Vascular

Frail elderly patients are at high risk of adverse clinical outcomes, including those due to polypharmacy. Several groups tackle “deprescribing” by developing lists of medications that are potentially inappropriate for the elderly, such as the Beers or STOPP/START criteria.^1–4

In contrast, our group (the Palliative and Therapeutic Harmonization [PATH] program and the Dalhousie Academic Detailing Service) has developed evidence-based, frailty-specific guidelines for treating hypertension⁵ and diabetes,⁶ in which we advocate less-stringent treatment targets and tapering or discontinuing medications, as needed.

The PATH program⁷ is a clinical approach that prioritizes the consideration of frailty when making treatment decisions. The Dalhousie Academic Detailing Service collaborates with the Nova Scotia Health Authority to research and develop evidence-informed educational messages about the treatment of common medical conditions.

Here, we address lipid-lowering therapy in this population.

CONSIDERING FRAILTY

Frailty is defined in several ways. The Fried model^8,9 identifies frailty when 3 of the following characteristics are present: unintentional weight loss, exhaustion, muscle weakness, slow walking speed, or low levels of activity. The Clinical Frailty Scale^10,11 and the Frailty Assessment for Care-planning Tool (FACT)⁵ use deficits in cognition, function, and mobility to define frailty. According to these scales, people are considered severely frail when they require assistance with basic activities of daily living (such as bathing or dressing), owing to cognitive or physical deficits from any cause.

In reviewing the evidence, we consider five questions:

• What is the quality of the evidence? (Up to 48% of clinical practice guideline recommendations may be based on low-level evidence or expert opinion.¹²)
• How did the study population compare with the frail?
• Are study outcomes and potential benefits clinically relevant to those who are frail?
• How long did it take for the clinical benefit of a treatment to become apparent, and are the frail elderly likely to live that long?
• Have the harms of treatment been sufficiently considered?

WHAT IS THE QUALITY OF THE EVIDENCE?

We found no studies that specifically evaluated the benefit of lipid-lowering for severely frail older adults. Therefore, we examined randomized controlled trials that enrolled non-frail older adults,^13–28 subgroup analyses of randomized controlled trials,^29,30 meta-analyses that analyzed subgroups of elderly populations,^31,32 and publications describing the study designs of randomized controlled trials.^33–37

Most of the evidence comes from post hoc subgroup analyses of elderly populations. Although meta-analysis is commonly used to compare subgroups, the Cochrane handbook and others consider subgroup comparisons observational by nature.^38,39 (See Table 1 for lipid-lowering studies discussed in this article.)

Studies of statins for primary prevention of cardiovascular disease

For evidence of benefit from lipid-lowering for primary prevention (ie, to reduce the risk of cardiovascular events in patients with no known cardiovascular disease at baseline but at increased risk), we reviewed the meta-analysis conducted by the Cholesterol Treatment Trialists’ (CTT) Collaborators.³² Since this meta-analysis included the major trials that enrolled elderly patients, individual publications of post hoc, elderly subgroups were, for the most part, not examined individually. The exception to this approach was a decision to report on the PROSPER¹³ and JUPITER²⁸ trials separately, because PROSPER is the most representative of the elderly population and JUPITER reached the lowest LDL-C of primary prevention trials published to date and included a large elderly subgroup (n = 5,695).

Savarese et al⁴⁰ evaluated the benefits of statins for older adults who did not have established cardiovascular disease. We did not report on this meta-analysis, as not all of the subjects that populated the meta-analysis were representative of a typical prevention population. For instance, in the Anglo-Scandinavian Cardiac Outcomes Trial lipid-lowering arm,⁴¹ 14% of the subjects had had a previous stroke or transient ischemic attack. In the Antihypertensive and Lipid-Lowering Treatment Trial,⁴² 16% of the population had a family history of premature coronary heart disease.

In addition, all the trials in the Savarese meta-analysis were also included in the CTT meta-analysis.³² The CTT reports on baseline risk using patient-level data stratified by age and risk, which may be more relevant to the question of primary prevention for older adults, as highlighted in our review.

PROSPER (Prospective Study of Pravastatin in the Elderly at Risk),¹³ a well-conducted, double-blind, randomized controlled trial with low probability of bias, compared pravastatin 40 mg and placebo. It was the only study that specifically enrolled older adults, with prespecified analysis of primary and secondary prevention subgroups. The primary prevention subgroup accounted for 56% of the 5,084 participants.

JUPITER (Justification for the Use of Statins in Prevention)²⁸ compared rosuvastatin 20 mg and placebo in 17,802 participants. All had low-density lipoprotein cholesterol (LDL-C) levels below 3.4 mmol/L (130 mg/dL) and elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP), ie, 2 mg/L or higher. Subsequently, Glynn et al performed a post hoc, exploratory subgroup analysis of elderly participants (N = 5,695).²⁹

The JUPITER trial had several limitations.^43,44 The planned follow-up period was 5 years, but the trial was stopped early at 1.9 years, after a statistically significant difference was detected in the primary composite outcome of reduction in all vascular events. Studies that are stopped early may exaggerate positive findings.⁴⁵

Further, JUPITER’s patients were a select group, with normal LDL-C levels, elevated hsCRP values, and without diabetes. Of 90,000 patients screened, 72,000 (80%) did not meet the inclusion criteria and were not enrolled. This high rate of exclusion limits the generalizability of study findings beyond the shortcomings of post hoc subgroup analysis.

The meta-analysis performed by the CTT Collaborators³² used individual participant data from large-scale randomized trials of lipid-modifying treatment. This analysis was specific to people at low risk of vascular disease. In a supplementary appendix, the authors described the reduction in major vascular events for each 1.0 mmol/L decrease in LDL-C in three age categories: under age 60, ages 61 to 70, and over age 70.

The authors also stratified the results by risk category and provided information about those with a risk of major vascular events of less than 20%, which would be more representative of a purer primary prevention population.

For the elderly subgroup at low risk, the CTT Collaborators³² only reported a composite of major vascular events (coronary death, nonfatal myocardial infarction [MI], ischemic stroke, or revascularization) and did not describe individual outcomes, such as prevention of coronary heart disease.

Study results are based on postrandomization findings and therefore may be observational, not experimental.⁴⁶

Studies of statins for secondary prevention of cardiovascular disease

The aim of secondary prevention is to reduce the risk of recurrent cardiovascular events in patients who already have cardiovascular disease.

To address the question of whether statins reduce cardiovascular risk, we reviewed:

PROSPER,¹³ which included a preplanned analysis of the secondary prevention population.

Afilalo et al,^31,47 who performed a meta-analysis of the elderly subgroups of nine major secondary prevention studies (19,569 patients) using published and unpublished data.

To address the question of whether statins benefit individuals with heart failure, we found two relevant studies:

GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca Heart Failure)²⁵ and CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure),²⁶ which were large, international, well-conducted randomized controlled trials that examined statin use in heart failure.

To answer the question of whether statins benefit individuals after a stroke or transient ischemic attack, we found one relevant study:

SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels),²⁷ which evaluated the benefit of statins in older adults with a history of stroke or transient ischemic attack. It was a prospective, double-blind, placebo-controlled, international trial conducted at 205 centers. One to 6 months after their cerebrovascular event, patients were randomized to receive either atorvastatin 80 mg or placebo. Given the young age of patients in this trial (mean age 63), we also reviewed a post hoc subgroup analysis of the elderly patients in SPARCL (age > 65).³⁰

HOW DID THE STUDY POPULATION COMPARE WITH THOSE WHO ARE FRAIL?

Frail older adults are almost always excluded from large-scale clinical trials,⁴⁸ leading to uncertainty about whether the conclusions can be applied to those with advanced frailty.

Although age is an imperfect proxy measure of frailty,⁴⁹ we consider the age of the study population as well as their comorbidities.

Participants in the studies we reviewed were generally younger and healthier than those who are frail, with mean ages of about 75 or less (Table 1).

PROSPER was the most representative study, as it specifically enrolled older adults, albeit without frailty,¹³ and excluded people with poor cognitive function as defined by a Mini Mental State Examination score less than 24.

JUPITER enrolled a select population, as described above. The median age in the elderly subgroup was 74 (interquartile range 72–78).²⁹

The Afilalo et al³¹ meta-analysis primarily included studies of young-elderly patients, with a mean age of less than 70. PROSPER¹³ was an exception.

The GISSI-HF study,²⁵ which examined the benefit of statins in heart failure, described their study population as frail, although the mean age was only 68. Compared with those in GISSI-HF, the CORONA patients²⁶ with heart failure were older (mean age 73) and had more severe heart failure. Accordingly, it is possible that many of the CORONA participants were frail.

ARE STUDY OUTCOMES CLINICALLY RELEVANT TO THOSE WHO ARE FRAIL?

Because baseline cardiovascular risk increases with age, the elderly should, in theory, experience greater absolute benefit from lipid-lowering. However, there is uncertainty about whether this is true in practice.

Some, but not all, epidemiologic studies show a weaker relationship between cholesterol levels and cardiovascular morbidity and mortality rates in older compared to younger adults.^50,51 This may be because those with high cholesterol levels die before they get old (time-related bias), or because those with life-threatening illness may have lower cholesterol levels.⁵⁰ In addition, classic risk factors such as age, sex, systolic blood pressure, cholesterol values, diabetes, smoking, and left ventricular hypertrophy on electrocardiography may have less power to predict cardiovascular risk among older patients.⁵²

The goal of treatment in frailty is to prevent further disability or improve quality of life. Therefore, meaningful outcomes for lipid-lowering therapy should include symptomatic nonfatal MI and its associated morbidity (eg, heart failure and persistent angina) or symptomatic nonfatal stroke leading to disability. Outcomes without sustained clinical impact, such as transient ischemic attack, nondisabling stroke, or silent MI, while potentially important in other populations, are less relevant in severe frailty. Notably, in many statin studies, outcomes include asymptomatic heart disease (eg, silent MI and “suspected events”) and nondisabling stroke (eg, mild stroke, transient ischemic attack). When symptomatic outcomes are not reported separately, the impact of the reported benefit on quality of life and function is uncertain.

The outcome of all-cause mortality is generally recognized as a gold standard for determining treatment benefit. However, since advanced frailty is characterized by multiple competing causes for mortality, a reduction in all-cause mortality that is achieved by addressing a single issue in nonfrail populations may not extend to the frail.

To more fully understand the impact of lipid-lowering therapy on quality of life and function, we examined the following questions:

Do statins as primary prevention reduce symptomatic heart disease?

Outcomes for coronary heart disease from PROSPER and JUPITER are summarized in Table 2.

PROSPER. In the PROSPER primary prevention group,¹³ statin therapy did not reduce the combined outcome of coronary heart disease death and nonfatal MI.

The JUPITER trial demonstrated a statistically significant benefit for preventing MI in the elderly subpopulation (ages 70–97),²⁹ but the number needed to treat was high (211 for 2 years), with a wide confidence interval (CI) (95% CI 106–32,924). The trial did not adequately differentiate between symptomatic and asymptomatic events, making it difficult to determine outcome relevance. Also, due to the methodologic limitations of JUPITER as described above, its results should be interpreted with caution.^43,44

The CTT Collaborators³² did not report individual outcomes (eg, coronary heart disease) for the elderly low-risk subgroup and, therefore, this meta-analysis does not answer the question of whether statins reduce symptomatic heart disease in primary prevention populations.

Taken together, these findings do not provide convincing evidence that statin therapy as primary prevention reduces the incidence of symptomatic heart disease for severely frail older adults.

Do statins as secondary prevention reduce symptomatic heart disease?

Most studies defined secondary prevention narrowly as treatment for patients with established coronary artery disease. For instance, in the Afilalo et al meta-analysis,³¹ the small number of studies that included individuals with other forms of vascular disease (such as peripheral vascular disease) enrolled few participants with noncardiac conditions (eg, 29% in PROSPER¹³ and 13% in the Heart Protection Study²⁰).

Therefore, any evidence of benefit for secondary prevention demonstrated in these studies is most applicable to patients with coronary heart disease, with less certainty for those with other forms of cardiovascular disease.

