Cholesterol Lowering in Older Adults: Should We Wait for Further Evidence?

PURPOSE OF REVIEW: Current guidelines for primary and secondary prevention of cardiovascular events in adults up to age 75 years are well-established. However, recommendations for lipid-lowering therapies (LLT), particularly for primary prevention, are inconclusive after age 75. In this review, we focus on adults ≥ 75 years to assess low-density lipoprotein-cholesterol (LDL-C) as a marker for predicting atherosclerotic cardiovascular disease (ASCVD) risk, review risk assessment tools, highlight guidelines for LLT, and discuss benefits, risks, and deprescribing strategies. RECENT FINDINGS: The relationship between LDL-C and all-cause mortality and cardiovascular outcomes in older adults is complex and confounded. Current ASCVD risk estimators heavily depend on age and lack geriatric-specific variables. Emerging tools may reclassify individuals based on biologic rather than chronologic age, with coronary artery calcium scores gaining popularity. After initiating LLT for primary or secondary prevention, target LDL-C levels for older adults are lacking, and non-statin therapy thresholds remain unknown, relying on evidence from younger populations. Shared decision-making is crucial, considering therapy's time to benefit, life expectancy, adverse events, and geriatric syndromes. Deprescribing is recommended in end-of-life care but remains unclear in fit or frail older adults. After an ASCVD event, LLT is appropriate for most older adults, and deprescribing can be considered for those approaching the last months of life. Ongoing trials will guide statin prescription and deprescribing among older adults free of ASCVD. In the interim, for adults ≥ 75 years without a limited life expectancy who are free of ASCVD, an LLT approach that includes both lifestyle and medications, specifically statins, may be considered after shared decision-making.

Initiation of Statins for Primary Prevention in Heart Failure With Preserved Ejection Fraction.

Background: Statins are highly effective for primary prevention of atherosclerotic cardiovascular disease (ASCVD) and mortality. Data on the benefit of statins in adults with heart failure with preserved ejection fraction (HFpEF) and without ASCVD are limited. Objectives: The purpose of this study was to determine whether statins are associated with a lower risk of mortality and major adverse cardiovascular events (MACE) in HFpEF. Methods: Veterans Health Administration data from 2002 to 2016, linked to Medicare and Medicaid claims and pharmaceutical data, were collected. Patients had a new HFpEF diagnosis and no known ASCVD or prior statin use at baseline. Cox proportional hazards models were fit to evaluate the association of new statin use with outcomes (all-cause mortality and MACE). Propensity score overlap weighting (PSW) was used to balance baseline characteristics. Results: Among 7,970 Veterans, 47% initiated a statin over a mean 6.0-year follow-up. At HFpEF diagnosis, mean age was 69 ± 12 years, 96% were male, 67% were White, 14% were Black, and mean EF was 60% ± 6%. Before PSW, statin users were younger with more prevalent metabolic syndrome, arthritis, and other chronic conditions. All characteristics were balanced after PSW. There were 5,314 deaths and 4,859 MACE events. After PSW, the hazard for all-cause mortality for statin users vs nonusers was 22% lower (HR: 0.78; 95% CI: 0.73-0.83). The HR for MACE was 0.79 (95% CI: 0.74-0.84), 0.69 (95% CI: 0.60-0.80) for all-cause hospitalization, and 0.72 (95% CI: 0.59-0.88) for HF hospitalization. Conclusions: New statin use was associated with reduced all-cause mortality, MACE, and hospitalization in Veterans with HFpEF without prevalent ASCVD.

The role of statin therapy in older adults: best practices and unmet challenges.

INTRODUCTION: Cardiovascular disease (CVD) is associated with significant morbidity, functional decline, and mortality in older adults. The role of statins for primary CVD prevention in older adults remains unclear, largely due to systematic exclusion of these individuals in trials that inform current practice guidelines, leading to conflicting national and international practice recommendations for statin use for primary prevention of CVD in adults aged 75 and older. AREAS COVERED: In this narrative review, we performed a literature review utilizing PubMed, and ultimately focus on seven major national and international guidelines of lipid lowering therapy. Through the lens of two clinical cases, we review physiologic changes in lipid metabolism with aging, discuss the relationship between cholesterol and cardiovascular events in older adults, examine the national and international guidelines and the available evidence informing these guidelines for statin use in primary prevention of CVD in older adults. Finally we review practical clinical considerations for drug monitoring and deprescribing in this population. EXPERT OPINION: Guidelines for the use of statins for primary CVD prevention in older adults is conflicting. Collectively, evidence to date suggests statin therapy may be beneficial for primary CVD prevention in older adults free of life-limiting comorbidities. Randomized controlled trials are currently underway to address current evidence gaps.

