

The data for this analysis in asymptomatic patients came from the first CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial; N Engl J Med. 2010 Jul 1;363[1]:11-23), which included 1,181 asymptomatic patients (nearly half the total enrollment, with symptomatic patients making up the balance) and had no age ceiling, as well as all 1,453 patients from the ACT 1 trial, which enrolled exclusively asymptomatic patients and limited enrollment to patients aged 79 years or less (N Engl J Med. 2016 Mar 17;374[11]: 1011-20). Because the maximum age of patients in ACT 1 was 79 years, for this analysis Dr. Voeks and associates only included the 1,091 asymptomatic CREST patients who also were within the same age ceiling. The resulting cohort of 2,544 included 1,637 patients who underwent CAS and 907 who underwent CEA (because of a 3:1 randomization ratio in ACT 1), creating the largest data set to compare CAS and CEA by age in asymptomatic patients, Dr. Voeks noted. When subdivided by age, 30% of the cohort was younger that 65 years, 54% were 65-74, and 16% were 75-79.

The primary outcome the researchers used for their analysis was the combined incidence of periprocedural stroke, MI, or death, plus the incidence of ipsilateral stroke during 4 years of follow-up post procedure. Among patients who underwent CAS, this outcome occurred in roughly 9% of patients aged 75-79 years and in about 3% of those younger than 65 years, a hazard ratio of 2.9 that was statistically significant. In contrast, the incidence of the primary outcome among patients aged 65-74 years was just 30% higher, compared with patients aged less than 65 years, a difference that was not statistically significant.

Patients who underwent CEA showed no similar relationship between age and outcome. The incidence of the primary outcome among the CEA patients was roughly the same, about 3.5%, regardless of their age.

A second analysis that considered age as a continuous variable showed a sharply spiked increase in the risk for CAS patients, compared with CEA patients once they reached about age 73-75 years. Until about age 72, the rate of the primary outcome was nearly the same regardless of whether patients underwent CAS or CEA, but the risk for adverse outcomes rose “steeply” starting at about age 75 so that by age 79 the rate of the primary outcome approached 300% higher among the CAS patients compared with CEA patients, Dr. Voeks said.

She cautioned that the analysis included just 115 total primary-outcome events, which makes the incidence rate estimates somewhat imprecise, and that the data reflect outcomes in patients who were treated more than a decade ago, but these data remain the only reported results from large randomized trials that compared CAS and CEA in asymptomatic patients.

Dr. Voeks reported no disclosures.

[email protected]

SOURCE: Voeks JH al. Stroke. 2020 Feb 12;51[suppl 1], Abstract 70.

LOS ANGELES – Carotid artery stenting in older, asymptomatic patients with severe carotid artery stenosis is, in general, as bad an idea as it has already proven to be in symptomatic patients, with a multifold increase in adverse short- and mid-term outcomes, compared with similar older, asymptomatic patients who underwent endarterectomy, according to a combined-study analysis with more than 2,500 patients.

Mitchel L. Zoler/MDedge News

The risk for poor outcomes in patients with severe but asymptomatic carotid artery disease who underwent carotid artery stenting (CAS), compared with patients who instead underwent carotid endarterectomy (CEA) “abruptly increased around age 75,” in an analysis that combined data from the two major, published, randomized trials that compared these two interventions in this patient population, Jenifer H. Voeks, PhD said at the International Stroke Conference sponsored by the American Heart Association.

These results “largely mirror” the findings from a similar combined analysis of data from four major, randomized trials that compared CEA and CAS in patients with symptomatic carotid disease, she noted (Lancet. 2016 Mar 26;387[10025]:1305-11). The new findings in an expanded population of asymptomatic patients derived from two separate studies showed that, in patients aged 70 years or less, “CAS appears to be a reasonable alternative to CEA, but above age 70, and certainly above age 75, age-related risk factors such as cerebrovascular anatomy and underlying cerebral pathology should be carefully considered before selecting patients for CAS,” said Dr. Voeks, a neurology researcher at the Medical University of South Carolina, Charleston. Many experts also believe that, for asymptomatic patients, intensive medical management may have returned as an alternative to either of these invasive approaches for treating severe carotid stenosis and has achieved a level of equipoise that led to the launch of CREST 2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial). CREST 2 is comparing CEA and CAS with medical management, and is scheduled to report results in 2021.

The data for this analysis in asymptomatic patients came from the first CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial; N Engl J Med. 2010 Jul 1;363[1]:11-23), which included 1,181 asymptomatic patients (nearly half the total enrollment, with symptomatic patients making up the balance) and had no age ceiling, as well as all 1,453 patients from the ACT 1 trial, which enrolled exclusively asymptomatic patients and limited enrollment to patients aged 79 years or less (N Engl J Med. 2016 Mar 17;374[11]: 1011-20). Because the maximum age of patients in ACT 1 was 79 years, for this analysis Dr. Voeks and associates only included the 1,091 asymptomatic CREST patients who also were within the same age ceiling. The resulting cohort of 2,544 included 1,637 patients who underwent CAS and 907 who underwent CEA (because of a 3:1 randomization ratio in ACT 1), creating the largest data set to compare CAS and CEA by age in asymptomatic patients, Dr. Voeks noted. When subdivided by age, 30% of the cohort was younger that 65 years, 54% were 65-74, and 16% were 75-79.

The primary outcome the researchers used for their analysis was the combined incidence of periprocedural stroke, MI, or death, plus the incidence of ipsilateral stroke during 4 years of follow-up post procedure. Among patients who underwent CAS, this outcome occurred in roughly 9% of patients aged 75-79 years and in about 3% of those younger than 65 years, a hazard ratio of 2.9 that was statistically significant. In contrast, the incidence of the primary outcome among patients aged 65-74 years was just 30% higher, compared with patients aged less than 65 years, a difference that was not statistically significant.

Patients who underwent CEA showed no similar relationship between age and outcome. The incidence of the primary outcome among the CEA patients was roughly the same, about 3.5%, regardless of their age.

A second analysis that considered age as a continuous variable showed a sharply spiked increase in the risk for CAS patients, compared with CEA patients once they reached about age 73-75 years. Until about age 72, the rate of the primary outcome was nearly the same regardless of whether patients underwent CAS or CEA, but the risk for adverse outcomes rose “steeply” starting at about age 75 so that by age 79 the rate of the primary outcome approached 300% higher among the CAS patients compared with CEA patients, Dr. Voeks said.

She cautioned that the analysis included just 115 total primary-outcome events, which makes the incidence rate estimates somewhat imprecise, and that the data reflect outcomes in patients who were treated more than a decade ago, but these data remain the only reported results from large randomized trials that compared CAS and CEA in asymptomatic patients.