In PROSPER,¹³ the secondary prevention group experienced benefit in the combined outcome of coronary heart disease death or nonfatal MI. In the treatment group, 12.7% experienced this outcome compared with 16.8% with placebo, an absolute risk reduction of 4.1% in 3 years (P = .004, number needed to treat 25, 95% CI 15–77). This measure includes coronary heart disease death, an outcome that may not be generalizable to those who are frail. In addition, the outcome of nonfatal MI includes both symptomatic and suspected events. As such, there is uncertainty whether the realized benefit is clinically relevant to frail older adults.

The Afilalo et al meta-analysis³¹ showed that the number needed to treat to prevent one nonfatal MI was 38 (95% CI 16–118) over 5 years (Table 2). However, this outcome included both symptomatic and asymptomatic (silent) events.

Based on the available data, we conclude that it is not possible to determine whether statins reduce symptomatic heart disease as secondary prevention for older adults who are frail.

Do statins reduce heart disease in combined populations?

In the combined primary and secondary population from PROSPER,¹³ pravastatin decreased the risk of nonfatal symptomatic MI from 4.3% in the placebo group to 3.4%, a relatively small reduction in absolute risk (0.9%) and not statistically significant by our chi-square calculation (P = .099).

Do statins prevent a first symptomatic stroke in people with or without preexisting cardiovascular disease?

Preventing strokes that cause functional decline is an important outcome for the frail elderly. Stroke outcomes from PROSPER,¹³ JUPITER,²⁹ and the Afilalo et al meta-analysis³¹ are summarized in Table 3.

For primary prevention:

In PROSPER (primary prevention),¹³ there was no statistically significant benefit in the combined outcome of fatal and nonfatal stroke or the single outcome of transient ischemic attack after 3.2 years.

JUPITER,²⁹ in contrast, found that rosuvastatin 20 mg reduced strokes in primary prevention, but the absolute benefit was small. In 2 years, 0.8% of the treatment group had strokes, compared with 1.4% with placebo, an absolute risk reduction of 0.6% (P = .023, number needed to treat 161, 95% CI 86–1,192).

Neither PROSPER nor JUPITER differentiated between disabling and nondisabling strokes.

For secondary prevention:

In PROSPER (secondary prevention),¹³ there was no statistically significant benefit in the combined outcome of fatal and nonfatal stroke or the single outcome of transient ischemic attack after 3.2 years.

The Afilalo et al secondary prevention meta-analysis demonstrated a 25% relative reduction in stroke (relative risk 0.75, 95% CI 0.56–0.94, number needed to treat 58, 95% CI 27–177).³¹

Notably, the stroke outcome in Afilalo included both disabling and nondisabling strokes. For example, in the Heart Protection Study,²⁰ the largest study in the Afilalo et al meta-analysis, approximately 50% of nonfatal, classifiable strokes in the overall study population (ie, both younger and older patients) were not disabling. Including disabling and nondisabling strokes in a composite outcome confounds the clinical meaningfulness of these findings in frailty, as the number needed to treat to prevent one disabling stroke cannot be calculated from the data provided.

Do statins prevent a second (symptomatic) stroke in people with a previous stroke?

SPARCL²⁷ (Table 3) examined the question of whether statins decrease the risk of recurrent ischemic stroke for patients with a prior history of stroke or transient ischemic attack. There was a statistically significant reduction in the primary composite outcome of fatal and nonfatal stroke, with 11.2% of the treatment group and 13.1% of the placebo group experiencing this outcome, an absolute risk reduction of 1.9% at 5 years (P = .03; number needed to treat 52, 95% CI 26–1,303). However, the difference in nonfatal stroke, which is the outcome of interest for frailty (since mortality has uncertain relevance), was not statistically significant (10.4% with treatment vs 11.8% with placebo, P =.11).

An exploratory subgroup analysis of SPARCL patients based on age³⁰ showed a smaller, nonsignificant reduction in the primary end point of fatal and nonfatal stroke in the group over age 65 (relative risk 0.90, 95% confidence interval 0.73–1.11, P = .33) compared with the younger group (age < 65) (relative risk 0.74, 95% CI 0.57–0.96, P = .02).

The applicability of these results to the frail elderly is uncertain, since the subgroup analysis was not powered to determine outcomes based on age stratification and there were differences between groups in characteristics such as blood pressure and smoking status. In addition, the outcome of interest, nonfatal stroke, is not provided for the elderly subgroup.

In conclusion, in both primary and secondary prevention populations, the evidence that statins reduce nonfatal, symptomatic stroke rates for older adults is uncertain.

Do statins decrease all-cause mortality for primary or secondary prevention?

Due to competing risks for death, the outcome of mortality may not be relevant to those who are frail; however, studies showed the following:

For primary prevention, there was no decrease in mortality in PROSPER¹³ or in the elderly subgroup of JUPITER.²⁹

For secondary prevention, an analysis of PROSPER trial data by Afilalo et al³¹ showed a significant 18% decrease in all-cause mortality (relative risk 0.82, 95% CI 0.69–0.98) using pravastatin 40 mg.

A decrease in all-cause mortality with statins was also reported in the pooled result of the Afilalo et al meta-analysis.³¹

What are the reported composite outcomes for primary and secondary prevention?

While we were most interested in the symptomatic outcomes described above, we recognize that the small numbers of events make it difficult to draw firm conclusions. Therefore, we also considered composite primary outcomes, even though most included multiple measures that have varying associations with disability and relevancy to frail older adults.

For primary prevention, in the PROSPER preplanned subgroup analysis,¹³ there was no statistical benefit for any outcome, including the primary composite measure. In contrast, the elderly subpopulation in the JUPITER trial²⁸ showed a treatment benefit with rosuvastatin 20 mg compared with placebo for the primary composite outcome of MI, stroke, cardiovascular death, hospitalization for unstable angina, or revascularization. The number needed to treat for 2 years was 62 (95% CI 39–148).

In the CTT meta-analysis,³² patients at all levels of baseline risk showed benefit up to age 70. However, there was no statistically significant benefit in the composite primary outcome of coronary deaths, nonfatal myocardial infarction, ischemic stroke, or revascularization in the population most representative of elderly primary prevention—those who were more than 70 years old with a 5-year baseline risk of less than 20%.

For secondary prevention, in PROSPER,¹³ the subpopulation of patients treated for secondary prevention experienced benefit in the primary composite outcome of coronary heart disease death, nonfatal MI, or fatal or nonfatal stroke, achieving a 4% absolute risk reduction with a number needed to treat of 23 (95% CI 14–81) over 3 years.

Do statins decrease disability?

PROSPER was the only study that reported on disability. Compared with placebo, pravastatin did not decrease disability in the total population as measured by basic and instrumental activities of daily living scales.

Do statins help patients with heart failure?

Neither GISSI-HF²⁵ nor CORONA²⁶ found significant benefit from rosuvastatin 10 mg, despite LDL-C lowering of 27% in GISSI-HF and 45% in CORONA.

Do ezetimibe or other nonstatin lipid-lowering agents improve outcomes?

There is no definitive evidence that ezetimibe provides clinically meaningful benefit as a single agent.

For combination therapy, the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)⁵³ showed that adding ezetimibe 10 mg to simvastatin 40 mg after an acute coronary syndrome reduced the risk of nonfatal myocardial infarction compared with simvastatin monotherapy (event rate 12.8% vs 14.4%; hazard ratio 0.87, 95% CI 0.80–0.95; P = .002) for a population with a mean age of 64. The risk of any stroke was also reduced; strokes occurred in 4.2% of those receiving combination therapy vs 4.8% with monotherapy (hazard ratio 0.86, 95% CI 0.73–1.00, P = .05). After a median of 6 years, 42% of patients in each group had discontinued treatment. Given the very specific clinical scenario of acute coronary syndrome and the young age of the patients in this trial, we do not think that this study justifies the use of ezetimibe for severely frail older adults.

There is no evidence that other combinations (ie, a statin plus another lipid-lowering drug) improve clinical outcomes for either primary or secondary prevention in any population.⁵⁴

WILL FRAIL PATIENTS LIVE LONG ENOUGH TO BENEFIT?

It is often difficult to determine the number of years that are needed to achieve benefit, as most trials do not provide a statistical analysis of varying time frames.

The PROSPER trial¹³ lasted 3.2 years. From the Kaplan-Meier curves in PROSPER, we estimate that it took about 1.5 years to achieve a 1% absolute risk reduction and 2.5 years for a 2% absolute risk reduction in coronary heart disease death and nonfatal MI in the combined primary and secondary groups.

JUPITER²⁸ was stopped early at 1.9 years. The Afilalo et al meta-analysis³¹ was based on follow-up over 4.9 years.

IMPROVE-IT⁵³ reported event rates at 7 years. The authors note that benefit in the primary composite outcome appeared to emerge at 1 year, although no statistical support is given for this statement and divergence in the Kaplan-Meier curves is not visually apparent.

The duration of other studies ranged between 2.7 and 4.9 years (Table 1).^26–28

It has been suggested that statins should be considered for elderly patients who have a life expectancy of at least 5 years.³ However, many older adults have already been taking statins for many years, which makes it difficult to interpret the available timeframe evidence.

In a multicenter, unblinded, randomized trial,⁵⁵ statins were either stopped or continued in older adults who had a short life expectancy and a median survival of approximately 7 months. Causes of death were evenly divided between cancer and noncancer diagnoses, and 22% of the patients were cognitively impaired. Discontinuing statin therapy did not increase mortality or cardiovascular events within 60 days. Nevertheless, stopping statin therapy did not achieve noninferiority for the primary end point, the proportion of participants who died within 60 days. Statin discontinuation was associated with improved quality of life, although the study was not blinded, which could have influenced results.

HAVE THE HARMS BEEN SUFFICIENTLY CONSIDERED?

Frail older adults commonly take multiple medications and are more vulnerable to adverse events.⁵⁶

Many statins require dose reduction with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m²), which would be a common consideration in severely frail older adults.

Myopathy

Myopathy, which includes myalgias and muscle weakness, is a statin-related adverse event that can impair quality of life. Myopathy typically develops within the first 6 months but can occur at any time during statin treatment.⁵⁷ When muscle-related adverse effects occur, they may affect the elderly more significantly, particularly their ability to perform activities of daily living, rise from a chair, or mobilize independently. Another concern is that older adults with dementia may not be able to accurately report muscle-related symptoms.

It is difficult to ascertain the true prevalence of myopathy, especially in advanced age and frailty. Randomized controlled trials report incidence rates of 1.5% to 5%, which is comparable to placebo.^57,58 However, inconsistent definitions of myopathy and exclusion of subjects with previous statin intolerance or adverse effects during run-in periods limit interpretability.⁵⁷ Clinical experience suggests that muscle complaints may be relatively common.^59–61

Advanced age, female sex, low body mass index, and multisystem disease are all associated with frailty and have also been described as risk factors for statin-associated muscle syndromes.⁶¹ Physiologic changes associated with frailty, such as reduced muscle strength, decreased lean body mass, impaired functional mobility, decreased reserve capacity, and altered drug metabolism may increase the risk and severity of myopathy.⁶²

Adverse cognitive events

Meta-analyses of randomized clinical trials and narrative reviews find no definitive relationship between statin therapy and adverse cognitive events.^63–67 Nevertheless, there have been case reports of memory loss associated with the use of statins, and the US Food and Drug Administration has issued a warning that statins have been associated with memory loss and confusion.⁶⁸

It may be difficult to determine whether a statin is causing or aggravating cognitive symptoms among individuals with dementia without a trial withdrawal of the drug.

OUR RECOMMENDATIONS

The recommendations below are intended for adults with severe or very severe frailty (ie, a score of 7 or 8 on the Clinical Frailty Scale¹¹ or FACT⁵ and therefore apply to most older adults living in long-term care facilities.

Primary prevention

There is no reason to prescribe or continue statins for primary prevention, as it is unlikely that they would provide benefit for outcomes that are relevant in this population.

Secondary prevention

Statin treatment is probably not necessary for secondary prevention in those with severe frailty, although there may be extenuating circumstances that justify statin use.

Heart failure

There is no reason to start or continue statins for heart failure, as there is insufficient evidence that they are effective for this indication in any population.

