Clin-STAR Corner: Practice Changing Advances in Cardiology

Abstract

Although cardiovascular disease is the leading cause of death and major disability in older adults, older patients have been consistently under-represented in most cardiovascular clinical trials. This article summarizes the results of 4 trials published from 2020–2022 with practice- changing implications directly applicable to the care of older adults. The key findings from these trials were that: (1) an initial conservative approach to managing selected patients with stable ischemic heart disease is reasonable, even in the setting of moderate or severe ischemia; (2) empagliflozin is effective in reducing heart failure hospitalizations in patients with heart failure and preserved ejection fraction, with or without diabetes; (3) an individually tailored physical rehabilitation program reduces deconditioning and functional decline in older patients hospitalized with heart failure; and (4) restricting dietary sodium intake to less than 1500 mg/day is unlikely to improve outcomes in most patients with heart failure.

Background

Cardiovascular disease (CVD) is the leading cause of death and major disability in older adults, with over 60% of all deaths attributable to CVD in the U.S. occurring in the 7% of the population over age 75.¹ Yet, despite the high prevalence of CVD and CVD risk factors in older adults, older individuals, especially those with multimorbidity, frailty, or cognitive impairment, have been markedly under-represented in most cardiovascular clinical trials.² In recent years, there has been increased attention to the study of older patients with CVD, and this article describes the results of 4 practice-changing trials and their implications for the care of older adults.

Methods

With the assistance of a medical librarian, the authors searched PubMed for major randomized cardiovascular trials published in leading medical (New England Journal of Medicine, Lancet, JAMA) or cardiology (Journal of the American College of Cardiology, Circulation, European Heart Journal) journals from 2020–2022 (Supplementary Appendix S1). These journals were selected due to their high impact and with the recognition that high-quality practice-changing trials are likely to be published in one of these journals. The search returned a total of 602 articles. Titles and abstracts of these articles were manually reviewed by the authors and candidate trials for this paper were selected based on 2 criteria: overall impact on the care of adult patients with cardiovascular disease, and relevance to older adults, defined as age ≥75 years. In addition to the literature search, late-breaking clinical trials presented at the 3 major cardiology meetings (American College of Cardiology, European Society of Cardiology, American Heart Association) were surveyed, but no additional relevant studies were identified. The selection process focused primarily on whether the study findings would likely be practice changing for geriatricians and other clinicians involved in the care of patients aged 75 or older. Candidate articles were reviewed by both authors and 4 studies were chosen for discussion by unanimous consensus. Table 1 provides a listing of other important trials published in 2020–2022 that are relevant to the care of older patients.

Table 1: Honorable Mention Studies.

CT: computed tomography; ECG: electrocardiogram; HFpEF: heart failure with preserved ejection fraction; LDL: low density lipoprotein