Dr. Voeks reported no disclosures.

[email protected]

SOURCE: Voeks JH al. Stroke. 2020 Feb 12;51[suppl 1], Abstract 70.

Study Overview

Objective. To determine whether percutaneous coronary intervention (PCI) of a nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) reduces the risk of cardiovascular death or myocardial infarction.

Design. International, multicenter, randomized controlled trial blinded to outcome.

Setting and participants. Patients with STEMI who had multivessel coronary disease and had undergone successful PCI to the culprit lesion.

Intervention. A total of 4041 patients were randomly assigned to either PCI of angiographically significant nonculprit lesions or optimal medical therapy without further revascularization. Randomization was stratified according to intended timing of nonculprit lesion PCI (either during or after the index hospitalization).

Main outcome measures. The first co-primary endpoint was the composite of cardiovascular death or myocardial infarction (MI). The second co-primary endpoint was the composite of cardiovascular death, MI or ischemia-driven revascularization.

Main results. At a median follow-up of 3 years, the composite of cardiovascular death or MI occurred in 158 of the 2016 patients (7.8%) in the nonculprit PCI group and in 213 of the 2025 patients (10.5%) in the culprit-lesion-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.60-0.91; P = 0.004). The second co-primary endpoint occurred in 179 patients (8.9%) in the nonculprit PCI group and in 339 patients (16.7%) in the culprit-lesion-only group (hazard ratio, 0.51; 95% CI, 0.43-0.61; P < 0.001).

Conclusion. Among patients with STEMI and multivessel disease, those who underwent complete revascularization with nonculprit lesion PCI had lower rates of cardiovascular death or MI compared to patients with culprit-lesion-only revascularization.

Patients presenting with STEMI often have multivessel disease.¹ Although it is known that mortality can be reduced by early revascularization of the culprit vessel,² whether the nonculprit vessel should be revascularized at the time of presentation with STEMI remains controversial.

Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI. Four trials (PRAMI, CvPRIT, DANAMI-PRIMULTI, and COMPARE ACUTE) investigated this clinical question with different designs, and all reported benefit of nonculprit vessel revascularization compared to a culprit-only strategy.^3-6 However, the differences in the composite endpoints were mainly driven by the softer endpoints used in these trials, such as refractory angina and ischemia-driven revascularization, and none of these previous trials had adequate power to evaluate differences in hard outcomes, such as death or MI.

In this context, Mehta et al investigated whether achieving complete revascularization by performing PCI on nonculprit vessels would improve the composite of cardiovascular death or MI compared to the culprit-only strategy by conducting a well-designed randomized controlled study. At median follow-up of 3 years, patients who underwent nonculprit vessel PCI had a lower incidence of death or MI compared to those who received the culprit-only strategy (7.8% versus 10.5%). The second co-primary endpoint (composite of death, MI, or ischemia-driven revascularization) also occurred significantly less frequently in the nonculprit PCI group than in the culprit-only PCI group (8.9% versus 16.7%).

The current study has a number of strengths. First, this was a multicenter, international study, and a large number of patients were enrolled (> 4000), achieving adequate power to evaluate for the composite of death and MI. Second, the treatments the patients received reflect contemporary medical therapy and interventional practice: the third-generation thienopyridine ticagrelor, high-dose statins, and ACE inhibitors were prescribed at high rates, and radial access (> 80%) and current-generation drug-eluting stents were used at high rates as well. Third, all angiograms were reviewed by the core lab to evaluate for completeness of revascularization. Fourth, the trial mandated use of fractional flow reserve to assess lesion stenosis 50% to 69% before considering revascularization, ensuring that only ischemic or very-high-grade lesions were revascularized. Fifth, the crossover rate in each group was low compared to the previous studies (4.7% into the complete revascularization group, 3.9% into the lesion-only group). Finally, this study evaluated the timing of the nonculprit PCI. Randomization to each group was stratified according to the intended timing of the nonculprit PCI during the index hospitalization or after hospital discharge (within 45 days). They found that benefit was consistent regardless of when the nonculprit PCI was performed.

Although the COMPLETE study’s design has a number of strengths, it is important to note that patients enrolled in this trial represent a lower-risk STEMI population. Patients with complex anatomy likely were not included, as evidenced by a lower SYNTAX score (mean, 16). Furthermore, no patients who presented with STEMI complicated by cardiogenic shock were enrolled. In the recent CULPRIT SHOCK trial, which focused on patients who had multivessel disease, acute MI, and cardiogenic shock, patients who underwent the culprit-only strategy had a lower rate of death or renal replacement therapy, as compared to patients who underwent immediate complete revascularization.⁷ Therefore, whether the findings from the COMPLETE study can be extended to a sicker population requires further study.

In 2015, the results from the previous trials, such as PRAMI and CvPRIT, led to a focused update of US PCI guidelines.⁸ Recommendations for noninfarct-related artery PCI in hemodynamically stable patients presenting with acute MI were upgraded from class III to class IIb. The results from the COMPLETE trial will likely influence the future guidelines, with stronger recommendations toward complete revascularization in patients presenting with hemodynamically stable STEMI.

Applications for Clinical Practice

In patients presenting with hemodynamically stable STEMI, staged complete revascularization, including the nonculprit vessel, should be considered.

– Taishi Hirai, MD, University of Missouri, Columbia, MO, and John EA Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine whether percutaneous coronary intervention (PCI) of a nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) reduces the risk of cardiovascular death or myocardial infarction.

Design. International, multicenter, randomized controlled trial blinded to outcome.

Setting and participants. Patients with STEMI who had multivessel coronary disease and had undergone successful PCI to the culprit lesion.

Intervention. A total of 4041 patients were randomly assigned to either PCI of angiographically significant nonculprit lesions or optimal medical therapy without further revascularization. Randomization was stratified according to intended timing of nonculprit lesion PCI (either during or after the index hospitalization).

Main outcome measures. The first co-primary endpoint was the composite of cardiovascular death or myocardial infarction (MI). The second co-primary endpoint was the composite of cardiovascular death, MI or ischemia-driven revascularization.

Main results. At a median follow-up of 3 years, the composite of cardiovascular death or MI occurred in 158 of the 2016 patients (7.8%) in the nonculprit PCI group and in 213 of the 2025 patients (10.5%) in the culprit-lesion-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.60-0.91; P = 0.004). The second co-primary endpoint occurred in 179 patients (8.9%) in the nonculprit PCI group and in 339 patients (16.7%) in the culprit-lesion-only group (hazard ratio, 0.51; 95% CI, 0.43-0.61; P < 0.001).