Ezetimibe

There is no evidence that ezetimibe reduces cardiovascular events in any population when used as monotherapy. For a select population with acute coronary syndromes, ezetimibe has a modest effect. Given the very specific clinical scenario of acute coronary syndrome, we do not think that the available evidence justifies the use of ezetimibe for severely frail older adults.

Agents other than ezetimibe combined with statins

There is no reason to start or continue other lipid-lowering drugs in conjunction with statins.

Statin dosing

As statin adverse effects have the potential to increase with advancing age and frailty, lower doses may be appropriate.⁶⁸

Adverse events

Consider stopping statins on a trial basis if there is concern regarding myopathy, drug interactions, or other adverse effects.

BOTTOM LINE: DO STATINS IMPROVE QUALITY OF LIFE OR FUNCTION?

In primary prevention for older adults, there is doubt that statins prevent cardiovascular disease and stroke-related events because the main study involving the elderly did not show a benefit in the primary prevention subgroup.¹³ Additionally, there is no conclusive evidence that statin treatment decreases mortality in primary prevention.^13,29

There is insufficient information to determine whether the frail elderly should receive statins for secondary prevention. Although there is evidence that treatment decreases measures of coronary heart disease and stroke, it is unclear whether it improves quality of life or function for those who are frail. To answer this question, we need more information about whether reported outcomes (such as stroke and MI) are associated with disability, which is not provided in many of the studies we reviewed. When disability was specifically considered in the PROSPER trial for the combined population of primary and secondary prevention, treatment with statins had no impact on basic and instrumental activities of daily living.

Some experts may not agree with our interpretation of the complex evidence presented in this article. Others may ask, “What is the harm in using statins, even if there is no definitive benefit?” However, the harms associated with statin therapy for the frail are poorly defined. In the face of these uncertainties and in the absence of definitive improvement in quality of life, we believe that “less is more” in the context of severe frailty.⁶⁹

The cost of medications should also be considered, especially in long-term care facilities, where there is an added expense of drug administration that diverts human resources away from interactions that are more congruent with respecting the lifestage of frailty.

Careful review of evidence before applying clinical practice guidelines to those who are frail should become the norm. When considering treatment of frail patients, the five questions described in this review shed light on the applicability of clinical trial evidence. Therapies that are highly effective in healthier populations may be less effective when individuals are severely frail. Accordingly, we propose that medications should only be used if they improve quality of life or function.

Frail elderly patients are at high risk of adverse clinical outcomes, including those due to polypharmacy. Several groups tackle “deprescribing” by developing lists of medications that are potentially inappropriate for the elderly, such as the Beers or STOPP/START criteria.^1–4

In contrast, our group (the Palliative and Therapeutic Harmonization [PATH] program and the Dalhousie Academic Detailing Service) has developed evidence-based, frailty-specific guidelines for treating hypertension⁵ and diabetes,⁶ in which we advocate less-stringent treatment targets and tapering or discontinuing medications, as needed.

The PATH program⁷ is a clinical approach that prioritizes the consideration of frailty when making treatment decisions. The Dalhousie Academic Detailing Service collaborates with the Nova Scotia Health Authority to research and develop evidence-informed educational messages about the treatment of common medical conditions.

Here, we address lipid-lowering therapy in this population.

CONSIDERING FRAILTY

Frailty is defined in several ways. The Fried model^8,9 identifies frailty when 3 of the following characteristics are present: unintentional weight loss, exhaustion, muscle weakness, slow walking speed, or low levels of activity. The Clinical Frailty Scale^10,11 and the Frailty Assessment for Care-planning Tool (FACT)⁵ use deficits in cognition, function, and mobility to define frailty. According to these scales, people are considered severely frail when they require assistance with basic activities of daily living (such as bathing or dressing), owing to cognitive or physical deficits from any cause.

In reviewing the evidence, we consider five questions:

• What is the quality of the evidence? (Up to 48% of clinical practice guideline recommendations may be based on low-level evidence or expert opinion.¹²)
• How did the study population compare with the frail?
• Are study outcomes and potential benefits clinically relevant to those who are frail?
• How long did it take for the clinical benefit of a treatment to become apparent, and are the frail elderly likely to live that long?
• Have the harms of treatment been sufficiently considered?

WHAT IS THE QUALITY OF THE EVIDENCE?

We found no studies that specifically evaluated the benefit of lipid-lowering for severely frail older adults. Therefore, we examined randomized controlled trials that enrolled non-frail older adults,^13–28 subgroup analyses of randomized controlled trials,^29,30 meta-analyses that analyzed subgroups of elderly populations,^31,32 and publications describing the study designs of randomized controlled trials.^33–37

Most of the evidence comes from post hoc subgroup analyses of elderly populations. Although meta-analysis is commonly used to compare subgroups, the Cochrane handbook and others consider subgroup comparisons observational by nature.^38,39 (See Table 1 for lipid-lowering studies discussed in this article.)

Studies of statins for primary prevention of cardiovascular disease

For evidence of benefit from lipid-lowering for primary prevention (ie, to reduce the risk of cardiovascular events in patients with no known cardiovascular disease at baseline but at increased risk), we reviewed the meta-analysis conducted by the Cholesterol Treatment Trialists’ (CTT) Collaborators.³² Since this meta-analysis included the major trials that enrolled elderly patients, individual publications of post hoc, elderly subgroups were, for the most part, not examined individually. The exception to this approach was a decision to report on the PROSPER¹³ and JUPITER²⁸ trials separately, because PROSPER is the most representative of the elderly population and JUPITER reached the lowest LDL-C of primary prevention trials published to date and included a large elderly subgroup (n = 5,695).

Savarese et al⁴⁰ evaluated the benefits of statins for older adults who did not have established cardiovascular disease. We did not report on this meta-analysis, as not all of the subjects that populated the meta-analysis were representative of a typical prevention population. For instance, in the Anglo-Scandinavian Cardiac Outcomes Trial lipid-lowering arm,⁴¹ 14% of the subjects had had a previous stroke or transient ischemic attack. In the Antihypertensive and Lipid-Lowering Treatment Trial,⁴² 16% of the population had a family history of premature coronary heart disease.

In addition, all the trials in the Savarese meta-analysis were also included in the CTT meta-analysis.³² The CTT reports on baseline risk using patient-level data stratified by age and risk, which may be more relevant to the question of primary prevention for older adults, as highlighted in our review.

PROSPER (Prospective Study of Pravastatin in the Elderly at Risk),¹³ a well-conducted, double-blind, randomized controlled trial with low probability of bias, compared pravastatin 40 mg and placebo. It was the only study that specifically enrolled older adults, with prespecified analysis of primary and secondary prevention subgroups. The primary prevention subgroup accounted for 56% of the 5,084 participants.

JUPITER (Justification for the Use of Statins in Prevention)²⁸ compared rosuvastatin 20 mg and placebo in 17,802 participants. All had low-density lipoprotein cholesterol (LDL-C) levels below 3.4 mmol/L (130 mg/dL) and elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP), ie, 2 mg/L or higher. Subsequently, Glynn et al performed a post hoc, exploratory subgroup analysis of elderly participants (N = 5,695).²⁹

The JUPITER trial had several limitations.^43,44 The planned follow-up period was 5 years, but the trial was stopped early at 1.9 years, after a statistically significant difference was detected in the primary composite outcome of reduction in all vascular events. Studies that are stopped early may exaggerate positive findings.⁴⁵

Further, JUPITER’s patients were a select group, with normal LDL-C levels, elevated hsCRP values, and without diabetes. Of 90,000 patients screened, 72,000 (80%) did not meet the inclusion criteria and were not enrolled. This high rate of exclusion limits the generalizability of study findings beyond the shortcomings of post hoc subgroup analysis.

The meta-analysis performed by the CTT Collaborators³² used individual participant data from large-scale randomized trials of lipid-modifying treatment. This analysis was specific to people at low risk of vascular disease. In a supplementary appendix, the authors described the reduction in major vascular events for each 1.0 mmol/L decrease in LDL-C in three age categories: under age 60, ages 61 to 70, and over age 70.

The authors also stratified the results by risk category and provided information about those with a risk of major vascular events of less than 20%, which would be more representative of a purer primary prevention population.

For the elderly subgroup at low risk, the CTT Collaborators³² only reported a composite of major vascular events (coronary death, nonfatal myocardial infarction [MI], ischemic stroke, or revascularization) and did not describe individual outcomes, such as prevention of coronary heart disease.

Study results are based on postrandomization findings and therefore may be observational, not experimental.⁴⁶

Studies of statins for secondary prevention of cardiovascular disease

The aim of secondary prevention is to reduce the risk of recurrent cardiovascular events in patients who already have cardiovascular disease.

To address the question of whether statins reduce cardiovascular risk, we reviewed:

PROSPER,¹³ which included a preplanned analysis of the secondary prevention population.

Afilalo et al,^31,47 who performed a meta-analysis of the elderly subgroups of nine major secondary prevention studies (19,569 patients) using published and unpublished data.

To address the question of whether statins benefit individuals with heart failure, we found two relevant studies:

GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca Heart Failure)²⁵ and CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure),²⁶ which were large, international, well-conducted randomized controlled trials that examined statin use in heart failure.

To answer the question of whether statins benefit individuals after a stroke or transient ischemic attack, we found one relevant study:

SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels),²⁷ which evaluated the benefit of statins in older adults with a history of stroke or transient ischemic attack. It was a prospective, double-blind, placebo-controlled, international trial conducted at 205 centers. One to 6 months after their cerebrovascular event, patients were randomized to receive either atorvastatin 80 mg or placebo. Given the young age of patients in this trial (mean age 63), we also reviewed a post hoc subgroup analysis of the elderly patients in SPARCL (age > 65).³⁰

HOW DID THE STUDY POPULATION COMPARE WITH THOSE WHO ARE FRAIL?

Frail older adults are almost always excluded from large-scale clinical trials,⁴⁸ leading to uncertainty about whether the conclusions can be applied to those with advanced frailty.

Although age is an imperfect proxy measure of frailty,⁴⁹ we consider the age of the study population as well as their comorbidities.

Participants in the studies we reviewed were generally younger and healthier than those who are frail, with mean ages of about 75 or less (Table 1).

PROSPER was the most representative study, as it specifically enrolled older adults, albeit without frailty,¹³ and excluded people with poor cognitive function as defined by a Mini Mental State Examination score less than 24.

JUPITER enrolled a select population, as described above. The median age in the elderly subgroup was 74 (interquartile range 72–78).²⁹

The Afilalo et al³¹ meta-analysis primarily included studies of young-elderly patients, with a mean age of less than 70. PROSPER¹³ was an exception.

The GISSI-HF study,²⁵ which examined the benefit of statins in heart failure, described their study population as frail, although the mean age was only 68. Compared with those in GISSI-HF, the CORONA patients²⁶ with heart failure were older (mean age 73) and had more severe heart failure. Accordingly, it is possible that many of the CORONA participants were frail.

ARE STUDY OUTCOMES CLINICALLY RELEVANT TO THOSE WHO ARE FRAIL?

Because baseline cardiovascular risk increases with age, the elderly should, in theory, experience greater absolute benefit from lipid-lowering. However, there is uncertainty about whether this is true in practice.

Some, but not all, epidemiologic studies show a weaker relationship between cholesterol levels and cardiovascular morbidity and mortality rates in older compared to younger adults.^50,51 This may be because those with high cholesterol levels die before they get old (time-related bias), or because those with life-threatening illness may have lower cholesterol levels.⁵⁰ In addition, classic risk factors such as age, sex, systolic blood pressure, cholesterol values, diabetes, smoking, and left ventricular hypertrophy on electrocardiography may have less power to predict cardiovascular risk among older patients.⁵²

The goal of treatment in frailty is to prevent further disability or improve quality of life. Therefore, meaningful outcomes for lipid-lowering therapy should include symptomatic nonfatal MI and its associated morbidity (eg, heart failure and persistent angina) or symptomatic nonfatal stroke leading to disability. Outcomes without sustained clinical impact, such as transient ischemic attack, nondisabling stroke, or silent MI, while potentially important in other populations, are less relevant in severe frailty. Notably, in many statin studies, outcomes include asymptomatic heart disease (eg, silent MI and “suspected events”) and nondisabling stroke (eg, mild stroke, transient ischemic attack). When symptomatic outcomes are not reported separately, the impact of the reported benefit on quality of life and function is uncertain.