Article	Outcome	Sample Size	Median Age (years)
Primary Prevention and Screening
Association of Statin Use With Disability-Free Survival and Cardiovascular Disease Among Healthy Older Adults. J Am Coll Cardiol. 2020 Jul 7;76(1):17–27.	In a sub-study of patients enrolled in ASPREE (community- dwelling adults >70 years of age), statin use did not prolong disability-free survival over 4.7 years of follow-up.	5,629	74.2
Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF Randomized Controlled Trial. Circulation. 2022 Mar 29;145(13):946–954.	16 primary care clinics were randomized to use a handheld single-lead ECG for patients >65 years of age without known atrial fibrillation. There was no difference in the rates of new atrial fibrillation diagnoses compared to usual care.	30,715	74
CT or Invasive Coronary Angiography in Stable Chest Pain. N Engl J Med. 2022 Apr 28;386(17):1591–1602.	Patients with stable chest pain and intermediate pretest probability were randomized to coronary CT vs. invasive angiography. The risk of major adverse cardiovascular events was similar in both groups but procedure-related complications were lower in the CT group.	3,561	60.9
Effect of a multi-domain lifestyle intervention on cardiovascular risk in older people: the FINGER trial. Eur Heart J. 2022 Jun 1;43(21):2054–2061.	Individuals aged 60–77 years were randomized to a 2-year multi-domain intervention. Using national health registries over 7.4 years, total cardiovascular events were lower.	1,259	69.4
Secondary Prevention and Management
Cognition After Lowering LDL-Cholesterol With Evolocumab. J Am Coll Cardiol. 2020 May 12;75(18):2283– 2293.	All patients enrolled in FOURIER completed a 23-item survey on memory and executive function. The addition of evolocumab had no impact on patient-reported cognition after 2.2 years, even among those with LDL < 20 mg/dL.	22,655	62.5
Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020 Oct 1;383(14):1305–1316.	Patients with atrial fibrillation diagnosed <1 year before enrollment randomized to early rhythm control had lower risk of adverse cardiovascular events vs. a rate control strategy.	2,789	70.3
Effect of an Emergency Department Care Bundle on 30-Day Hospital Discharge and Survival Among Elderly Patients With Acute Heart Failure: The ELISABETH Randomized Clinical Trial. JAMA. 2020 Nov 17;324(19):1948–1956.	In a cluster randomized trial of patients >75 years presenting with acute heart failure to 15 French emergency departments, a care bundle compared to usual care did not result in a difference in days alive and out of the hospital at 30 days.	503	87
Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Circulation. 2021 Nov 2;144(18):1476–1484.	Influenza vaccination shortly after myocardial infarction or high-risk stable coronary heart disease reduced a 12-month cardiovascular composite endpoint.	2,571	59.8
Effect of β-Blocker Withdrawal on Functional Capacity in Heart Failure and Preserved Ejection Fraction. J Am Coll Cardiol. 2021 Nov 23;78(21):2042–2056.	Based on cardiopulmonary exercise testing, beta-blocker withdrawal improved maximal functional capacity in patients with HFpEF and chronotropic incompetence.	52	72.6
Association Between Age and Outcomes of Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: Results From the CABANA Trial. Circulation. 2022 Mar 15;145(11):796–804.	Stratification of patients in CABANA to <65, 65-to-74, and >75 years of age illustrated variations in clinical outcomes for catheter ablation. The largest relative and absolute benefits were in younger patients with no benefit in patients >75 years.	2,204	68

Summary of studies

Initial invasive or conservative strategy for stable coronary disease (ISCHEMIA)³

Summary.

Urgent coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) is of proven benefit in patients who present with acute coronary syndromes, including older adults. Conversely, medical therapy is associated with favorable outcomes in most patients with stable coronary artery disease (CAD), defined as a stable pattern of symptoms without rapid progression or acute change in severity.⁴ What has long been controversial, however, is whether routine revascularization with modern PCI or CABG reduces mortality or coronary events or improves quality of life in patients with stable CAD. The ISCHEMIA trial, sponsored by the National Heart, Lung, and Blood Institute, randomized 5179 patients with stable CAD and moderate or severe ischemia on stress testing to an initial invasive strategy (coronary angiography and revascularization, if feasible) or to an initial conservative strategy (medical therapy alone with option for angiography in the event of treatment failure).^3,5 The primary outcome was a composite of cardiovascular death, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. The median age was 64 years (IQR 58–70 years), 22.6% of participants were women, and the median follow-up was 3.2 years. At 6 months, the primary composite outcome occurred more frequently in the invasive arm (5.3% vs. 3.4%), but the difference was not significant.³ At 5-years follow-up, cumulative event rates were higher in the conservative arm (18.2% vs. 16.4%), but again the difference was not significant. Overall, there were 145 deaths in the invasive group and 144 deaths in the conservative group. Quality of life, assessed by the Seattle Angina Questionnaire summary score, improved in both groups, but to a significantly greater extent in the invasive arm (absolute difference at 12 months 4.2 points; 95% credible interval, 3.3 to 5.1).⁵ The improved quality of life with invasive treatment occurred primarily in patients with more angina at baseline. All findings were reportedly similar in older and younger patients, although detailed subgroup analysis by age has not been published.

Limitations.

Patients were excluded if there was left main coronary stenosis >50%, left ventricular ejection <35%, New York Heart Association (NYHA) class III or IV heart failure, or estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 M². Although 25% of patients were over age 70, overall comorbidity burden was low, and it is likely that few older patients with multimorbidity or other geriatric syndromes were enrolled. Black patients were under-represented, in part reflecting that only about 20% of patients were enrolled in the United Sates.