Conclusion. Among patients with STEMI and multivessel disease, those who underwent complete revascularization with nonculprit lesion PCI had lower rates of cardiovascular death or MI compared to patients with culprit-lesion-only revascularization.

Patients presenting with STEMI often have multivessel disease.¹ Although it is known that mortality can be reduced by early revascularization of the culprit vessel,² whether the nonculprit vessel should be revascularized at the time of presentation with STEMI remains controversial.

Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI. Four trials (PRAMI, CvPRIT, DANAMI-PRIMULTI, and COMPARE ACUTE) investigated this clinical question with different designs, and all reported benefit of nonculprit vessel revascularization compared to a culprit-only strategy.^3-6 However, the differences in the composite endpoints were mainly driven by the softer endpoints used in these trials, such as refractory angina and ischemia-driven revascularization, and none of these previous trials had adequate power to evaluate differences in hard outcomes, such as death or MI.

In this context, Mehta et al investigated whether achieving complete revascularization by performing PCI on nonculprit vessels would improve the composite of cardiovascular death or MI compared to the culprit-only strategy by conducting a well-designed randomized controlled study. At median follow-up of 3 years, patients who underwent nonculprit vessel PCI had a lower incidence of death or MI compared to those who received the culprit-only strategy (7.8% versus 10.5%). The second co-primary endpoint (composite of death, MI, or ischemia-driven revascularization) also occurred significantly less frequently in the nonculprit PCI group than in the culprit-only PCI group (8.9% versus 16.7%).

The current study has a number of strengths. First, this was a multicenter, international study, and a large number of patients were enrolled (> 4000), achieving adequate power to evaluate for the composite of death and MI. Second, the treatments the patients received reflect contemporary medical therapy and interventional practice: the third-generation thienopyridine ticagrelor, high-dose statins, and ACE inhibitors were prescribed at high rates, and radial access (> 80%) and current-generation drug-eluting stents were used at high rates as well. Third, all angiograms were reviewed by the core lab to evaluate for completeness of revascularization. Fourth, the trial mandated use of fractional flow reserve to assess lesion stenosis 50% to 69% before considering revascularization, ensuring that only ischemic or very-high-grade lesions were revascularized. Fifth, the crossover rate in each group was low compared to the previous studies (4.7% into the complete revascularization group, 3.9% into the lesion-only group). Finally, this study evaluated the timing of the nonculprit PCI. Randomization to each group was stratified according to the intended timing of the nonculprit PCI during the index hospitalization or after hospital discharge (within 45 days). They found that benefit was consistent regardless of when the nonculprit PCI was performed.

Although the COMPLETE study’s design has a number of strengths, it is important to note that patients enrolled in this trial represent a lower-risk STEMI population. Patients with complex anatomy likely were not included, as evidenced by a lower SYNTAX score (mean, 16). Furthermore, no patients who presented with STEMI complicated by cardiogenic shock were enrolled. In the recent CULPRIT SHOCK trial, which focused on patients who had multivessel disease, acute MI, and cardiogenic shock, patients who underwent the culprit-only strategy had a lower rate of death or renal replacement therapy, as compared to patients who underwent immediate complete revascularization.⁷ Therefore, whether the findings from the COMPLETE study can be extended to a sicker population requires further study.

In 2015, the results from the previous trials, such as PRAMI and CvPRIT, led to a focused update of US PCI guidelines.⁸ Recommendations for noninfarct-related artery PCI in hemodynamically stable patients presenting with acute MI were upgraded from class III to class IIb. The results from the COMPLETE trial will likely influence the future guidelines, with stronger recommendations toward complete revascularization in patients presenting with hemodynamically stable STEMI.

Applications for Clinical Practice

In patients presenting with hemodynamically stable STEMI, staged complete revascularization, including the nonculprit vessel, should be considered.

– Taishi Hirai, MD, University of Missouri, Columbia, MO, and John EA Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine whether percutaneous coronary intervention (PCI) of a nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) reduces the risk of cardiovascular death or myocardial infarction.

Design. International, multicenter, randomized controlled trial blinded to outcome.

Setting and participants. Patients with STEMI who had multivessel coronary disease and had undergone successful PCI to the culprit lesion.

Intervention. A total of 4041 patients were randomly assigned to either PCI of angiographically significant nonculprit lesions or optimal medical therapy without further revascularization. Randomization was stratified according to intended timing of nonculprit lesion PCI (either during or after the index hospitalization).

Main outcome measures. The first co-primary endpoint was the composite of cardiovascular death or myocardial infarction (MI). The second co-primary endpoint was the composite of cardiovascular death, MI or ischemia-driven revascularization.

Main results. At a median follow-up of 3 years, the composite of cardiovascular death or MI occurred in 158 of the 2016 patients (7.8%) in the nonculprit PCI group and in 213 of the 2025 patients (10.5%) in the culprit-lesion-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.60-0.91; P = 0.004). The second co-primary endpoint occurred in 179 patients (8.9%) in the nonculprit PCI group and in 339 patients (16.7%) in the culprit-lesion-only group (hazard ratio, 0.51; 95% CI, 0.43-0.61; P < 0.001).

Conclusion. Among patients with STEMI and multivessel disease, those who underwent complete revascularization with nonculprit lesion PCI had lower rates of cardiovascular death or MI compared to patients with culprit-lesion-only revascularization.

Patients presenting with STEMI often have multivessel disease.¹ Although it is known that mortality can be reduced by early revascularization of the culprit vessel,² whether the nonculprit vessel should be revascularized at the time of presentation with STEMI remains controversial.

Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI. Four trials (PRAMI, CvPRIT, DANAMI-PRIMULTI, and COMPARE ACUTE) investigated this clinical question with different designs, and all reported benefit of nonculprit vessel revascularization compared to a culprit-only strategy.^3-6 However, the differences in the composite endpoints were mainly driven by the softer endpoints used in these trials, such as refractory angina and ischemia-driven revascularization, and none of these previous trials had adequate power to evaluate differences in hard outcomes, such as death or MI.

In this context, Mehta et al investigated whether achieving complete revascularization by performing PCI on nonculprit vessels would improve the composite of cardiovascular death or MI compared to the culprit-only strategy by conducting a well-designed randomized controlled study. At median follow-up of 3 years, patients who underwent nonculprit vessel PCI had a lower incidence of death or MI compared to those who received the culprit-only strategy (7.8% versus 10.5%). The second co-primary endpoint (composite of death, MI, or ischemia-driven revascularization) also occurred significantly less frequently in the nonculprit PCI group than in the culprit-only PCI group (8.9% versus 16.7%).