TAVR in Older Adults: Moving Toward a Comprehensive Geriatric Assessment and Away From Chronological Age: JACC Family Series.

Calcific aortic stenosis can be considered a model for geriatric cardiovascular conditions due to a confluence of factors. The remarkable technological development of transcatheter aortic valve replacement was studied initially on older adult populations with prohibitive or high-risk for surgical valve replacement. Through these trials, the cardiovascular community has recognized that stratification of these chronologically older adults can be improved incrementally by invoking the concept of frailty and other geriatric risks. Given the complexity of the aging process, stratification by chronological age should only be the initial step but is no longer sufficient to optimally quantify cardiovascular and noncardiovascular risk. In this review, we employ a geriatric cardiology lens to focus on the diagnosis and the comprehensive management of aortic stenosis in older adults to enhance shared decision-making with patients and their families and optimize patient-centered outcomes. Finally, we highlight knowledge gaps that are critical for future areas of study.

What is the additive value of nutritional deficiency to VA-FI in the risk assessment for heart failure patients?

OBJECTIVES: To assess the impact of adding the Prognostic Nutritional Index (PNI) to the U.S. Veterans Health Administration frailty index (VA-FI) for the prediction of time-to-death and other clinical outcomes in Veterans hospitalized with Heart Failure. METHODS: A retrospective cohort study of veterans hospitalized for heart failure (HF) from October 2015 to October 2018. Veterans ≥50 years with albumin and lymphocyte counts, needed to calculate the PNI, in the year prior to hospitalization were included. We defined malnutrition as PNI ≤43.6, based on the Youden index. VA-FI was calculated from the year prior to the hospitalization and identified three groups: robust (≤0.1), prefrail (0.1-0.2), and frail (>0.2). Malnutrition was added to the VA-FI (VA-FI-Nutrition) as a 32nd deficit with the total number of deficits divided by 32. Frailty levels used the same cut-offs as the VA-FI. We compared categories based on VA-FI to those based on VA-FI-Nutrition and estimated the hazard ratio (HR) for post-discharge all-cause mortality over the study period as the primary outcome and other adverse events as secondary outcomes among patients with reduced or preserved ejection fraction in each VA-FI and VA-FI-Nutrition frailty groups. RESULTS: We identified 37,601 Veterans hospitalized for HF (mean age: 73.4 ± 10.3 years, BMI: 31.3 ± 7.4 kg/m2). In general, VA-FI-Nutrition reclassified 1959 (18.6%) Veterans to a higher frailty level. The VA-FI identified 1,880 (5%) as robust, 8,644 (23%) as prefrail, and 27,077 (72%) as frail. The VA-FI-Nutrition reclassified 382 (20.3%) from robust to prefrail and 1577 (18.2%) from prefrail to frail creating the modified-prefrail and modified-frail categories based on the VA-FI-Nutrition. We observed shorter time-to-death among Veterans reclassified to a higher frailty status vs. those who remained in their original group (Median of 2.8 years (IQR:0.5,6.8) in modified-prefrail vs. 6.3 (IQR:1.8,6.8) years in robust, and 2.2 (IQR:0.7,5.7) years in modified-frail vs. 3.9 (IQR:1.4,6.8) years in prefrail). The adjusted HR in the reclassified groups was also significantly higher in the VA-FI-Nutrition frailty categories with a 38% increase in overall all-cause mortality among modified-prefrail and a 50% increase among modified-frails. Similar trends of increasing adverse events were also observed among reclassified groups for other clinical outcomes. CONCLUSION: Adding PNI to VA-FI provides a more accurate and comprehensive assessment among Veterans hospitalized for HF. Clinicians should consider adding a specific nutrition algorithm to automated frailty tools to improve the validity of risk prediction in patients hospitalized with HF.

Assessment and Management of Atrial Fibrillation in Older Adults with Frailty.