Implications.

ISCHEMIA is a landmark study that validates an initial conservative approach to management in selected patients with stable CAD, even in the context of moderate to severe ischemia. Patients with persistent limiting symptoms despite medical therapy may be considered for revascularization when consistent with goals of care, with the expectation that quality of life will be improved without affecting survival.

Empagliflozin in heart failure with a preserved ejection fraction (EMPEROR-Preserved)⁶

Summary.

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure in older adults, especially women.⁷ Until recently, there has been no proven effective therapy for this condition. The EMPEROR-Preserved trial, funded by Boehringer Ingelheim and Eli Lilly, randomized 5988 patients with NYHA class II-IV heart failure and an ejection fraction of 40% or higher to empagliflozin 10 mg daily or placebo in addition to usual therapy.⁶ The primary outcome was a composite of cardiovascular death or hospitalization for heart failure, and the median follow-up was 26 months. The mean age was 72 years, 45% of participants were women, and 49% had diabetes. The primary outcome occurred in 13.8% of patients in the empagliflozin group compared to 17.1% in the placebo group (hazard ratio 0.79, 95% CI 0.69–0.90, p<0.001). Heart failure hospitalizations were reduced by 27%, but there was no difference in cardiovascular or all-cause mortality. Outcomes were similar across age, sex, and racial subgroups, as well as in patients with or without diabetes and those with or without eGFR<60 ml/min/1.73 M².

Hypotension and uncomplicated genital and urinary tract infections were more common in the empagliflozin group, but serious adverse events overall were more common in the control group.

Limitations.

Patients with advanced comorbidity were excluded, e.g., chronic lung disease requiring supplemental oxygen, eGFR<20 ml/min/1.73 M², or chronic liver disease. Although the study enrolled 3838 patients aged 70 or older, detailed analysis by age has not been reported. In addition, black patients were under-represented in the trial.

Implications.

Empagliflozin is now approved for the treatment of heart failure regardless of ejection fraction, and with the recent publication of the DELIVER trial,⁸ dapagliflozin could receive an expanded indication in the near future. Importantly, these agents reduce heart failure hospitalizations for patients with or without diabetes, they are not associated with hypoglycemia in patients without diabetes, and they tend to have a favorable effect on renal function.⁹ The principal limitation, from a practical standpoint, is cost, as they are often not fully covered by insurance. It is also imperative that a diagnosis of heart failure be established prior to initiation. A normal nt-proBNP level (<450 pg/mL for patients age 75 or older) suggests a non-heart failure etiology of dyspnea or exercise intolerance and thus empagliflozin would not be indicated.

Physical rehabilitation for older patients hospitalized for heart failure (REHAB-HF)¹⁰

Summary.

Acute decompensated heart failure is the most common reason for hospitalization and rehospitalization in older adults. Moreover, admission for heart failure is frequently associated with functional decline in older patients, and there have been no proven interventions to reduce functional decline or improve clinical outcomes. The multicenter REHAB-HF trial, sponsored by the National Institute on Aging, randomized 349 patients 60 years of age or older admitted with acute decompensated heart failure to an individually tailored progressive rehabilitation intervention that focused on 4 functional domains (strength, balance, mobility, endurance), or to usual care.¹⁰ The intervention was initiated in the hospital, when feasible, and then transitioned to the outpatient setting, either at a facility or at home. Outpatient sessions were one-on-one with a therapist, lasted 60 minutes, and occurred 3 days per week for 12 weeks. The primary outcome was the Short Physical Performance Battery (SPPB) score (range 0–12; lower scores indicate worse physical function) at 3 months follow-up. The mean age was 73 years, 52% of participants were women, 49% were non-white, 55% were frail and an additional 42% were pre-frail by Fried criteria, and the mean baseline SPPB score was 6.0. The retention rate in the intervention group was 82% and the mean number of outpatient sessions completed was 24. At 3-months follow-up, the SPPB score was significantly higher (better) in the intervention group (8.3 vs. 6.9, p<0.001). In addition to an improvement in SPPB, patients randomized to the intervention group had significant relative improvements in 6-minute walk distance, gait speed, and quality of life (based on the KCCQ). There was also a trend to improvement in frailty score. A subsequent analysis suggested that patients with HFpEF had greater physical impairment at baseline and were more likely to benefit from the intervention.¹¹

Limitations.