The outcome of all-cause mortality is generally recognized as a gold standard for determining treatment benefit. However, since advanced frailty is characterized by multiple competing causes for mortality, a reduction in all-cause mortality that is achieved by addressing a single issue in nonfrail populations may not extend to the frail.

To more fully understand the impact of lipid-lowering therapy on quality of life and function, we examined the following questions:

Do statins as primary prevention reduce symptomatic heart disease?

Outcomes for coronary heart disease from PROSPER and JUPITER are summarized in Table 2.

PROSPER. In the PROSPER primary prevention group,¹³ statin therapy did not reduce the combined outcome of coronary heart disease death and nonfatal MI.

The JUPITER trial demonstrated a statistically significant benefit for preventing MI in the elderly subpopulation (ages 70–97),²⁹ but the number needed to treat was high (211 for 2 years), with a wide confidence interval (CI) (95% CI 106–32,924). The trial did not adequately differentiate between symptomatic and asymptomatic events, making it difficult to determine outcome relevance. Also, due to the methodologic limitations of JUPITER as described above, its results should be interpreted with caution.^43,44

The CTT Collaborators³² did not report individual outcomes (eg, coronary heart disease) for the elderly low-risk subgroup and, therefore, this meta-analysis does not answer the question of whether statins reduce symptomatic heart disease in primary prevention populations.

Taken together, these findings do not provide convincing evidence that statin therapy as primary prevention reduces the incidence of symptomatic heart disease for severely frail older adults.

Do statins as secondary prevention reduce symptomatic heart disease?

Most studies defined secondary prevention narrowly as treatment for patients with established coronary artery disease. For instance, in the Afilalo et al meta-analysis,³¹ the small number of studies that included individuals with other forms of vascular disease (such as peripheral vascular disease) enrolled few participants with noncardiac conditions (eg, 29% in PROSPER¹³ and 13% in the Heart Protection Study²⁰).

Therefore, any evidence of benefit for secondary prevention demonstrated in these studies is most applicable to patients with coronary heart disease, with less certainty for those with other forms of cardiovascular disease.

In PROSPER,¹³ the secondary prevention group experienced benefit in the combined outcome of coronary heart disease death or nonfatal MI. In the treatment group, 12.7% experienced this outcome compared with 16.8% with placebo, an absolute risk reduction of 4.1% in 3 years (P = .004, number needed to treat 25, 95% CI 15–77). This measure includes coronary heart disease death, an outcome that may not be generalizable to those who are frail. In addition, the outcome of nonfatal MI includes both symptomatic and suspected events. As such, there is uncertainty whether the realized benefit is clinically relevant to frail older adults.

The Afilalo et al meta-analysis³¹ showed that the number needed to treat to prevent one nonfatal MI was 38 (95% CI 16–118) over 5 years (Table 2). However, this outcome included both symptomatic and asymptomatic (silent) events.

Based on the available data, we conclude that it is not possible to determine whether statins reduce symptomatic heart disease as secondary prevention for older adults who are frail.

Do statins reduce heart disease in combined populations?

In the combined primary and secondary population from PROSPER,¹³ pravastatin decreased the risk of nonfatal symptomatic MI from 4.3% in the placebo group to 3.4%, a relatively small reduction in absolute risk (0.9%) and not statistically significant by our chi-square calculation (P = .099).

Do statins prevent a first symptomatic stroke in people with or without preexisting cardiovascular disease?

Preventing strokes that cause functional decline is an important outcome for the frail elderly. Stroke outcomes from PROSPER,¹³ JUPITER,²⁹ and the Afilalo et al meta-analysis³¹ are summarized in Table 3.

For primary prevention:

In PROSPER (primary prevention),¹³ there was no statistically significant benefit in the combined outcome of fatal and nonfatal stroke or the single outcome of transient ischemic attack after 3.2 years.

JUPITER,²⁹ in contrast, found that rosuvastatin 20 mg reduced strokes in primary prevention, but the absolute benefit was small. In 2 years, 0.8% of the treatment group had strokes, compared with 1.4% with placebo, an absolute risk reduction of 0.6% (P = .023, number needed to treat 161, 95% CI 86–1,192).

Neither PROSPER nor JUPITER differentiated between disabling and nondisabling strokes.

For secondary prevention:

In PROSPER (secondary prevention),¹³ there was no statistically significant benefit in the combined outcome of fatal and nonfatal stroke or the single outcome of transient ischemic attack after 3.2 years.

The Afilalo et al secondary prevention meta-analysis demonstrated a 25% relative reduction in stroke (relative risk 0.75, 95% CI 0.56–0.94, number needed to treat 58, 95% CI 27–177).³¹

Notably, the stroke outcome in Afilalo included both disabling and nondisabling strokes. For example, in the Heart Protection Study,²⁰ the largest study in the Afilalo et al meta-analysis, approximately 50% of nonfatal, classifiable strokes in the overall study population (ie, both younger and older patients) were not disabling. Including disabling and nondisabling strokes in a composite outcome confounds the clinical meaningfulness of these findings in frailty, as the number needed to treat to prevent one disabling stroke cannot be calculated from the data provided.

Do statins prevent a second (symptomatic) stroke in people with a previous stroke?

SPARCL²⁷ (Table 3) examined the question of whether statins decrease the risk of recurrent ischemic stroke for patients with a prior history of stroke or transient ischemic attack. There was a statistically significant reduction in the primary composite outcome of fatal and nonfatal stroke, with 11.2% of the treatment group and 13.1% of the placebo group experiencing this outcome, an absolute risk reduction of 1.9% at 5 years (P = .03; number needed to treat 52, 95% CI 26–1,303). However, the difference in nonfatal stroke, which is the outcome of interest for frailty (since mortality has uncertain relevance), was not statistically significant (10.4% with treatment vs 11.8% with placebo, P =.11).

An exploratory subgroup analysis of SPARCL patients based on age³⁰ showed a smaller, nonsignificant reduction in the primary end point of fatal and nonfatal stroke in the group over age 65 (relative risk 0.90, 95% confidence interval 0.73–1.11, P = .33) compared with the younger group (age < 65) (relative risk 0.74, 95% CI 0.57–0.96, P = .02).

The applicability of these results to the frail elderly is uncertain, since the subgroup analysis was not powered to determine outcomes based on age stratification and there were differences between groups in characteristics such as blood pressure and smoking status. In addition, the outcome of interest, nonfatal stroke, is not provided for the elderly subgroup.

In conclusion, in both primary and secondary prevention populations, the evidence that statins reduce nonfatal, symptomatic stroke rates for older adults is uncertain.

Do statins decrease all-cause mortality for primary or secondary prevention?

Due to competing risks for death, the outcome of mortality may not be relevant to those who are frail; however, studies showed the following:

For primary prevention, there was no decrease in mortality in PROSPER¹³ or in the elderly subgroup of JUPITER.²⁹

For secondary prevention, an analysis of PROSPER trial data by Afilalo et al³¹ showed a significant 18% decrease in all-cause mortality (relative risk 0.82, 95% CI 0.69–0.98) using pravastatin 40 mg.

A decrease in all-cause mortality with statins was also reported in the pooled result of the Afilalo et al meta-analysis.³¹

What are the reported composite outcomes for primary and secondary prevention?

While we were most interested in the symptomatic outcomes described above, we recognize that the small numbers of events make it difficult to draw firm conclusions. Therefore, we also considered composite primary outcomes, even though most included multiple measures that have varying associations with disability and relevancy to frail older adults.

For primary prevention, in the PROSPER preplanned subgroup analysis,¹³ there was no statistical benefit for any outcome, including the primary composite measure. In contrast, the elderly subpopulation in the JUPITER trial²⁸ showed a treatment benefit with rosuvastatin 20 mg compared with placebo for the primary composite outcome of MI, stroke, cardiovascular death, hospitalization for unstable angina, or revascularization. The number needed to treat for 2 years was 62 (95% CI 39–148).

In the CTT meta-analysis,³² patients at all levels of baseline risk showed benefit up to age 70. However, there was no statistically significant benefit in the composite primary outcome of coronary deaths, nonfatal myocardial infarction, ischemic stroke, or revascularization in the population most representative of elderly primary prevention—those who were more than 70 years old with a 5-year baseline risk of less than 20%.

For secondary prevention, in PROSPER,¹³ the subpopulation of patients treated for secondary prevention experienced benefit in the primary composite outcome of coronary heart disease death, nonfatal MI, or fatal or nonfatal stroke, achieving a 4% absolute risk reduction with a number needed to treat of 23 (95% CI 14–81) over 3 years.

Do statins decrease disability?

PROSPER was the only study that reported on disability. Compared with placebo, pravastatin did not decrease disability in the total population as measured by basic and instrumental activities of daily living scales.

Do statins help patients with heart failure?

Neither GISSI-HF²⁵ nor CORONA²⁶ found significant benefit from rosuvastatin 10 mg, despite LDL-C lowering of 27% in GISSI-HF and 45% in CORONA.

Do ezetimibe or other nonstatin lipid-lowering agents improve outcomes?

There is no definitive evidence that ezetimibe provides clinically meaningful benefit as a single agent.

For combination therapy, the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)⁵³ showed that adding ezetimibe 10 mg to simvastatin 40 mg after an acute coronary syndrome reduced the risk of nonfatal myocardial infarction compared with simvastatin monotherapy (event rate 12.8% vs 14.4%; hazard ratio 0.87, 95% CI 0.80–0.95; P = .002) for a population with a mean age of 64. The risk of any stroke was also reduced; strokes occurred in 4.2% of those receiving combination therapy vs 4.8% with monotherapy (hazard ratio 0.86, 95% CI 0.73–1.00, P = .05). After a median of 6 years, 42% of patients in each group had discontinued treatment. Given the very specific clinical scenario of acute coronary syndrome and the young age of the patients in this trial, we do not think that this study justifies the use of ezetimibe for severely frail older adults.

There is no evidence that other combinations (ie, a statin plus another lipid-lowering drug) improve clinical outcomes for either primary or secondary prevention in any population.⁵⁴

WILL FRAIL PATIENTS LIVE LONG ENOUGH TO BENEFIT?

It is often difficult to determine the number of years that are needed to achieve benefit, as most trials do not provide a statistical analysis of varying time frames.

The PROSPER trial¹³ lasted 3.2 years. From the Kaplan-Meier curves in PROSPER, we estimate that it took about 1.5 years to achieve a 1% absolute risk reduction and 2.5 years for a 2% absolute risk reduction in coronary heart disease death and nonfatal MI in the combined primary and secondary groups.

JUPITER²⁸ was stopped early at 1.9 years. The Afilalo et al meta-analysis³¹ was based on follow-up over 4.9 years.

IMPROVE-IT⁵³ reported event rates at 7 years. The authors note that benefit in the primary composite outcome appeared to emerge at 1 year, although no statistical support is given for this statement and divergence in the Kaplan-Meier curves is not visually apparent.

The duration of other studies ranged between 2.7 and 4.9 years (Table 1).^26–28

It has been suggested that statins should be considered for elderly patients who have a life expectancy of at least 5 years.³ However, many older adults have already been taking statins for many years, which makes it difficult to interpret the available timeframe evidence.

In a multicenter, unblinded, randomized trial,⁵⁵ statins were either stopped or continued in older adults who had a short life expectancy and a median survival of approximately 7 months. Causes of death were evenly divided between cancer and noncancer diagnoses, and 22% of the patients were cognitively impaired. Discontinuing statin therapy did not increase mortality or cardiovascular events within 60 days. Nevertheless, stopping statin therapy did not achieve noninferiority for the primary end point, the proportion of participants who died within 60 days. Statin discontinuation was associated with improved quality of life, although the study was not blinded, which could have influenced results.

HAVE THE HARMS BEEN SUFFICIENTLY CONSIDERED?

Frail older adults commonly take multiple medications and are more vulnerable to adverse events.⁵⁶

Many statins require dose reduction with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m²), which would be a common consideration in severely frail older adults.