The current study has a number of strengths. First, this was a multicenter, international study, and a large number of patients were enrolled (> 4000), achieving adequate power to evaluate for the composite of death and MI. Second, the treatments the patients received reflect contemporary medical therapy and interventional practice: the third-generation thienopyridine ticagrelor, high-dose statins, and ACE inhibitors were prescribed at high rates, and radial access (> 80%) and current-generation drug-eluting stents were used at high rates as well. Third, all angiograms were reviewed by the core lab to evaluate for completeness of revascularization. Fourth, the trial mandated use of fractional flow reserve to assess lesion stenosis 50% to 69% before considering revascularization, ensuring that only ischemic or very-high-grade lesions were revascularized. Fifth, the crossover rate in each group was low compared to the previous studies (4.7% into the complete revascularization group, 3.9% into the lesion-only group). Finally, this study evaluated the timing of the nonculprit PCI. Randomization to each group was stratified according to the intended timing of the nonculprit PCI during the index hospitalization or after hospital discharge (within 45 days). They found that benefit was consistent regardless of when the nonculprit PCI was performed.

Although the COMPLETE study’s design has a number of strengths, it is important to note that patients enrolled in this trial represent a lower-risk STEMI population. Patients with complex anatomy likely were not included, as evidenced by a lower SYNTAX score (mean, 16). Furthermore, no patients who presented with STEMI complicated by cardiogenic shock were enrolled. In the recent CULPRIT SHOCK trial, which focused on patients who had multivessel disease, acute MI, and cardiogenic shock, patients who underwent the culprit-only strategy had a lower rate of death or renal replacement therapy, as compared to patients who underwent immediate complete revascularization.⁷ Therefore, whether the findings from the COMPLETE study can be extended to a sicker population requires further study.

In 2015, the results from the previous trials, such as PRAMI and CvPRIT, led to a focused update of US PCI guidelines.⁸ Recommendations for noninfarct-related artery PCI in hemodynamically stable patients presenting with acute MI were upgraded from class III to class IIb. The results from the COMPLETE trial will likely influence the future guidelines, with stronger recommendations toward complete revascularization in patients presenting with hemodynamically stable STEMI.

Applications for Clinical Practice

In patients presenting with hemodynamically stable STEMI, staged complete revascularization, including the nonculprit vessel, should be considered.

– Taishi Hirai, MD, University of Missouri, Columbia, MO, and John EA Blair, MD, University of Chicago Medical Center, Chicago, IL

ATLANTA – One of the goals in soon-to-be-published Takayasu’s arteritis guidelines from the American College of Rheumatology is to wean patients off high-dose steroids once they are in remission.

M. Alexander Otto

This recommendation is in opposition to another option – namely, switching these patients to low-dose glucocorticoids. The idea is to prevent long-term side effects, particularly in children. The guidelines also recommend against escalating immunotherapy for asymptomatic increases in inflammatory markers and generally recommend against surgery – stenting in most cases – unless there is threat to life, limb, or organ and also if limb pain is so severe it cramps quality of life and dose escalation doesn’t get the job done. If surgery is planned, patients should be on perioperative steroids if there’s active disease.

It’s draft guidance for now, but it’s probably what the final document will say when it’s published in 2020, according to a presentation at the annual meeting of the American College of Rheumatology by one of the authors, Anisha Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. She gave a sneak preview at the meeting.

In general, severe, active Takayasu’s calls for high-dose oral steroids in conjunction with a nonsteroid immunosuppressive, such as methotrexate, azathioprine, leflunomide, or mycophenolate mofetil. There’s evidence that dual therapy gives a more durable remission and also reduces the need for steroids.

When that approach doesn’t do the trick, the next step is a tumor necrosis factor (TNF) inhibitor. There’s evidence for infliximab, adalimumab, certolizumab, and etanercept. Dr. Dua noted, “We still can consider” tocilizumab, but it failed to meet its primary endpoint in a randomized trial, and evidence for other biologics is sparse or nonexistent. “TNF inhibitors are the first line” for refractory disease, Dr. Dua said.

The steroid taper comes after 6-12 months of remission. Given their toxicity, “our goal for steroids is zero,” especially in pediatric populations. Even in remission, patients should have a clinical assessment, including inflammatory markers, every 3-12 months.

A rise in C-reactive protein or erythrocyte sedimentation rate, with no new symptoms, might be a reason for more frequent monitoring, but it’s not a reason to escalate immunosuppression. That should be kept in reserve for new vascular lesions, rapid progression on an old one, or worsening of organ or limb ischemia.

“We recommend [escalation] over surgical intervention” because patients often develop collateral circulation that solves the problem; it also gives the disease time to quiet down should the patient eventually go into surgery. Immediate surgery is reserved for organ or life-threatening disease, Dr. Dua said.

“Takayasu’s is different from other vasculitides in the sense that patients often present with certain nonspecific constitutional symptoms,” and there’s not a lot of pathology or histology to work with, “so we do tend to rely on imaging a lot,” Dr. Dua said.

Angiography has fallen out of favor because it’s invasive and exposes patients to radiation, among other problems. The field has moved to noninvasive imaging such as color Doppler ultrasound, CT angiography, magnetic resonance angiography, and PET CT.

“We do recommend regularly scheduled, noninvasive imaging every 6-12 months, in addition to the routine clinical assessment,” except in children with inactive disease; the risk of sedation outweighs the imaging benefit, Dr. Dua said.

In patients with single-vessel cranial or cervical stenosis, without symptoms, “we recommend medical over surgical management because of the risk of surgery. Surgery can be considered for multivessel involvement,” she said.

She and her colleagues also recommend medical management for renal artery stenosis, including antihypertensives and immunotherapy escalation for active disease. Surgery is considered for refractory hypertension or worsening kidney function

Dr. Dua is a primary investigator and adviser for Chemocentryx and an adviser for Novartis and AbbVie.

[email protected]

ATLANTA – One of the goals in soon-to-be-published Takayasu’s arteritis guidelines from the American College of Rheumatology is to wean patients off high-dose steroids once they are in remission.

M. Alexander Otto

This recommendation is in opposition to another option – namely, switching these patients to low-dose glucocorticoids. The idea is to prevent long-term side effects, particularly in children. The guidelines also recommend against escalating immunotherapy for asymptomatic increases in inflammatory markers and generally recommend against surgery – stenting in most cases – unless there is threat to life, limb, or organ and also if limb pain is so severe it cramps quality of life and dose escalation doesn’t get the job done. If surgery is planned, patients should be on perioperative steroids if there’s active disease.