Atrial fibrillation (AF) is a major driver of morbidity and mortality among older adults with frailty. Moreover, frailty is highly prevalent in older adults with AF. Understanding and addressing the needs of frail older adults with AF is imperative to guide clinicians caring for older adults. In this review, we summarize current evidence to support the assessment and management of older adults with AF and frailty, incorporating numerous recent landmark trials and studies in the context of the 2023 US AF guideline.

Aligning goals with care: Advance directives in older adults with implantable cardioverter-defibrillators.

BACKGROUND: Patients ≥80 with implantable cardioverter-defibrillators (ICDs) have high rates of hospitalization and mortality, yet few have documented advance directives. We sought to determine the prevalence of advance directives in adults ≥80 years with ICDs, focusing on those with frailty and cognitive impairment. METHODS: Prospective cohort study (July 2016-May 2019) in an electrophysiology clinic. Presence of advance directives (health care proxies [HCP] and living wills [LW], or medical orders for life-sustaining treatment [MOLST]) was determined by medical record review. Frailty and cognitive impairment were screened using 4-m gait speed and Mini-Cog. RESULTS: 77 Veterans were evaluated. Mean age 84 years, 100% male, 70% frail. Overall, 52 (68%) had an HCP and 37 (48%) had a LW/MOLST. Of 67 with cognitive testing, 36% were impaired. HCP documentation was similar among frail and non-frail (69% vs. 65%). LW/MOLST was more prevalent among frail versus non-frail (52% vs. 39%). There was no difference in HCP documentation by cognitive status (67%). A LW/MOLST was more frequent for cognitively impaired versus non-impaired (50% vs. 42%). Among 19 Veterans who were frail and cognitively impaired, 14 (74%) had an HCP and 11 (58%) had a LW/MOLST. CONCLUSIONS: Most Veterans had a documented advance directive, but a significant minority did not. Simple frailty and cognitive screening tools can rapidly identify patients for whom discussion of advance directives is especially important.

New horizons in frailty identification via electronic frailty indices: early implementation lessons from experiences in England and the United States.

Frailty represents an integrative prognostic marker of risk that associates with a myriad of age-related adverse outcomes in older adults. As a concept, frailty can help to target scarce resources and identify subgroups of vulnerable older adults that may benefit from interventions or changes in medical management, such as pursing less aggressive glycaemic targets for frail older adults with diabetes. In practice, however, there are several operational challenges to implementing frailty screening outside the confines of geriatric medicine. Electronic frailty indices (eFIs) based on the theory of deficit accumulation, derived from routine data housed in the electronic health record, have emerged as a rapid, feasible and valid approach to screen for frailty at scale. The goal of this paper is to describe the early experience of three diverse groups in developing, implementing and adopting eFIs (The English National Health Service, US Department of Veterans Affairs and Atrium Health-Wake Forest Baptist). These groups span different countries and organisational complexity, using eFIs for both research and clinical care, and represent different levels of progress with clinical implementation. Using an implementation science framework, we describe common elements of successful implementation in these settings and set an agenda for future research and expansion of eFI-informed initiatives.

Role of Cognitive Frailty in Older Adults With Cardiovascular Disease.

As the older adult population expands, an increasing number of patients affected by geriatric syndromes are seen by cardiovascular clinicians. One such syndrome that has been associated with poor outcomes is cognitive frailty: the simultaneous presence of cognitive impairment, without evidence of dementia, and physical frailty, which results in decreased cognitive reserve. Driven by common pathophysiologic underpinnings (eg, inflammation and neurohormonal dysregulation), cardiovascular disease, cognitive impairment, and frailty also share the following risk factors: hypertension, diabetes, obesity, sedentary behavior, and tobacco use. Cardiovascular disease has been associated with the onset and progression of cognitive frailty, which may be reversible in early stages, making it essential for clinicians to diagnose the condition in a timely manner and prescribe appropriate interventions. Additional research is required to elucidate the mechanisms underlying the development of cognitive frailty, establish preventive and therapeutic strategies to address the needs of older patients with cardiovascular disease at risk for cognitive frailty, and ultimately facilitate targeted intervention studies.

Progression of Frailty and Cardiovascular Outcomes Among Medicare Beneficiaries.