Myopathy

Myopathy, which includes myalgias and muscle weakness, is a statin-related adverse event that can impair quality of life. Myopathy typically develops within the first 6 months but can occur at any time during statin treatment.⁵⁷ When muscle-related adverse effects occur, they may affect the elderly more significantly, particularly their ability to perform activities of daily living, rise from a chair, or mobilize independently. Another concern is that older adults with dementia may not be able to accurately report muscle-related symptoms.

It is difficult to ascertain the true prevalence of myopathy, especially in advanced age and frailty. Randomized controlled trials report incidence rates of 1.5% to 5%, which is comparable to placebo.^57,58 However, inconsistent definitions of myopathy and exclusion of subjects with previous statin intolerance or adverse effects during run-in periods limit interpretability.⁵⁷ Clinical experience suggests that muscle complaints may be relatively common.^59–61

Advanced age, female sex, low body mass index, and multisystem disease are all associated with frailty and have also been described as risk factors for statin-associated muscle syndromes.⁶¹ Physiologic changes associated with frailty, such as reduced muscle strength, decreased lean body mass, impaired functional mobility, decreased reserve capacity, and altered drug metabolism may increase the risk and severity of myopathy.⁶²

Adverse cognitive events

Meta-analyses of randomized clinical trials and narrative reviews find no definitive relationship between statin therapy and adverse cognitive events.^63–67 Nevertheless, there have been case reports of memory loss associated with the use of statins, and the US Food and Drug Administration has issued a warning that statins have been associated with memory loss and confusion.⁶⁸

It may be difficult to determine whether a statin is causing or aggravating cognitive symptoms among individuals with dementia without a trial withdrawal of the drug.

OUR RECOMMENDATIONS

The recommendations below are intended for adults with severe or very severe frailty (ie, a score of 7 or 8 on the Clinical Frailty Scale¹¹ or FACT⁵ and therefore apply to most older adults living in long-term care facilities.

Primary prevention

There is no reason to prescribe or continue statins for primary prevention, as it is unlikely that they would provide benefit for outcomes that are relevant in this population.

Secondary prevention

Statin treatment is probably not necessary for secondary prevention in those with severe frailty, although there may be extenuating circumstances that justify statin use.

Heart failure

There is no reason to start or continue statins for heart failure, as there is insufficient evidence that they are effective for this indication in any population.

Ezetimibe

There is no evidence that ezetimibe reduces cardiovascular events in any population when used as monotherapy. For a select population with acute coronary syndromes, ezetimibe has a modest effect. Given the very specific clinical scenario of acute coronary syndrome, we do not think that the available evidence justifies the use of ezetimibe for severely frail older adults.

Agents other than ezetimibe combined with statins

There is no reason to start or continue other lipid-lowering drugs in conjunction with statins.

Statin dosing

As statin adverse effects have the potential to increase with advancing age and frailty, lower doses may be appropriate.⁶⁸

Adverse events

Consider stopping statins on a trial basis if there is concern regarding myopathy, drug interactions, or other adverse effects.

BOTTOM LINE: DO STATINS IMPROVE QUALITY OF LIFE OR FUNCTION?

In primary prevention for older adults, there is doubt that statins prevent cardiovascular disease and stroke-related events because the main study involving the elderly did not show a benefit in the primary prevention subgroup.¹³ Additionally, there is no conclusive evidence that statin treatment decreases mortality in primary prevention.^13,29

There is insufficient information to determine whether the frail elderly should receive statins for secondary prevention. Although there is evidence that treatment decreases measures of coronary heart disease and stroke, it is unclear whether it improves quality of life or function for those who are frail. To answer this question, we need more information about whether reported outcomes (such as stroke and MI) are associated with disability, which is not provided in many of the studies we reviewed. When disability was specifically considered in the PROSPER trial for the combined population of primary and secondary prevention, treatment with statins had no impact on basic and instrumental activities of daily living.

Some experts may not agree with our interpretation of the complex evidence presented in this article. Others may ask, “What is the harm in using statins, even if there is no definitive benefit?” However, the harms associated with statin therapy for the frail are poorly defined. In the face of these uncertainties and in the absence of definitive improvement in quality of life, we believe that “less is more” in the context of severe frailty.⁶⁹

The cost of medications should also be considered, especially in long-term care facilities, where there is an added expense of drug administration that diverts human resources away from interactions that are more congruent with respecting the lifestage of frailty.

Careful review of evidence before applying clinical practice guidelines to those who are frail should become the norm. When considering treatment of frail patients, the five questions described in this review shed light on the applicability of clinical trial evidence. Therapies that are highly effective in healthier populations may be less effective when individuals are severely frail. Accordingly, we propose that medications should only be used if they improve quality of life or function.

Frail elderly patients are at high risk of adverse clinical outcomes, including those due to polypharmacy. Several groups tackle “deprescribing” by developing lists of medications that are potentially inappropriate for the elderly, such as the Beers or STOPP/START criteria.^1–4

In contrast, our group (the Palliative and Therapeutic Harmonization [PATH] program and the Dalhousie Academic Detailing Service) has developed evidence-based, frailty-specific guidelines for treating hypertension⁵ and diabetes,⁶ in which we advocate less-stringent treatment targets and tapering or discontinuing medications, as needed.

The PATH program⁷ is a clinical approach that prioritizes the consideration of frailty when making treatment decisions. The Dalhousie Academic Detailing Service collaborates with the Nova Scotia Health Authority to research and develop evidence-informed educational messages about the treatment of common medical conditions.

Here, we address lipid-lowering therapy in this population.

CONSIDERING FRAILTY

Frailty is defined in several ways. The Fried model^8,9 identifies frailty when 3 of the following characteristics are present: unintentional weight loss, exhaustion, muscle weakness, slow walking speed, or low levels of activity. The Clinical Frailty Scale^10,11 and the Frailty Assessment for Care-planning Tool (FACT)⁵ use deficits in cognition, function, and mobility to define frailty. According to these scales, people are considered severely frail when they require assistance with basic activities of daily living (such as bathing or dressing), owing to cognitive or physical deficits from any cause.

In reviewing the evidence, we consider five questions:

• What is the quality of the evidence? (Up to 48% of clinical practice guideline recommendations may be based on low-level evidence or expert opinion.¹²)
• How did the study population compare with the frail?
• Are study outcomes and potential benefits clinically relevant to those who are frail?
• How long did it take for the clinical benefit of a treatment to become apparent, and are the frail elderly likely to live that long?
• Have the harms of treatment been sufficiently considered?

WHAT IS THE QUALITY OF THE EVIDENCE?

We found no studies that specifically evaluated the benefit of lipid-lowering for severely frail older adults. Therefore, we examined randomized controlled trials that enrolled non-frail older adults,^13–28 subgroup analyses of randomized controlled trials,^29,30 meta-analyses that analyzed subgroups of elderly populations,^31,32 and publications describing the study designs of randomized controlled trials.^33–37

Most of the evidence comes from post hoc subgroup analyses of elderly populations. Although meta-analysis is commonly used to compare subgroups, the Cochrane handbook and others consider subgroup comparisons observational by nature.^38,39 (See Table 1 for lipid-lowering studies discussed in this article.)

Studies of statins for primary prevention of cardiovascular disease

For evidence of benefit from lipid-lowering for primary prevention (ie, to reduce the risk of cardiovascular events in patients with no known cardiovascular disease at baseline but at increased risk), we reviewed the meta-analysis conducted by the Cholesterol Treatment Trialists’ (CTT) Collaborators.³² Since this meta-analysis included the major trials that enrolled elderly patients, individual publications of post hoc, elderly subgroups were, for the most part, not examined individually. The exception to this approach was a decision to report on the PROSPER¹³ and JUPITER²⁸ trials separately, because PROSPER is the most representative of the elderly population and JUPITER reached the lowest LDL-C of primary prevention trials published to date and included a large elderly subgroup (n = 5,695).

Savarese et al⁴⁰ evaluated the benefits of statins for older adults who did not have established cardiovascular disease. We did not report on this meta-analysis, as not all of the subjects that populated the meta-analysis were representative of a typical prevention population. For instance, in the Anglo-Scandinavian Cardiac Outcomes Trial lipid-lowering arm,⁴¹ 14% of the subjects had had a previous stroke or transient ischemic attack. In the Antihypertensive and Lipid-Lowering Treatment Trial,⁴² 16% of the population had a family history of premature coronary heart disease.

In addition, all the trials in the Savarese meta-analysis were also included in the CTT meta-analysis.³² The CTT reports on baseline risk using patient-level data stratified by age and risk, which may be more relevant to the question of primary prevention for older adults, as highlighted in our review.

PROSPER (Prospective Study of Pravastatin in the Elderly at Risk),¹³ a well-conducted, double-blind, randomized controlled trial with low probability of bias, compared pravastatin 40 mg and placebo. It was the only study that specifically enrolled older adults, with prespecified analysis of primary and secondary prevention subgroups. The primary prevention subgroup accounted for 56% of the 5,084 participants.

JUPITER (Justification for the Use of Statins in Prevention)²⁸ compared rosuvastatin 20 mg and placebo in 17,802 participants. All had low-density lipoprotein cholesterol (LDL-C) levels below 3.4 mmol/L (130 mg/dL) and elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP), ie, 2 mg/L or higher. Subsequently, Glynn et al performed a post hoc, exploratory subgroup analysis of elderly participants (N = 5,695).²⁹

The JUPITER trial had several limitations.^43,44 The planned follow-up period was 5 years, but the trial was stopped early at 1.9 years, after a statistically significant difference was detected in the primary composite outcome of reduction in all vascular events. Studies that are stopped early may exaggerate positive findings.⁴⁵

Further, JUPITER’s patients were a select group, with normal LDL-C levels, elevated hsCRP values, and without diabetes. Of 90,000 patients screened, 72,000 (80%) did not meet the inclusion criteria and were not enrolled. This high rate of exclusion limits the generalizability of study findings beyond the shortcomings of post hoc subgroup analysis.

The meta-analysis performed by the CTT Collaborators³² used individual participant data from large-scale randomized trials of lipid-modifying treatment. This analysis was specific to people at low risk of vascular disease. In a supplementary appendix, the authors described the reduction in major vascular events for each 1.0 mmol/L decrease in LDL-C in three age categories: under age 60, ages 61 to 70, and over age 70.

The authors also stratified the results by risk category and provided information about those with a risk of major vascular events of less than 20%, which would be more representative of a purer primary prevention population.

For the elderly subgroup at low risk, the CTT Collaborators³² only reported a composite of major vascular events (coronary death, nonfatal myocardial infarction [MI], ischemic stroke, or revascularization) and did not describe individual outcomes, such as prevention of coronary heart disease.

Study results are based on postrandomization findings and therefore may be observational, not experimental.⁴⁶

Studies of statins for secondary prevention of cardiovascular disease

The aim of secondary prevention is to reduce the risk of recurrent cardiovascular events in patients who already have cardiovascular disease.

To address the question of whether statins reduce cardiovascular risk, we reviewed:

PROSPER,¹³ which included a preplanned analysis of the secondary prevention population.

Afilalo et al,^31,47 who performed a meta-analysis of the elderly subgroups of nine major secondary prevention studies (19,569 patients) using published and unpublished data.

To address the question of whether statins benefit individuals with heart failure, we found two relevant studies:

GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca Heart Failure)²⁵ and CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure),²⁶ which were large, international, well-conducted randomized controlled trials that examined statin use in heart failure.

To answer the question of whether statins benefit individuals after a stroke or transient ischemic attack, we found one relevant study:

SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels),²⁷ which evaluated the benefit of statins in older adults with a history of stroke or transient ischemic attack. It was a prospective, double-blind, placebo-controlled, international trial conducted at 205 centers. One to 6 months after their cerebrovascular event, patients were randomized to receive either atorvastatin 80 mg or placebo. Given the young age of patients in this trial (mean age 63), we also reviewed a post hoc subgroup analysis of the elderly patients in SPARCL (age > 65).³⁰

HOW DID THE STUDY POPULATION COMPARE WITH THOSE WHO ARE FRAIL?

Frail older adults are almost always excluded from large-scale clinical trials,⁴⁸ leading to uncertainty about whether the conclusions can be applied to those with advanced frailty.

Although age is an imperfect proxy measure of frailty,⁴⁹ we consider the age of the study population as well as their comorbidities.