It’s draft guidance for now, but it’s probably what the final document will say when it’s published in 2020, according to a presentation at the annual meeting of the American College of Rheumatology by one of the authors, Anisha Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. She gave a sneak preview at the meeting.

In general, severe, active Takayasu’s calls for high-dose oral steroids in conjunction with a nonsteroid immunosuppressive, such as methotrexate, azathioprine, leflunomide, or mycophenolate mofetil. There’s evidence that dual therapy gives a more durable remission and also reduces the need for steroids.

When that approach doesn’t do the trick, the next step is a tumor necrosis factor (TNF) inhibitor. There’s evidence for infliximab, adalimumab, certolizumab, and etanercept. Dr. Dua noted, “We still can consider” tocilizumab, but it failed to meet its primary endpoint in a randomized trial, and evidence for other biologics is sparse or nonexistent. “TNF inhibitors are the first line” for refractory disease, Dr. Dua said.

The steroid taper comes after 6-12 months of remission. Given their toxicity, “our goal for steroids is zero,” especially in pediatric populations. Even in remission, patients should have a clinical assessment, including inflammatory markers, every 3-12 months.

A rise in C-reactive protein or erythrocyte sedimentation rate, with no new symptoms, might be a reason for more frequent monitoring, but it’s not a reason to escalate immunosuppression. That should be kept in reserve for new vascular lesions, rapid progression on an old one, or worsening of organ or limb ischemia.

“We recommend [escalation] over surgical intervention” because patients often develop collateral circulation that solves the problem; it also gives the disease time to quiet down should the patient eventually go into surgery. Immediate surgery is reserved for organ or life-threatening disease, Dr. Dua said.

“Takayasu’s is different from other vasculitides in the sense that patients often present with certain nonspecific constitutional symptoms,” and there’s not a lot of pathology or histology to work with, “so we do tend to rely on imaging a lot,” Dr. Dua said.

Angiography has fallen out of favor because it’s invasive and exposes patients to radiation, among other problems. The field has moved to noninvasive imaging such as color Doppler ultrasound, CT angiography, magnetic resonance angiography, and PET CT.

“We do recommend regularly scheduled, noninvasive imaging every 6-12 months, in addition to the routine clinical assessment,” except in children with inactive disease; the risk of sedation outweighs the imaging benefit, Dr. Dua said.

In patients with single-vessel cranial or cervical stenosis, without symptoms, “we recommend medical over surgical management because of the risk of surgery. Surgery can be considered for multivessel involvement,” she said.

She and her colleagues also recommend medical management for renal artery stenosis, including antihypertensives and immunotherapy escalation for active disease. Surgery is considered for refractory hypertension or worsening kidney function

Dr. Dua is a primary investigator and adviser for Chemocentryx and an adviser for Novartis and AbbVie.

[email protected]

ATLANTA – One of the goals in soon-to-be-published Takayasu’s arteritis guidelines from the American College of Rheumatology is to wean patients off high-dose steroids once they are in remission.

M. Alexander Otto

This recommendation is in opposition to another option – namely, switching these patients to low-dose glucocorticoids. The idea is to prevent long-term side effects, particularly in children. The guidelines also recommend against escalating immunotherapy for asymptomatic increases in inflammatory markers and generally recommend against surgery – stenting in most cases – unless there is threat to life, limb, or organ and also if limb pain is so severe it cramps quality of life and dose escalation doesn’t get the job done. If surgery is planned, patients should be on perioperative steroids if there’s active disease.

It’s draft guidance for now, but it’s probably what the final document will say when it’s published in 2020, according to a presentation at the annual meeting of the American College of Rheumatology by one of the authors, Anisha Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. She gave a sneak preview at the meeting.

In general, severe, active Takayasu’s calls for high-dose oral steroids in conjunction with a nonsteroid immunosuppressive, such as methotrexate, azathioprine, leflunomide, or mycophenolate mofetil. There’s evidence that dual therapy gives a more durable remission and also reduces the need for steroids.

When that approach doesn’t do the trick, the next step is a tumor necrosis factor (TNF) inhibitor. There’s evidence for infliximab, adalimumab, certolizumab, and etanercept. Dr. Dua noted, “We still can consider” tocilizumab, but it failed to meet its primary endpoint in a randomized trial, and evidence for other biologics is sparse or nonexistent. “TNF inhibitors are the first line” for refractory disease, Dr. Dua said.

The steroid taper comes after 6-12 months of remission. Given their toxicity, “our goal for steroids is zero,” especially in pediatric populations. Even in remission, patients should have a clinical assessment, including inflammatory markers, every 3-12 months.

A rise in C-reactive protein or erythrocyte sedimentation rate, with no new symptoms, might be a reason for more frequent monitoring, but it’s not a reason to escalate immunosuppression. That should be kept in reserve for new vascular lesions, rapid progression on an old one, or worsening of organ or limb ischemia.

“We recommend [escalation] over surgical intervention” because patients often develop collateral circulation that solves the problem; it also gives the disease time to quiet down should the patient eventually go into surgery. Immediate surgery is reserved for organ or life-threatening disease, Dr. Dua said.

“Takayasu’s is different from other vasculitides in the sense that patients often present with certain nonspecific constitutional symptoms,” and there’s not a lot of pathology or histology to work with, “so we do tend to rely on imaging a lot,” Dr. Dua said.

Angiography has fallen out of favor because it’s invasive and exposes patients to radiation, among other problems. The field has moved to noninvasive imaging such as color Doppler ultrasound, CT angiography, magnetic resonance angiography, and PET CT.

“We do recommend regularly scheduled, noninvasive imaging every 6-12 months, in addition to the routine clinical assessment,” except in children with inactive disease; the risk of sedation outweighs the imaging benefit, Dr. Dua said.

In patients with single-vessel cranial or cervical stenosis, without symptoms, “we recommend medical over surgical management because of the risk of surgery. Surgery can be considered for multivessel involvement,” she said.

She and her colleagues also recommend medical management for renal artery stenosis, including antihypertensives and immunotherapy escalation for active disease. Surgery is considered for refractory hypertension or worsening kidney function

Dr. Dua is a primary investigator and adviser for Chemocentryx and an adviser for Novartis and AbbVie.