Background: Frailty is associated with adverse cardiovascular outcomes independent of age and comorbidities, yet the independent influence of frailty progression remains uncertain. Methods: Medicare Fee-for-service beneficiaries ≥ 65 years at cohort inception with continuous enrollment from 2003-2015 were included. Frailty trajectory was measured by annualized change in a validated claims-based frailty index (CFI) over a 5-year period. Linear mixed effects models, adjusting for baseline frailty, were used to estimate CFI change over a 5-year period. Survival analysis was used to evaluate associations of frailty progression and future health outcomes (major adverse cardiovascular and cerebrovascular events [MACCE], all-cause death, heart failure, myocardial infarction, ischemic stroke, and days alive at home [DAH] within the following calendar year). Results: 26.4 million unique beneficiaries were included (mean age 75.4 ± 7.0 years, 57% female, 13% non-White). In total, 20% had frailty progression, 66% had no change in frailty, and 14% frailty regression over median follow-up of 2.4 years. Compared to those without a change in CFI, when adjusting for baseline frailty, those with frailty progression had significantly greater risk of incident MACCE (hazard ratio [HR] 2.30, 95% confidence interval [CI] 2.30-2.31), all-cause mortality (HR 1.59, 95% CI 1.58-1.59), acute myocardial infarction (HR 1.78, 95% CI 1.77-1.79), heart failure (HR 2.78, 95% CI 2.77-2.79), and stroke (HR 1.78, 95% CI 1.77-1.79). There was also a graded increase in risk of each outcome with more rapid progression and significantly fewer DAH with the most rapid vs. the slowest progression group (270.4 ± 112.3 vs. 308.6 ± 93.0 days, rate ratio 0.88, 95% CI 0.87-0.88, p < 0.001). Conclusions: In this large, nationwide sample of Medicare beneficiaries, frailty progression, independent of baseline frailty, was associated with fewer DAH and a graded risk of MACCE, all-cause mortality, myocardial infarction, heart failure, and stroke compared to those without progression.

The impact of yoga on aging physiology: A review.

Frailty represents diminished reserve across multiple physiologic systems, accompanied by increased vulnerability to stressors and increased morbidity and mortality. With population aging, strategies to prevent and manage frailty are priorities in clinical medicine and public health. Current evidence-based approaches to frailty management are multimodal in nature. Yoga, an increasingly popular and highly adaptable mind-body practice, is multi-component, incorporating physical postures, breathing practices, meditation, and other elements, and may be a strategy for frailty management. Here, we summarize the evidence linking yoga practice to mitigation of age-related degradation across multiple physiologic systems, including cardiovascular, pulmonary, musculoskeletal, and nervous systems. We discuss putative mechanisms of action including modulation of the hypothalamic-pituitary-adrenal axis. Finally, we consider implications for clinical practice and future research.

Is the Montreal cognitive assessment culturally valid in a diverse geriatric primary care setting? Lessons from the Bronx.

BACKGROUND: Efficacy and validity of the MoCA for cognitive screening in ethnoculturally and linguistically diverse settings is unclear. We sought to examine the utility and discriminative validity of the Spanish and English MoCA versions to identify cognitive impairment among diverse community-dwelling older adults. METHODS: Participants aged ≥65 with cognitive concerns attending outpatient primary care in Bronx, NY, were recruited. MoCA and neuropsychological measures were administered in Spanish or English, and a neuropsychologist determined cognitive status (normal with subjective cognitive concerns [SCC], mild cognitive impairment [MCI], and dementia). One-way ANOVA compared cognitive statuses. ROC analyses identified optimal MoCA cutpoints for discriminating possible cognitive impairment. RESULTS: There were 231 participants, with mean age 73, 72% women, 43% Hispanic; 39% Black/African American; 113 (49%) completed testing in English and 118 (51%) in Spanish. Overall MoCA mean was 17.7 (SD = 4.3). Neuropsychological assessment identified 90 as cognitively normal/SCC, average MoCA 19.9 (SD = 4.1), 133 with MCI, average MoCA 16.6 (SD = 3.7), and 8 with dementia, average MoCA 10.6 (SD = 3.1). Mean English MoCA average was 18.6 (SD = 4.1) versus Spanish 16.7 (SD = 4.3). The published cutpoint ≤23 for MCI yielded a high false-positive rate (79%). ROC analyses identified ≤18.5 as the score to identify MCI or dementia using the English MoCA (65% sensitivity; 77% specificity) and ≤16.5 for the Spanish MoCA (64% sensitivity;73% specificity) in this sample of older adults with cognitive concerns. CONCLUSIONS: Current MoCA cutpoints were inappropriately high in a culturally/linguistically diverse urban setting, leading to a high false-positive rate. Lower Spanish and English MoCA cutpoints may improve diagnostic accuracy for identifying cognitive impairment in this group, highlighting the need for the creation and validation of accurate cognitive screeners for ethnoculturally and linguistically diverse older adults.