Participants in the studies we reviewed were generally younger and healthier than those who are frail, with mean ages of about 75 or less (Table 1).

PROSPER was the most representative study, as it specifically enrolled older adults, albeit without frailty,¹³ and excluded people with poor cognitive function as defined by a Mini Mental State Examination score less than 24.

JUPITER enrolled a select population, as described above. The median age in the elderly subgroup was 74 (interquartile range 72–78).²⁹

The Afilalo et al³¹ meta-analysis primarily included studies of young-elderly patients, with a mean age of less than 70. PROSPER¹³ was an exception.

The GISSI-HF study,²⁵ which examined the benefit of statins in heart failure, described their study population as frail, although the mean age was only 68. Compared with those in GISSI-HF, the CORONA patients²⁶ with heart failure were older (mean age 73) and had more severe heart failure. Accordingly, it is possible that many of the CORONA participants were frail.

ARE STUDY OUTCOMES CLINICALLY RELEVANT TO THOSE WHO ARE FRAIL?

Because baseline cardiovascular risk increases with age, the elderly should, in theory, experience greater absolute benefit from lipid-lowering. However, there is uncertainty about whether this is true in practice.

Some, but not all, epidemiologic studies show a weaker relationship between cholesterol levels and cardiovascular morbidity and mortality rates in older compared to younger adults.^50,51 This may be because those with high cholesterol levels die before they get old (time-related bias), or because those with life-threatening illness may have lower cholesterol levels.⁵⁰ In addition, classic risk factors such as age, sex, systolic blood pressure, cholesterol values, diabetes, smoking, and left ventricular hypertrophy on electrocardiography may have less power to predict cardiovascular risk among older patients.⁵²

The goal of treatment in frailty is to prevent further disability or improve quality of life. Therefore, meaningful outcomes for lipid-lowering therapy should include symptomatic nonfatal MI and its associated morbidity (eg, heart failure and persistent angina) or symptomatic nonfatal stroke leading to disability. Outcomes without sustained clinical impact, such as transient ischemic attack, nondisabling stroke, or silent MI, while potentially important in other populations, are less relevant in severe frailty. Notably, in many statin studies, outcomes include asymptomatic heart disease (eg, silent MI and “suspected events”) and nondisabling stroke (eg, mild stroke, transient ischemic attack). When symptomatic outcomes are not reported separately, the impact of the reported benefit on quality of life and function is uncertain.

The outcome of all-cause mortality is generally recognized as a gold standard for determining treatment benefit. However, since advanced frailty is characterized by multiple competing causes for mortality, a reduction in all-cause mortality that is achieved by addressing a single issue in nonfrail populations may not extend to the frail.

To more fully understand the impact of lipid-lowering therapy on quality of life and function, we examined the following questions:

Do statins as primary prevention reduce symptomatic heart disease?

Outcomes for coronary heart disease from PROSPER and JUPITER are summarized in Table 2.

PROSPER. In the PROSPER primary prevention group,¹³ statin therapy did not reduce the combined outcome of coronary heart disease death and nonfatal MI.

The JUPITER trial demonstrated a statistically significant benefit for preventing MI in the elderly subpopulation (ages 70–97),²⁹ but the number needed to treat was high (211 for 2 years), with a wide confidence interval (CI) (95% CI 106–32,924). The trial did not adequately differentiate between symptomatic and asymptomatic events, making it difficult to determine outcome relevance. Also, due to the methodologic limitations of JUPITER as described above, its results should be interpreted with caution.^43,44

The CTT Collaborators³² did not report individual outcomes (eg, coronary heart disease) for the elderly low-risk subgroup and, therefore, this meta-analysis does not answer the question of whether statins reduce symptomatic heart disease in primary prevention populations.

Taken together, these findings do not provide convincing evidence that statin therapy as primary prevention reduces the incidence of symptomatic heart disease for severely frail older adults.

Do statins as secondary prevention reduce symptomatic heart disease?

Most studies defined secondary prevention narrowly as treatment for patients with established coronary artery disease. For instance, in the Afilalo et al meta-analysis,³¹ the small number of studies that included individuals with other forms of vascular disease (such as peripheral vascular disease) enrolled few participants with noncardiac conditions (eg, 29% in PROSPER¹³ and 13% in the Heart Protection Study²⁰).

Therefore, any evidence of benefit for secondary prevention demonstrated in these studies is most applicable to patients with coronary heart disease, with less certainty for those with other forms of cardiovascular disease.

In PROSPER,¹³ the secondary prevention group experienced benefit in the combined outcome of coronary heart disease death or nonfatal MI. In the treatment group, 12.7% experienced this outcome compared with 16.8% with placebo, an absolute risk reduction of 4.1% in 3 years (P = .004, number needed to treat 25, 95% CI 15–77). This measure includes coronary heart disease death, an outcome that may not be generalizable to those who are frail. In addition, the outcome of nonfatal MI includes both symptomatic and suspected events. As such, there is uncertainty whether the realized benefit is clinically relevant to frail older adults.

The Afilalo et al meta-analysis³¹ showed that the number needed to treat to prevent one nonfatal MI was 38 (95% CI 16–118) over 5 years (Table 2). However, this outcome included both symptomatic and asymptomatic (silent) events.

Based on the available data, we conclude that it is not possible to determine whether statins reduce symptomatic heart disease as secondary prevention for older adults who are frail.

Do statins reduce heart disease in combined populations?

In the combined primary and secondary population from PROSPER,¹³ pravastatin decreased the risk of nonfatal symptomatic MI from 4.3% in the placebo group to 3.4%, a relatively small reduction in absolute risk (0.9%) and not statistically significant by our chi-square calculation (P = .099).

Do statins prevent a first symptomatic stroke in people with or without preexisting cardiovascular disease?

Preventing strokes that cause functional decline is an important outcome for the frail elderly. Stroke outcomes from PROSPER,¹³ JUPITER,²⁹ and the Afilalo et al meta-analysis³¹ are summarized in Table 3.

For primary prevention:

In PROSPER (primary prevention),¹³ there was no statistically significant benefit in the combined outcome of fatal and nonfatal stroke or the single outcome of transient ischemic attack after 3.2 years.

JUPITER,²⁹ in contrast, found that rosuvastatin 20 mg reduced strokes in primary prevention, but the absolute benefit was small. In 2 years, 0.8% of the treatment group had strokes, compared with 1.4% with placebo, an absolute risk reduction of 0.6% (P = .023, number needed to treat 161, 95% CI 86–1,192).

Neither PROSPER nor JUPITER differentiated between disabling and nondisabling strokes.

For secondary prevention:

In PROSPER (secondary prevention),¹³ there was no statistically significant benefit in the combined outcome of fatal and nonfatal stroke or the single outcome of transient ischemic attack after 3.2 years.

The Afilalo et al secondary prevention meta-analysis demonstrated a 25% relative reduction in stroke (relative risk 0.75, 95% CI 0.56–0.94, number needed to treat 58, 95% CI 27–177).³¹

Notably, the stroke outcome in Afilalo included both disabling and nondisabling strokes. For example, in the Heart Protection Study,²⁰ the largest study in the Afilalo et al meta-analysis, approximately 50% of nonfatal, classifiable strokes in the overall study population (ie, both younger and older patients) were not disabling. Including disabling and nondisabling strokes in a composite outcome confounds the clinical meaningfulness of these findings in frailty, as the number needed to treat to prevent one disabling stroke cannot be calculated from the data provided.

Do statins prevent a second (symptomatic) stroke in people with a previous stroke?

SPARCL²⁷ (Table 3) examined the question of whether statins decrease the risk of recurrent ischemic stroke for patients with a prior history of stroke or transient ischemic attack. There was a statistically significant reduction in the primary composite outcome of fatal and nonfatal stroke, with 11.2% of the treatment group and 13.1% of the placebo group experiencing this outcome, an absolute risk reduction of 1.9% at 5 years (P = .03; number needed to treat 52, 95% CI 26–1,303). However, the difference in nonfatal stroke, which is the outcome of interest for frailty (since mortality has uncertain relevance), was not statistically significant (10.4% with treatment vs 11.8% with placebo, P =.11).

An exploratory subgroup analysis of SPARCL patients based on age³⁰ showed a smaller, nonsignificant reduction in the primary end point of fatal and nonfatal stroke in the group over age 65 (relative risk 0.90, 95% confidence interval 0.73–1.11, P = .33) compared with the younger group (age < 65) (relative risk 0.74, 95% CI 0.57–0.96, P = .02).

The applicability of these results to the frail elderly is uncertain, since the subgroup analysis was not powered to determine outcomes based on age stratification and there were differences between groups in characteristics such as blood pressure and smoking status. In addition, the outcome of interest, nonfatal stroke, is not provided for the elderly subgroup.

In conclusion, in both primary and secondary prevention populations, the evidence that statins reduce nonfatal, symptomatic stroke rates for older adults is uncertain.

Do statins decrease all-cause mortality for primary or secondary prevention?

Due to competing risks for death, the outcome of mortality may not be relevant to those who are frail; however, studies showed the following:

For primary prevention, there was no decrease in mortality in PROSPER¹³ or in the elderly subgroup of JUPITER.²⁹

For secondary prevention, an analysis of PROSPER trial data by Afilalo et al³¹ showed a significant 18% decrease in all-cause mortality (relative risk 0.82, 95% CI 0.69–0.98) using pravastatin 40 mg.

A decrease in all-cause mortality with statins was also reported in the pooled result of the Afilalo et al meta-analysis.³¹

What are the reported composite outcomes for primary and secondary prevention?

While we were most interested in the symptomatic outcomes described above, we recognize that the small numbers of events make it difficult to draw firm conclusions. Therefore, we also considered composite primary outcomes, even though most included multiple measures that have varying associations with disability and relevancy to frail older adults.

For primary prevention, in the PROSPER preplanned subgroup analysis,¹³ there was no statistical benefit for any outcome, including the primary composite measure. In contrast, the elderly subpopulation in the JUPITER trial²⁸ showed a treatment benefit with rosuvastatin 20 mg compared with placebo for the primary composite outcome of MI, stroke, cardiovascular death, hospitalization for unstable angina, or revascularization. The number needed to treat for 2 years was 62 (95% CI 39–148).

In the CTT meta-analysis,³² patients at all levels of baseline risk showed benefit up to age 70. However, there was no statistically significant benefit in the composite primary outcome of coronary deaths, nonfatal myocardial infarction, ischemic stroke, or revascularization in the population most representative of elderly primary prevention—those who were more than 70 years old with a 5-year baseline risk of less than 20%.

For secondary prevention, in PROSPER,¹³ the subpopulation of patients treated for secondary prevention experienced benefit in the primary composite outcome of coronary heart disease death, nonfatal MI, or fatal or nonfatal stroke, achieving a 4% absolute risk reduction with a number needed to treat of 23 (95% CI 14–81) over 3 years.

Do statins decrease disability?

PROSPER was the only study that reported on disability. Compared with placebo, pravastatin did not decrease disability in the total population as measured by basic and instrumental activities of daily living scales.

Do statins help patients with heart failure?

Neither GISSI-HF²⁵ nor CORONA²⁶ found significant benefit from rosuvastatin 10 mg, despite LDL-C lowering of 27% in GISSI-HF and 45% in CORONA.

Do ezetimibe or other nonstatin lipid-lowering agents improve outcomes?

There is no definitive evidence that ezetimibe provides clinically meaningful benefit as a single agent.

For combination therapy, the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)⁵³ showed that adding ezetimibe 10 mg to simvastatin 40 mg after an acute coronary syndrome reduced the risk of nonfatal myocardial infarction compared with simvastatin monotherapy (event rate 12.8% vs 14.4%; hazard ratio 0.87, 95% CI 0.80–0.95; P = .002) for a population with a mean age of 64. The risk of any stroke was also reduced; strokes occurred in 4.2% of those receiving combination therapy vs 4.8% with monotherapy (hazard ratio 0.86, 95% CI 0.73–1.00, P = .05). After a median of 6 years, 42% of patients in each group had discontinued treatment. Given the very specific clinical scenario of acute coronary syndrome and the young age of the patients in this trial, we do not think that this study justifies the use of ezetimibe for severely frail older adults.