This is a relatively small study and larger studies are needed to validate the intervention and assess its impact on clinical outcomes, including mortality, readmissions, day-to-day functioning, and other patient-centered outcomes. The intervention is resource intensive, adherence rates were unusually high, and scalability is uncertain.

Implications.

This proof-of-concept study provides strong support for the potential efficacy of an individually tailored intervention designed to reduce functional decline in patients hospitalized with acute medical illness. A larger multicenter follow-up trial focusing specifically on patients with HFpEF has recently been funded by the National Institute on Aging.

Reduction of dietary sodium to less than 1500 mg in heart failure: an international, open- label, randomised, controlled trial (SODIUM-HF)¹²

Summary.

Dietary sodium restriction is recommended in patients with chronic heart failure, but evidence to support this recommendation is sparse. The SODIUM-HF trial randomized 806 ambulatory patients with NYHA class II or III chronic heart failure, regardless of ejection fraction, on guideline-directed medical therapy in 6 countries (Australia, Canada, Chile, Colombia, Mexico, New Zealand) to a reduced sodium diet (<1500 mg/day) or to usual care.¹² The primary outcome was a composite of all-cause death or hospitalization or emergency department visit for cardiovascular causes within 12 months. The mean age was 67 years, 33% of participants were female, and the mean ejection fraction was 35%. The primary outcome occurred in 15% of patients in the low sodium group and 17% of patients in the usual care group (hazard ratio 0.89, 95% CI 0.63–1.26, p=0.53). There were numerically more deaths from all causes in the low sodium group (22 [5.5%] vs.17 [4.2%]), but the difference was not significant. Similarly, there was no significant difference between groups with respect to cardiovascular hospitalizations.

Limitations.

The sample size is modest and the study may be underpowered to detect a clinically important difference in hospitalizations and other outcomes. Baseline sodium consumption was relatively low compared to a typical U.S. diet, so the value of a reduced sodium diet in Americans with heart failure remains unclear.

Implications.

This study and others suggest that excessive sodium restriction, such as less than 1500 mg/day, is unlikely to improve outcomes in patients with clinically stable heart failure. These findings may be particularly relevant to older adults, especially those with renal insufficiency or other comorbidities impacting fluid and electrolyte homeostasis, for whom unnecessary dietary restrictions can adversely affect quality of life and nutritional well-being.

Conclusion

While these 4 studies each had a mean age below 75 years, they all provide novel insights into the management of cardiovascular conditions that are highly prevalent in the geriatric population. As summarized in Figure 1, these studies support significant changes in practice for clinicians caring for older adults. As the population continues to age, it will be important to enroll more representative cohorts of older adults in clinical trials to ensure that study findings are applicable to older adults typically seen in clinical practice. While additional research is needed, the lessons articulated are suitable for implementation in appropriately selected older patients.

Figure 1.

Summary of Practice-Changing Implications from 4 Recent Cardiology Trials

Key points:

1. A conservative approach to managing older patients with stable coronary artery disease is reasonable, even when a stress test demonstrates moderate or severe ischemia.

2. Sodium-glucose cotransporter inhibitors should be considered first-line therapy for older patients with heart failure and preserved ejection fraction.

3. Sodium restriction to <1500 mg daily is unlikely to improve clinical outcomes in most ambulatory older adults with chronic heart failure.

Why does this paper matter?

The 4 recently published randomized clinical trials summarized in this review provide novel insights into the management of 2 cardiovascular conditions that are highly prevalent in the geriatric population, i.e., coronary artery disease and heart failure. Each of these studies supports significant practice changes for clinicians caring for older adults. While additional research is needed, especially in older patients with multimorbidity and in nursing home residents, the findings of these trials are suitable for implementation in appropriately selected older adults.