Incidence and prognostic significance of newly-diagnosed atrial fibrillation among older U.S. veterans hospitalized with COVID-19.

Most prior studies on the prognostic significance of newly-diagnosed atrial fibrillation (AF) in COVID-19 did not differentiate newly-diagnosed AF from pre-existing AF. To determine the association between newly-diagnosed AF and in-hospital and 30-day mortality among regular users of Veterans Health Administration using data linked to Medicare. We identified Veterans aged ≥ 65 years who were hospitalized for ≥ 24 h with COVID-19 from 06/01/2020 to 1/31/2022 and had ≥ 2 primary care visits within 24 months prior to the index hospitalization. We performed multivariable logistic regression analyses to estimate adjusted risks, risk differences (RD), and odds ratios (OR) for the association between newly-diagnosed AF and the mortality outcomes adjusting for patient demographics, baseline comorbidities, and presence of acute organ dysfunction on admission. Of 23,299 patients in the study cohort, 5.3% had newly-diagnosed AF, and 29.2% had pre-existing AF. In newly-diagnosed AF adjusted in-hospital and 30-day mortality were 16.5% and 22.7%, respectively. Newly-diagnosed AF was associated with increased mortality compared to pre-existing AF (in-hospital: OR 2.02, 95% confidence interval [CI] 1.72-2.37; RD 7.58%, 95% CI 5.54-9.62) (30-day: OR 1.86; 95% CI 1.60-2.16; RD 9.04%, 95% CI 6.61-11.5) or no AF (in-hospital: OR 2.24, 95% CI 1.93-2.60; RD 8.40%, 95% CI 6.44-10.4) (30-day: 2.07, 95% CI 1.80-2.37; RD 10.2%, 95% CI 7.89-12.6). There was a smaller association between pre-existing AF and the mortality outcomes. Newly-diagnosed AF is an important prognostic marker for patients hospitalized with COVID-19. Whether prevention or treatment of AF improves clinical outcomes in these patients remains unknown.

Holistic frailty prevention: The promise of movement-based mind-body therapies.

Aging is characterized by fundamental cellular and molecular hallmarks that result in physiologic decline of most body systems. This may culminate in frailty, a state of decreased reserve. Because frailty is a state of multisystem dysregulation, multimodal interventions may be necessary to mitigate and prevent progression rather than interventions targeting a single system. Movement-based mind-body therapies, such as tai chi and yoga, are promising multimodal strategies for frailty prevention and treatment given their inherent multicomponent nature. In this review, we summarize the links between hallmarks of aging and frailty and how tai chi and yoga may impact these hallmarks. We review trial evidence for the impact of tai chi and yoga on frailty in older populations and discuss opportunities for future research.

New statin use, mortality, and first cardiovascular events in older US Veterans by frailty status.