[email protected]

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

Mitchel L. Zoler/MDedge News

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

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

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

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

Mitchel L. Zoler/MDedge News

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

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

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

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

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

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

[email protected]

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

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

Mitchel L. Zoler/MDedge News

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

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

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

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

Mitchel L. Zoler/MDedge News

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

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

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

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

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

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

[email protected]

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

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

Mitchel L. Zoler/MDedge News

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

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

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

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

Mitchel L. Zoler/MDedge News

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

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

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

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

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

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

[email protected]

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

NEW YORK – Published 12 months apart, guidelines on management of abdominal aortic aneurysm (AAA) from the European Society for Vascular Surgery are similar but diverged in instructive ways from those of the Society for Vascular Surgery, according to a critical review at a symposium on vascular and endovascular issues sponsored by the Cleveland Clinic Foundation. “Some of the differences were almost unavoidable in the sense that the ESVS guidelines represent multiple idiosyncratic health care systems across Europe,” reported Ronald L. Dalman, MD, chief of vascular surgery, Stanford (Calif.) University.

Ted Bosworth/MDedge News

As a result, the ESVS guidelines provide very little specificity about pharmacologic options because of the differences in availability of these treatments within specific health systems. In addition, both open and endovascular aneurysm repair (EVAR) are given similar emphasis because of the limited availability of EVAR in some parts of Europe.

“The ESVS guidelines specifically recommend repair of an aneurysm within 8 weeks when repair is indicated, but there are not many aneurysms that go 8 weeks in the U.S. without being fixed by a fee-for-service surgeon,” Dr. Dalman observed.

The SVS AAA guidelines were published in January 2018 (J Vasc Surg 2018;67:2-77) and the ESVS guidelines followed 1 year later (Eur J Vasc Surg 2019;57:8-93).

The differences in the guidelines, although modest, are interesting because each set of guidelines was based largely on the same set of trials and published studies, according to Dr. Dalman, who was a coauthor of the SVS guidelines and an external reviewer for the ESVS guidelines.

In the lag between completion of the two guidelines, new information led to three ESVS additions not found in the SVS guidelines, according to Dr. Dalman. They involved the importance of considering aneurysm diameter as a prognostic factor, new understanding of the limitations on endovascular aneurysm sealing (EVAS), and new information about how aneurysm size should affect frequency of surveillance.

Overall, the U.S. guidelines contain 111 recommendations based on 177 references, while the ESVS guidelines contain 125 guidelines based on 189 references. In retrospect, Dr. Dalman believes both sets of guidelines omitted some clinically meaningful information, such as the risk of large-diameter devices for causing endoleaks.

The authors of the ESVS guidelines did have an opportunity to review of a draft of the SVS guidelines, so differences can be interpreted as intentional. For example, the SVS guidelines recommend risk calculators, but Dr. Dalman suggested that the authors of the ESVS guidelines were less convinced that their utility was established.

The decision not to recommend a door-to-treatment time for ruptured aneurysms, as in the SVS recommendations, might have been in deference to disparate practice across European countries, Dr. Dalman suggested.

Ultimately, the guidelines are “substantially similar,” according to Dr. Dalman, but he expressed concerned that neither guideline is accompanied by a specific mechanism or recommended strategy to ensure implementation.

Many of the SVS recommendations are likely to be translated into quality metrics at U.S. institutions, but “there are implementation issues” for ensuring that each guideline is applied, Dr. Dalman said.

Given the agreement on the vast majority of the recommendations, Dr. Dalman suggested that “it might be time to consider global guidelines” for management of AAA and other vascular diseases. Some type of language might be required to accommodate divergent resources or practices across borders, but Dr. Dalman questioned the need to review the same literature to arrive at mostly the same conclusions.

NEW YORK – Published 12 months apart, guidelines on management of abdominal aortic aneurysm (AAA) from the European Society for Vascular Surgery are similar but diverged in instructive ways from those of the Society for Vascular Surgery, according to a critical review at a symposium on vascular and endovascular issues sponsored by the Cleveland Clinic Foundation. “Some of the differences were almost unavoidable in the sense that the ESVS guidelines represent multiple idiosyncratic health care systems across Europe,” reported Ronald L. Dalman, MD, chief of vascular surgery, Stanford (Calif.) University.

Ted Bosworth/MDedge News

As a result, the ESVS guidelines provide very little specificity about pharmacologic options because of the differences in availability of these treatments within specific health systems. In addition, both open and endovascular aneurysm repair (EVAR) are given similar emphasis because of the limited availability of EVAR in some parts of Europe.

“The ESVS guidelines specifically recommend repair of an aneurysm within 8 weeks when repair is indicated, but there are not many aneurysms that go 8 weeks in the U.S. without being fixed by a fee-for-service surgeon,” Dr. Dalman observed.

The SVS AAA guidelines were published in January 2018 (J Vasc Surg 2018;67:2-77) and the ESVS guidelines followed 1 year later (Eur J Vasc Surg 2019;57:8-93).

The differences in the guidelines, although modest, are interesting because each set of guidelines was based largely on the same set of trials and published studies, according to Dr. Dalman, who was a coauthor of the SVS guidelines and an external reviewer for the ESVS guidelines.

In the lag between completion of the two guidelines, new information led to three ESVS additions not found in the SVS guidelines, according to Dr. Dalman. They involved the importance of considering aneurysm diameter as a prognostic factor, new understanding of the limitations on endovascular aneurysm sealing (EVAS), and new information about how aneurysm size should affect frequency of surveillance.

Overall, the U.S. guidelines contain 111 recommendations based on 177 references, while the ESVS guidelines contain 125 guidelines based on 189 references. In retrospect, Dr. Dalman believes both sets of guidelines omitted some clinically meaningful information, such as the risk of large-diameter devices for causing endoleaks.

The authors of the ESVS guidelines did have an opportunity to review of a draft of the SVS guidelines, so differences can be interpreted as intentional. For example, the SVS guidelines recommend risk calculators, but Dr. Dalman suggested that the authors of the ESVS guidelines were less convinced that their utility was established.

The decision not to recommend a door-to-treatment time for ruptured aneurysms, as in the SVS recommendations, might have been in deference to disparate practice across European countries, Dr. Dalman suggested.

Ultimately, the guidelines are “substantially similar,” according to Dr. Dalman, but he expressed concerned that neither guideline is accompanied by a specific mechanism or recommended strategy to ensure implementation.

Many of the SVS recommendations are likely to be translated into quality metrics at U.S. institutions, but “there are implementation issues” for ensuring that each guideline is applied, Dr. Dalman said.

Given the agreement on the vast majority of the recommendations, Dr. Dalman suggested that “it might be time to consider global guidelines” for management of AAA and other vascular diseases. Some type of language might be required to accommodate divergent resources or practices across borders, but Dr. Dalman questioned the need to review the same literature to arrive at mostly the same conclusions.