There is no evidence that other combinations (ie, a statin plus another lipid-lowering drug) improve clinical outcomes for either primary or secondary prevention in any population.⁵⁴

WILL FRAIL PATIENTS LIVE LONG ENOUGH TO BENEFIT?

It is often difficult to determine the number of years that are needed to achieve benefit, as most trials do not provide a statistical analysis of varying time frames.

The PROSPER trial¹³ lasted 3.2 years. From the Kaplan-Meier curves in PROSPER, we estimate that it took about 1.5 years to achieve a 1% absolute risk reduction and 2.5 years for a 2% absolute risk reduction in coronary heart disease death and nonfatal MI in the combined primary and secondary groups.

JUPITER²⁸ was stopped early at 1.9 years. The Afilalo et al meta-analysis³¹ was based on follow-up over 4.9 years.

IMPROVE-IT⁵³ reported event rates at 7 years. The authors note that benefit in the primary composite outcome appeared to emerge at 1 year, although no statistical support is given for this statement and divergence in the Kaplan-Meier curves is not visually apparent.

The duration of other studies ranged between 2.7 and 4.9 years (Table 1).^26–28

It has been suggested that statins should be considered for elderly patients who have a life expectancy of at least 5 years.³ However, many older adults have already been taking statins for many years, which makes it difficult to interpret the available timeframe evidence.

In a multicenter, unblinded, randomized trial,⁵⁵ statins were either stopped or continued in older adults who had a short life expectancy and a median survival of approximately 7 months. Causes of death were evenly divided between cancer and noncancer diagnoses, and 22% of the patients were cognitively impaired. Discontinuing statin therapy did not increase mortality or cardiovascular events within 60 days. Nevertheless, stopping statin therapy did not achieve noninferiority for the primary end point, the proportion of participants who died within 60 days. Statin discontinuation was associated with improved quality of life, although the study was not blinded, which could have influenced results.

HAVE THE HARMS BEEN SUFFICIENTLY CONSIDERED?

Frail older adults commonly take multiple medications and are more vulnerable to adverse events.⁵⁶

Many statins require dose reduction with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m²), which would be a common consideration in severely frail older adults.

Myopathy

Myopathy, which includes myalgias and muscle weakness, is a statin-related adverse event that can impair quality of life. Myopathy typically develops within the first 6 months but can occur at any time during statin treatment.⁵⁷ When muscle-related adverse effects occur, they may affect the elderly more significantly, particularly their ability to perform activities of daily living, rise from a chair, or mobilize independently. Another concern is that older adults with dementia may not be able to accurately report muscle-related symptoms.

It is difficult to ascertain the true prevalence of myopathy, especially in advanced age and frailty. Randomized controlled trials report incidence rates of 1.5% to 5%, which is comparable to placebo.^57,58 However, inconsistent definitions of myopathy and exclusion of subjects with previous statin intolerance or adverse effects during run-in periods limit interpretability.⁵⁷ Clinical experience suggests that muscle complaints may be relatively common.^59–61

Advanced age, female sex, low body mass index, and multisystem disease are all associated with frailty and have also been described as risk factors for statin-associated muscle syndromes.⁶¹ Physiologic changes associated with frailty, such as reduced muscle strength, decreased lean body mass, impaired functional mobility, decreased reserve capacity, and altered drug metabolism may increase the risk and severity of myopathy.⁶²

Adverse cognitive events

Meta-analyses of randomized clinical trials and narrative reviews find no definitive relationship between statin therapy and adverse cognitive events.^63–67 Nevertheless, there have been case reports of memory loss associated with the use of statins, and the US Food and Drug Administration has issued a warning that statins have been associated with memory loss and confusion.⁶⁸

It may be difficult to determine whether a statin is causing or aggravating cognitive symptoms among individuals with dementia without a trial withdrawal of the drug.

OUR RECOMMENDATIONS

The recommendations below are intended for adults with severe or very severe frailty (ie, a score of 7 or 8 on the Clinical Frailty Scale¹¹ or FACT⁵ and therefore apply to most older adults living in long-term care facilities.

Primary prevention

There is no reason to prescribe or continue statins for primary prevention, as it is unlikely that they would provide benefit for outcomes that are relevant in this population.

Secondary prevention

Statin treatment is probably not necessary for secondary prevention in those with severe frailty, although there may be extenuating circumstances that justify statin use.

Heart failure

There is no reason to start or continue statins for heart failure, as there is insufficient evidence that they are effective for this indication in any population.

Ezetimibe

There is no evidence that ezetimibe reduces cardiovascular events in any population when used as monotherapy. For a select population with acute coronary syndromes, ezetimibe has a modest effect. Given the very specific clinical scenario of acute coronary syndrome, we do not think that the available evidence justifies the use of ezetimibe for severely frail older adults.

Agents other than ezetimibe combined with statins

There is no reason to start or continue other lipid-lowering drugs in conjunction with statins.

Statin dosing

As statin adverse effects have the potential to increase with advancing age and frailty, lower doses may be appropriate.⁶⁸

Adverse events

Consider stopping statins on a trial basis if there is concern regarding myopathy, drug interactions, or other adverse effects.

BOTTOM LINE: DO STATINS IMPROVE QUALITY OF LIFE OR FUNCTION?

In primary prevention for older adults, there is doubt that statins prevent cardiovascular disease and stroke-related events because the main study involving the elderly did not show a benefit in the primary prevention subgroup.¹³ Additionally, there is no conclusive evidence that statin treatment decreases mortality in primary prevention.^13,29

There is insufficient information to determine whether the frail elderly should receive statins for secondary prevention. Although there is evidence that treatment decreases measures of coronary heart disease and stroke, it is unclear whether it improves quality of life or function for those who are frail. To answer this question, we need more information about whether reported outcomes (such as stroke and MI) are associated with disability, which is not provided in many of the studies we reviewed. When disability was specifically considered in the PROSPER trial for the combined population of primary and secondary prevention, treatment with statins had no impact on basic and instrumental activities of daily living.

Some experts may not agree with our interpretation of the complex evidence presented in this article. Others may ask, “What is the harm in using statins, even if there is no definitive benefit?” However, the harms associated with statin therapy for the frail are poorly defined. In the face of these uncertainties and in the absence of definitive improvement in quality of life, we believe that “less is more” in the context of severe frailty.⁶⁹

The cost of medications should also be considered, especially in long-term care facilities, where there is an added expense of drug administration that diverts human resources away from interactions that are more congruent with respecting the lifestage of frailty.

Careful review of evidence before applying clinical practice guidelines to those who are frail should become the norm. When considering treatment of frail patients, the five questions described in this review shed light on the applicability of clinical trial evidence. Therapies that are highly effective in healthier populations may be less effective when individuals are severely frail. Accordingly, we propose that medications should only be used if they improve quality of life or function.

The growing elderly population varies widely in functional capacity and mental agility. Age by itself is not a reliable indicator of physiologic performance in patients with cardiovascular disease.¹

See related article

The concept of frailty helps to identify elderly patients most susceptible to adverse outcomes. Frailty is a powerful indicator of disability, loss of independence, hospitalization, and death. In a patient whose health is declining, frailty is an appropriate impetus for the clinician and patient to reevaluate the goals of care.

In this issue of the Journal, Mallery et al² address an important topic: the use of preventive lipid-lowering therapies in frail patients with limited life expectancy. For these patients, they recommend against lipid-lowering therapy for primary prevention, and only in extenuating circumstances for secondary prevention.

No trials have evaluated lipid-lowering therapy specifically in frail older adults, and therefore, these recommendations are based on an evidence-informed appraisal of the literature. Mallery et al² suggest that in the frail elderly, improvement in function and quality of life are more relevant end points than traditional cardiovascular outcomes. They conclude that available evidence does not support lipid-lowering therapy for most patients with advanced frailty.

POINTS TO CONSIDER

Mallery et al² effectively articulate the need for frailty-specific care. Multimorbidity, polypharmacy, and increased adverse drug effects require special attention in the frail elderly. The authors make a sound argument against lipid-lowering therapy for primary prevention in the severely frail elderly, in whom the evidence for short-term benefit is not compelling. They also recommend against nonstatin lipid-lowering medications, and against statin therapy for heart failure, which is consistent with major guidelines. In the modern era of reflexive testing and prescribing, the authors’ “less is more” approach provides needed encouragement for thoughtful care in these vulnerable patients.

However, certain points of contention deserve additional consideration, including the imprecise definition of frailty, potential benefits and harms of statin therapy in high-risk patients, and the importance of shared decision-making.

How should frailty be defined?

Frailty biology is a field of ongoing research, and there is a lack of consensus on how best to define the condition.³ Estimates of the prevalence of frailty among older adults with cardiovascular disease range from 10% to 60%, owing to considerable variability in the tools used for frailty assessment.⁴

Mallery et al² consider an individual to be severely frail if he or she requires assistance with basic activities of daily living as the result of any physical or cognitive deficit (derived from the Clinical Frailty Scale or Frailty Assessment for Care Planning Tool). While functional dependence may be a consequence of frailty, this generalized definition does not characterize the clinical phenotype, which includes slowness, weakness, low physical activity, exhaustion, and unintentional weight loss.

Furthermore, this definition offers no insight into the unique characteristics, causes, and clinical course related to frailty. Significant heterogeneity among “frail” patients precludes a uniform treatment approach in this population.

Do statins benefit frail patients at high risk?

Regarding secondary prevention, the authors highlight a meta-analysis by Afilalo et al,⁵ the most comprehensive assessment to date of statin therapy in elderly patients with documented coronary heart disease. This study included nearly 20,000 elderly patients in nine secondary prevention trials, including the secondary prevention subgroup of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial.⁶

Afilalo et al⁵ calculated that statin therapy reduced the rates of all-cause mortality by 22% and coronary death by 30%, with even greater reductions in the rates of nonfatal myocardial infarction, stroke, and revascularization. Furthermore, the absolute risk reduction was higher and the number needed to treat was lower in those over age 80. Overall, these data convincingly showed that high-risk patients ages 65 to 82 enrolled in clinical trials derive substantial benefit from statin therapy.

Mallery et al² contend that many of the secondary prevention statin trials evaluated composite outcomes over many years of follow-up and therefore are not generalizable to the frail elderly. However, the Afilalo meta-analysis⁵ does not provide patient-level data, and therefore the benefit for different clinical and demographic subgroups is unknown. It is only speculative to infer that those with frailty are unlikely to benefit. In fact, the improved outcomes observed with increasing age would argue against this notion.

Given the compelling data supporting statin therapy in the high-risk elderly population, some patients and clinicians may reasonably feel there is value in statin therapy—even in those with advanced frailty.

What about symptoms, disability, quality of life, and short-term benefits? Asymptomatic or “silent” myocardial infarction is associated with angina, congestive heart failure, and subsequent symptomatic myocardial infarction.^7,8 Dismissing the importance of these end points in clinical trials fails to recognize potential downstream effects that are directly relevant to a patient’s overall health status.

The Study Assessing Goals in the Elderly (SAGE) trial⁹ assessed the effect of statin therapy on ischemia burden in patients ages 65 to 85 with stable coronary disease. The results showed that both moderate and intensive statin dosing significantly reduced myocardial ischemia at 3 and 12 months, as detected by continuous electrocardiographic monitoring.

More research is needed to determine the effect of statin therapy on functional capacity and quality of life. Currently, it is premature to conclude that statins have no relevance to these important patient-centered outcomes.

What are the potential harms?

Mallery et al² cite numerous articles that emphasize the potential adverse effects of statin therapy in the elderly. Unfortunately, data supporting the safety of statin therapy in the elderly were not included. This should be stressed, given that older statin-eligible patients are often undertreated in contemporary practice.¹⁰

A 2015 systematic review and meta-analysis indicated that statin-related events are relatively rare in the elderly.¹¹ Another study showed elderly patients who started statin therapy after a myocardial infarction had no change in short-term cognitive or physical function.¹²

Older age and low body mass index are risk factors for statin myopathy, underscoring the need for close monitoring in frail patients. However, it is important to maintain an objective and balanced approach when considering potential harms.