BACKGROUND: Statins are part of long-term medical regimens for many older adults. Whether frailty modifies the protective relationship between statins, mortality, and major adverse cardiovascular events (MACE) is unknown. METHODS: This was a retrospective study of US Veterans ≥65, without CVD or prior statin use seen in 2002-2012, followed through 2017. A 31-item frailty index was used. The co-primary endpoint was all-cause mortality or MACE (MI, stroke/TIA, revascularization, or cardiovascular death). Cox proportional hazards models were developed to evaluate the association of statin use with outcomes; propensity score overlap weighting accounted for confounding by indication. RESULTS: We identified 710,313 Veterans (mean age (SD) 75.3(6.5), 98% male, 89% white); 86,327 (12.1%) were frail. Over mean follow-up of 8 (5) years, there were 48.6 and 72.6 deaths per 1000 person-years (PY) among non-frail statin-users vs nonusers (weighted Incidence Rate Difference (wIRD)/1000 person years (PY), -24.0[95% CI, -24.5 to -23.6]), and 90.4 and 130.4 deaths per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -40.0[95% CI, -41.8 to -38.2]). There were 51.7 and 60.8 MACE per 1000PY among non-frail statin-users vs nonusers (wIRD/1000PY, -9.1[95% CI, -9.7 to -8.5]), and 88.2 and 102.0 MACE per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -13.8[95% CI, -16.2 to -11.4]). There were no significant interactions by frailty for statin users vs non-users by either mortality or MACE outcomes, p-interaction 0.770 and 0.319, respectively. Statin use was associated with lower risk of all-cause mortality (HR, 0.61 (0.60-0.61)) and MACE (HR 0.86 (0.85-0.87)). CONCLUSIONS: New statin use is associated with a lower risk of mortality and MACE, independent of frailty. These findings should be confirmed in a randomized clinical trial.

Effect of canakinumab on frailty: A post hoc analysis of the CANTOS trial.

Although inflammation is strongly associated with frailty, whether medications that lower inflammation decrease frailty is unclear and randomized trial evidence is scant. We sought to test whether canakinumab, a therapeutic monoclonal antibody that inhibits IL-1ß and reduces C-reactive protein (CRP), can lower frailty risk. This was a post hoc analysis of the Canakinumab ANti-inflammatory Thrombosis Outcome Study (CANTOS), a randomized double-blind placebo-controlled trial of 10,061 stable postmyocardial infarction patients randomized to subcutaneous canakinumab once every 3 months. Incident frailty was measured using a 34-item cumulative-deficit Frailty Index (FI). Time-to-event analysis using intent to treat. A total of 9942 CANTOS participants had data to calculate a baseline FI. Median age was 61 (IQR 54-68); 74% were male, 12% Asian, 3% Black, 80% White, and 16% Hispanic/Latino. At baseline, mean FI score was 0.12 and 13% were frail using a cutoff of 0.2. Over 5 years, 1080 participants (12.5%) became frail and mean FI scores increased to 0.14. There was no effect on frailty incidence according to randomization to any canakinumab dose versus placebo over time, HR 1.03 (0.91-1.17), p = 0.63. Results were similar using phenotypic frailty. Additionally, the primary findings of CANTOS in terms of canakinumab-associated cardiovascular event reduction were unchanged in analyses stratified by baseline frailty. In conclusion, among stable adult patients with atherosclerosis, random allocation to interleukin-1b inhibition with canakinumab versus placebo did not lower risk of incident frailty over 5 years. More randomized data are needed to understand the role of targeted anti-inflammatory medications for frailty prevention in older adults.

How Would You Manage This Patient With Heart Failure With Preserved Ejection Fraction? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

The proportion of patients with new-onset heart failure who have preserved rather than reduced left ventricular ejection fraction (HFpEF and HFrEF) has been increasing over recent decades. In fact, HFpEF now outweighs HFrEF as the predominant heart failure subtype and likely remains underdiagnosed in the community. This is due in part to an aging population and a rise in other risk factors for HFpEF, including obesity and associated cardiometabolic disease. Whereas the diagnosis of HFrEF is relatively straightforward, the diagnosis of HFpEF is often more challenging because there can be other causes for symptoms, including dyspnea and fatigue, and cardinal physical examination findings of elevated jugular venous pressure or pulmonary congestion may not be evident at rest. In 2022, the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America published a comprehensive guideline on heart failure that included recommendations for the management of HFpEF. The use of diuretics for the management of congestion remained the only class 1 (strong) recommendation. New recommendations included broader use of sodium-glucose cotransporter-2 inhibitors (SGLT2i, class 2a), and angiotensin receptor-neprilysin inhibitors (class 2b). In 2023, the American College of Cardiology published an expert consensus decision pathway for the management of HFpEF that suggests treatment strategies based on sex assigned at birth, ejection fraction, clinical evidence of congestion, and candidacy for SGLT2i therapy. Here, 2 experts, a cardiologist and a geriatrician, discuss their approach to the diagnosis and management of HFpEF and how they would apply guidelines to an individual patient.