NEW YORK – Published 12 months apart, guidelines on management of abdominal aortic aneurysm (AAA) from the European Society for Vascular Surgery are similar but diverged in instructive ways from those of the Society for Vascular Surgery, according to a critical review at a symposium on vascular and endovascular issues sponsored by the Cleveland Clinic Foundation. “Some of the differences were almost unavoidable in the sense that the ESVS guidelines represent multiple idiosyncratic health care systems across Europe,” reported Ronald L. Dalman, MD, chief of vascular surgery, Stanford (Calif.) University.

Ted Bosworth/MDedge News

As a result, the ESVS guidelines provide very little specificity about pharmacologic options because of the differences in availability of these treatments within specific health systems. In addition, both open and endovascular aneurysm repair (EVAR) are given similar emphasis because of the limited availability of EVAR in some parts of Europe.

“The ESVS guidelines specifically recommend repair of an aneurysm within 8 weeks when repair is indicated, but there are not many aneurysms that go 8 weeks in the U.S. without being fixed by a fee-for-service surgeon,” Dr. Dalman observed.

The SVS AAA guidelines were published in January 2018 (J Vasc Surg 2018;67:2-77) and the ESVS guidelines followed 1 year later (Eur J Vasc Surg 2019;57:8-93).

The differences in the guidelines, although modest, are interesting because each set of guidelines was based largely on the same set of trials and published studies, according to Dr. Dalman, who was a coauthor of the SVS guidelines and an external reviewer for the ESVS guidelines.

In the lag between completion of the two guidelines, new information led to three ESVS additions not found in the SVS guidelines, according to Dr. Dalman. They involved the importance of considering aneurysm diameter as a prognostic factor, new understanding of the limitations on endovascular aneurysm sealing (EVAS), and new information about how aneurysm size should affect frequency of surveillance.

Overall, the U.S. guidelines contain 111 recommendations based on 177 references, while the ESVS guidelines contain 125 guidelines based on 189 references. In retrospect, Dr. Dalman believes both sets of guidelines omitted some clinically meaningful information, such as the risk of large-diameter devices for causing endoleaks.

The authors of the ESVS guidelines did have an opportunity to review of a draft of the SVS guidelines, so differences can be interpreted as intentional. For example, the SVS guidelines recommend risk calculators, but Dr. Dalman suggested that the authors of the ESVS guidelines were less convinced that their utility was established.

The decision not to recommend a door-to-treatment time for ruptured aneurysms, as in the SVS recommendations, might have been in deference to disparate practice across European countries, Dr. Dalman suggested.

Ultimately, the guidelines are “substantially similar,” according to Dr. Dalman, but he expressed concerned that neither guideline is accompanied by a specific mechanism or recommended strategy to ensure implementation.

Many of the SVS recommendations are likely to be translated into quality metrics at U.S. institutions, but “there are implementation issues” for ensuring that each guideline is applied, Dr. Dalman said.

Given the agreement on the vast majority of the recommendations, Dr. Dalman suggested that “it might be time to consider global guidelines” for management of AAA and other vascular diseases. Some type of language might be required to accommodate divergent resources or practices across borders, but Dr. Dalman questioned the need to review the same literature to arrive at mostly the same conclusions.

NEW YORK – The dual challenges of teaching open vascular surgery techniques when few are performed and reaching a generation that has a different attitude to absorbing information requires new and innovative approaches, according to an academic surgeon speaking at symposium on vascular and endovascular issues sponsored by the Cleveland Clinic Foundation.

Ted Bosworth/MDedge News

“The see one, do one, teach one approach to surgical training is no longer possible,” explained R. Clement Darling III, MD, chief of the division of vascular surgery at Albany (N.Y.) Medical Center Hospital.

For open procedures, the problem is a rapidly declining number of cases in the era of endovascular surgery, but Dr. Darling also recommended adjusting training to the outlook and expectations of a new generation. First observed in the millennial generation, an attitude of firm work-related boundaries is also being seen in generation Z. Generation Z, characterized by birth after 1995, is just now beginning to reach residency programs.

“The approach to work-life balance is extremely different for these individuals than it was for my generation,” Dr. Darling said. While previous generations were often motivated by fear and pressure, newer generations appear to respond less well to anxiety.

“People learn differently. Some from their tactile sense, some intellectually, and some from fear or pressure, but mostly, particularly those who are younger, now learn from positive reinforcement,” Dr. Darling said.

For teaching open procedures at his own institution, Dr. Darling has switched from the traditional model of one-on-one instruction undertaken in the surgical suite to a group approach. The limited number of open cases was the impetus, but group instruction now extends beyond the operating room.

“We have a meeting before the case, when we go over the technical aspects,” Dr. Darling explained. Fellows are asked to envision and describe potential problems and potential solutions.

“We try to make them visualize as well as verbalize exactly what will be done in the operating room,” Dr. Darling said. The plans are outlined carefully “so no one does any thinking in the OR. All the thinking is done in advance.”

Videos and simulators are teaching aids, but a great deal of learning can be accomplished independent of doing, according to Dr. Darling. Moreover, understanding the anatomy, which comes before developing surgical skills, is the same for open and endovascular procedures, so each is relevant to the other.

After witnessing an open case, all of the trainees along with the nurses and attending physicians go through a debriefing to consider the potential lessons. At Dr. Darling’s center, open procedures increasingly involve sicker and older patients, conferring case analysis with a particularly vital learning function in the curriculum.

Because of the diminishing number of open cases and the diminishing open skills, even among experienced vascular surgeons, residents in an increasing number of training programs “graduate without any open experience, which is a little shocking,” Dr. Darling said.

Importantly, group instruction, although valuable and necessary for exposing residents and fellows to open vascular surgery, has its own lessons to impart even if it was born out of necessity.

“We always emphasize that it is not the sewing that counts, it is the setup that counts,” said Dr. Darling, indicating that this is a clear message when the group is assembled for case planning. The group planning also emphasizes that surgery is a team sport.

“All of us is smarter than one of us,” said Dr. Darling, articulating the implicit message of group training.

Although this is a departure from a bygone era where infallible surgeons ruled the OR, it is fits nicely with changing attitudes about the best attributes of a competent surgeon.

NEW YORK – The dual challenges of teaching open vascular surgery techniques when few are performed and reaching a generation that has a different attitude to absorbing information requires new and innovative approaches, according to an academic surgeon speaking at symposium on vascular and endovascular issues sponsored by the Cleveland Clinic Foundation.

Ted Bosworth/MDedge News

“The see one, do one, teach one approach to surgical training is no longer possible,” explained R. Clement Darling III, MD, chief of the division of vascular surgery at Albany (N.Y.) Medical Center Hospital.

For open procedures, the problem is a rapidly declining number of cases in the era of endovascular surgery, but Dr. Darling also recommended adjusting training to the outlook and expectations of a new generation. First observed in the millennial generation, an attitude of firm work-related boundaries is also being seen in generation Z. Generation Z, characterized by birth after 1995, is just now beginning to reach residency programs.

“The approach to work-life balance is extremely different for these individuals than it was for my generation,” Dr. Darling said. While previous generations were often motivated by fear and pressure, newer generations appear to respond less well to anxiety.

“People learn differently. Some from their tactile sense, some intellectually, and some from fear or pressure, but mostly, particularly those who are younger, now learn from positive reinforcement,” Dr. Darling said.

For teaching open procedures at his own institution, Dr. Darling has switched from the traditional model of one-on-one instruction undertaken in the surgical suite to a group approach. The limited number of open cases was the impetus, but group instruction now extends beyond the operating room.

“We have a meeting before the case, when we go over the technical aspects,” Dr. Darling explained. Fellows are asked to envision and describe potential problems and potential solutions.

“We try to make them visualize as well as verbalize exactly what will be done in the operating room,” Dr. Darling said. The plans are outlined carefully “so no one does any thinking in the OR. All the thinking is done in advance.”

Videos and simulators are teaching aids, but a great deal of learning can be accomplished independent of doing, according to Dr. Darling. Moreover, understanding the anatomy, which comes before developing surgical skills, is the same for open and endovascular procedures, so each is relevant to the other.

After witnessing an open case, all of the trainees along with the nurses and attending physicians go through a debriefing to consider the potential lessons. At Dr. Darling’s center, open procedures increasingly involve sicker and older patients, conferring case analysis with a particularly vital learning function in the curriculum.

Because of the diminishing number of open cases and the diminishing open skills, even among experienced vascular surgeons, residents in an increasing number of training programs “graduate without any open experience, which is a little shocking,” Dr. Darling said.

Importantly, group instruction, although valuable and necessary for exposing residents and fellows to open vascular surgery, has its own lessons to impart even if it was born out of necessity.

“We always emphasize that it is not the sewing that counts, it is the setup that counts,” said Dr. Darling, indicating that this is a clear message when the group is assembled for case planning. The group planning also emphasizes that surgery is a team sport.

“All of us is smarter than one of us,” said Dr. Darling, articulating the implicit message of group training.

Although this is a departure from a bygone era where infallible surgeons ruled the OR, it is fits nicely with changing attitudes about the best attributes of a competent surgeon.

NEW YORK – The dual challenges of teaching open vascular surgery techniques when few are performed and reaching a generation that has a different attitude to absorbing information requires new and innovative approaches, according to an academic surgeon speaking at symposium on vascular and endovascular issues sponsored by the Cleveland Clinic Foundation.

Ted Bosworth/MDedge News

“The see one, do one, teach one approach to surgical training is no longer possible,” explained R. Clement Darling III, MD, chief of the division of vascular surgery at Albany (N.Y.) Medical Center Hospital.

For open procedures, the problem is a rapidly declining number of cases in the era of endovascular surgery, but Dr. Darling also recommended adjusting training to the outlook and expectations of a new generation. First observed in the millennial generation, an attitude of firm work-related boundaries is also being seen in generation Z. Generation Z, characterized by birth after 1995, is just now beginning to reach residency programs.

“The approach to work-life balance is extremely different for these individuals than it was for my generation,” Dr. Darling said. While previous generations were often motivated by fear and pressure, newer generations appear to respond less well to anxiety.

“People learn differently. Some from their tactile sense, some intellectually, and some from fear or pressure, but mostly, particularly those who are younger, now learn from positive reinforcement,” Dr. Darling said.

For teaching open procedures at his own institution, Dr. Darling has switched from the traditional model of one-on-one instruction undertaken in the surgical suite to a group approach. The limited number of open cases was the impetus, but group instruction now extends beyond the operating room.

“We have a meeting before the case, when we go over the technical aspects,” Dr. Darling explained. Fellows are asked to envision and describe potential problems and potential solutions.

“We try to make them visualize as well as verbalize exactly what will be done in the operating room,” Dr. Darling said. The plans are outlined carefully “so no one does any thinking in the OR. All the thinking is done in advance.”

Videos and simulators are teaching aids, but a great deal of learning can be accomplished independent of doing, according to Dr. Darling. Moreover, understanding the anatomy, which comes before developing surgical skills, is the same for open and endovascular procedures, so each is relevant to the other.

After witnessing an open case, all of the trainees along with the nurses and attending physicians go through a debriefing to consider the potential lessons. At Dr. Darling’s center, open procedures increasingly involve sicker and older patients, conferring case analysis with a particularly vital learning function in the curriculum.

Because of the diminishing number of open cases and the diminishing open skills, even among experienced vascular surgeons, residents in an increasing number of training programs “graduate without any open experience, which is a little shocking,” Dr. Darling said.

Importantly, group instruction, although valuable and necessary for exposing residents and fellows to open vascular surgery, has its own lessons to impart even if it was born out of necessity.

“We always emphasize that it is not the sewing that counts, it is the setup that counts,” said Dr. Darling, indicating that this is a clear message when the group is assembled for case planning. The group planning also emphasizes that surgery is a team sport.

“All of us is smarter than one of us,” said Dr. Darling, articulating the implicit message of group training.

Although this is a departure from a bygone era where infallible surgeons ruled the OR, it is fits nicely with changing attitudes about the best attributes of a competent surgeon.

A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.

On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.

Results of laboratory testing revealed persistent pancytopenia:

• Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
• Total white blood cell count 0.8 × 10⁹/L (4.5–11.0)
• Platelet count 8 × 10⁹/L (150–400).

The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 10⁹/L.

He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.

SPLENIC RUPTURE IN AML

Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.¹

The literature includes a few reports of splenic rupture in patients with AML.^2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.

The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.

In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.

A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.

On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.

Results of laboratory testing revealed persistent pancytopenia:

• Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
• Total white blood cell count 0.8 × 10⁹/L (4.5–11.0)
• Platelet count 8 × 10⁹/L (150–400).

The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 10⁹/L.

He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.

SPLENIC RUPTURE IN AML

Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.¹

The literature includes a few reports of splenic rupture in patients with AML.^2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.

The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.

In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.

A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.

On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.

Results of laboratory testing revealed persistent pancytopenia:

• Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
• Total white blood cell count 0.8 × 10⁹/L (4.5–11.0)
• Platelet count 8 × 10⁹/L (150–400).

The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 10⁹/L.

He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.

SPLENIC RUPTURE IN AML

Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.¹

The literature includes a few reports of splenic rupture in patients with AML.^2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.

The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.

In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.