Need for shared decision-making

Mallery et al² make no mention of shared decision-making. Best practice guidelines for the management of frailty support a holistic medical review to establish an individualized care plan for each patient.¹³ Firm recommendations based on indeterminate evidence undermine the patient-physician relationship and do not allow for personal preferences of care. In an environment of uncertain benefit and harm, the patient’s priorities and values should serve as the cornerstone for clinical decisions.

The growing elderly population varies widely in functional capacity and mental agility. Age by itself is not a reliable indicator of physiologic performance in patients with cardiovascular disease.¹

See related article

The concept of frailty helps to identify elderly patients most susceptible to adverse outcomes. Frailty is a powerful indicator of disability, loss of independence, hospitalization, and death. In a patient whose health is declining, frailty is an appropriate impetus for the clinician and patient to reevaluate the goals of care.

In this issue of the Journal, Mallery et al² address an important topic: the use of preventive lipid-lowering therapies in frail patients with limited life expectancy. For these patients, they recommend against lipid-lowering therapy for primary prevention, and only in extenuating circumstances for secondary prevention.

No trials have evaluated lipid-lowering therapy specifically in frail older adults, and therefore, these recommendations are based on an evidence-informed appraisal of the literature. Mallery et al² suggest that in the frail elderly, improvement in function and quality of life are more relevant end points than traditional cardiovascular outcomes. They conclude that available evidence does not support lipid-lowering therapy for most patients with advanced frailty.

POINTS TO CONSIDER

Mallery et al² effectively articulate the need for frailty-specific care. Multimorbidity, polypharmacy, and increased adverse drug effects require special attention in the frail elderly. The authors make a sound argument against lipid-lowering therapy for primary prevention in the severely frail elderly, in whom the evidence for short-term benefit is not compelling. They also recommend against nonstatin lipid-lowering medications, and against statin therapy for heart failure, which is consistent with major guidelines. In the modern era of reflexive testing and prescribing, the authors’ “less is more” approach provides needed encouragement for thoughtful care in these vulnerable patients.

However, certain points of contention deserve additional consideration, including the imprecise definition of frailty, potential benefits and harms of statin therapy in high-risk patients, and the importance of shared decision-making.

How should frailty be defined?

Frailty biology is a field of ongoing research, and there is a lack of consensus on how best to define the condition.³ Estimates of the prevalence of frailty among older adults with cardiovascular disease range from 10% to 60%, owing to considerable variability in the tools used for frailty assessment.⁴

Mallery et al² consider an individual to be severely frail if he or she requires assistance with basic activities of daily living as the result of any physical or cognitive deficit (derived from the Clinical Frailty Scale or Frailty Assessment for Care Planning Tool). While functional dependence may be a consequence of frailty, this generalized definition does not characterize the clinical phenotype, which includes slowness, weakness, low physical activity, exhaustion, and unintentional weight loss.

Furthermore, this definition offers no insight into the unique characteristics, causes, and clinical course related to frailty. Significant heterogeneity among “frail” patients precludes a uniform treatment approach in this population.

Do statins benefit frail patients at high risk?

Regarding secondary prevention, the authors highlight a meta-analysis by Afilalo et al,⁵ the most comprehensive assessment to date of statin therapy in elderly patients with documented coronary heart disease. This study included nearly 20,000 elderly patients in nine secondary prevention trials, including the secondary prevention subgroup of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial.⁶

Afilalo et al⁵ calculated that statin therapy reduced the rates of all-cause mortality by 22% and coronary death by 30%, with even greater reductions in the rates of nonfatal myocardial infarction, stroke, and revascularization. Furthermore, the absolute risk reduction was higher and the number needed to treat was lower in those over age 80. Overall, these data convincingly showed that high-risk patients ages 65 to 82 enrolled in clinical trials derive substantial benefit from statin therapy.

Mallery et al² contend that many of the secondary prevention statin trials evaluated composite outcomes over many years of follow-up and therefore are not generalizable to the frail elderly. However, the Afilalo meta-analysis⁵ does not provide patient-level data, and therefore the benefit for different clinical and demographic subgroups is unknown. It is only speculative to infer that those with frailty are unlikely to benefit. In fact, the improved outcomes observed with increasing age would argue against this notion.

Given the compelling data supporting statin therapy in the high-risk elderly population, some patients and clinicians may reasonably feel there is value in statin therapy—even in those with advanced frailty.

What about symptoms, disability, quality of life, and short-term benefits? Asymptomatic or “silent” myocardial infarction is associated with angina, congestive heart failure, and subsequent symptomatic myocardial infarction.^7,8 Dismissing the importance of these end points in clinical trials fails to recognize potential downstream effects that are directly relevant to a patient’s overall health status.

The Study Assessing Goals in the Elderly (SAGE) trial⁹ assessed the effect of statin therapy on ischemia burden in patients ages 65 to 85 with stable coronary disease. The results showed that both moderate and intensive statin dosing significantly reduced myocardial ischemia at 3 and 12 months, as detected by continuous electrocardiographic monitoring.

More research is needed to determine the effect of statin therapy on functional capacity and quality of life. Currently, it is premature to conclude that statins have no relevance to these important patient-centered outcomes.

What are the potential harms?

Mallery et al² cite numerous articles that emphasize the potential adverse effects of statin therapy in the elderly. Unfortunately, data supporting the safety of statin therapy in the elderly were not included. This should be stressed, given that older statin-eligible patients are often undertreated in contemporary practice.¹⁰

A 2015 systematic review and meta-analysis indicated that statin-related events are relatively rare in the elderly.¹¹ Another study showed elderly patients who started statin therapy after a myocardial infarction had no change in short-term cognitive or physical function.¹²

Older age and low body mass index are risk factors for statin myopathy, underscoring the need for close monitoring in frail patients. However, it is important to maintain an objective and balanced approach when considering potential harms.

Need for shared decision-making

Mallery et al² make no mention of shared decision-making. Best practice guidelines for the management of frailty support a holistic medical review to establish an individualized care plan for each patient.¹³ Firm recommendations based on indeterminate evidence undermine the patient-physician relationship and do not allow for personal preferences of care. In an environment of uncertain benefit and harm, the patient’s priorities and values should serve as the cornerstone for clinical decisions.

The growing elderly population varies widely in functional capacity and mental agility. Age by itself is not a reliable indicator of physiologic performance in patients with cardiovascular disease.¹

See related article

The concept of frailty helps to identify elderly patients most susceptible to adverse outcomes. Frailty is a powerful indicator of disability, loss of independence, hospitalization, and death. In a patient whose health is declining, frailty is an appropriate impetus for the clinician and patient to reevaluate the goals of care.

In this issue of the Journal, Mallery et al² address an important topic: the use of preventive lipid-lowering therapies in frail patients with limited life expectancy. For these patients, they recommend against lipid-lowering therapy for primary prevention, and only in extenuating circumstances for secondary prevention.

No trials have evaluated lipid-lowering therapy specifically in frail older adults, and therefore, these recommendations are based on an evidence-informed appraisal of the literature. Mallery et al² suggest that in the frail elderly, improvement in function and quality of life are more relevant end points than traditional cardiovascular outcomes. They conclude that available evidence does not support lipid-lowering therapy for most patients with advanced frailty.

POINTS TO CONSIDER

Mallery et al² effectively articulate the need for frailty-specific care. Multimorbidity, polypharmacy, and increased adverse drug effects require special attention in the frail elderly. The authors make a sound argument against lipid-lowering therapy for primary prevention in the severely frail elderly, in whom the evidence for short-term benefit is not compelling. They also recommend against nonstatin lipid-lowering medications, and against statin therapy for heart failure, which is consistent with major guidelines. In the modern era of reflexive testing and prescribing, the authors’ “less is more” approach provides needed encouragement for thoughtful care in these vulnerable patients.

However, certain points of contention deserve additional consideration, including the imprecise definition of frailty, potential benefits and harms of statin therapy in high-risk patients, and the importance of shared decision-making.

How should frailty be defined?

Frailty biology is a field of ongoing research, and there is a lack of consensus on how best to define the condition.³ Estimates of the prevalence of frailty among older adults with cardiovascular disease range from 10% to 60%, owing to considerable variability in the tools used for frailty assessment.⁴

Mallery et al² consider an individual to be severely frail if he or she requires assistance with basic activities of daily living as the result of any physical or cognitive deficit (derived from the Clinical Frailty Scale or Frailty Assessment for Care Planning Tool). While functional dependence may be a consequence of frailty, this generalized definition does not characterize the clinical phenotype, which includes slowness, weakness, low physical activity, exhaustion, and unintentional weight loss.

Furthermore, this definition offers no insight into the unique characteristics, causes, and clinical course related to frailty. Significant heterogeneity among “frail” patients precludes a uniform treatment approach in this population.

Do statins benefit frail patients at high risk?

Regarding secondary prevention, the authors highlight a meta-analysis by Afilalo et al,⁵ the most comprehensive assessment to date of statin therapy in elderly patients with documented coronary heart disease. This study included nearly 20,000 elderly patients in nine secondary prevention trials, including the secondary prevention subgroup of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial.⁶

Afilalo et al⁵ calculated that statin therapy reduced the rates of all-cause mortality by 22% and coronary death by 30%, with even greater reductions in the rates of nonfatal myocardial infarction, stroke, and revascularization. Furthermore, the absolute risk reduction was higher and the number needed to treat was lower in those over age 80. Overall, these data convincingly showed that high-risk patients ages 65 to 82 enrolled in clinical trials derive substantial benefit from statin therapy.

Mallery et al² contend that many of the secondary prevention statin trials evaluated composite outcomes over many years of follow-up and therefore are not generalizable to the frail elderly. However, the Afilalo meta-analysis⁵ does not provide patient-level data, and therefore the benefit for different clinical and demographic subgroups is unknown. It is only speculative to infer that those with frailty are unlikely to benefit. In fact, the improved outcomes observed with increasing age would argue against this notion.

Given the compelling data supporting statin therapy in the high-risk elderly population, some patients and clinicians may reasonably feel there is value in statin therapy—even in those with advanced frailty.

What about symptoms, disability, quality of life, and short-term benefits? Asymptomatic or “silent” myocardial infarction is associated with angina, congestive heart failure, and subsequent symptomatic myocardial infarction.^7,8 Dismissing the importance of these end points in clinical trials fails to recognize potential downstream effects that are directly relevant to a patient’s overall health status.

The Study Assessing Goals in the Elderly (SAGE) trial⁹ assessed the effect of statin therapy on ischemia burden in patients ages 65 to 85 with stable coronary disease. The results showed that both moderate and intensive statin dosing significantly reduced myocardial ischemia at 3 and 12 months, as detected by continuous electrocardiographic monitoring.

More research is needed to determine the effect of statin therapy on functional capacity and quality of life. Currently, it is premature to conclude that statins have no relevance to these important patient-centered outcomes.

What are the potential harms?

Mallery et al² cite numerous articles that emphasize the potential adverse effects of statin therapy in the elderly. Unfortunately, data supporting the safety of statin therapy in the elderly were not included. This should be stressed, given that older statin-eligible patients are often undertreated in contemporary practice.¹⁰

A 2015 systematic review and meta-analysis indicated that statin-related events are relatively rare in the elderly.¹¹ Another study showed elderly patients who started statin therapy after a myocardial infarction had no change in short-term cognitive or physical function.¹²

Older age and low body mass index are risk factors for statin myopathy, underscoring the need for close monitoring in frail patients. However, it is important to maintain an objective and balanced approach when considering potential harms.

Need for shared decision-making

Mallery et al² make no mention of shared decision-making. Best practice guidelines for the management of frailty support a holistic medical review to establish an individualized care plan for each patient.¹³ Firm recommendations based on indeterminate evidence undermine the patient-physician relationship and do not allow for personal preferences of care. In an environment of uncertain benefit and harm, the patient’s priorities and values should serve as the cornerstone for clinical decisions.

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.

CHICAGO – Catheter dependence is often the final option available for hemodialysis patients who have exhausted upper extremity access because of central venous obstruction. But an alternative device that combines a standard expanded polytetrafluoroethylene (ePTFE) arterial graft component with an entirely internalized central venous catheter component may provide an additional option that can help avoid catheters in selected patients, according to pooled results reported at a symposium on vascular surgery sponsored by Northwestern University.

Virginia L. Wong, MD, of University Hospitals Cleveland Medical Center, reported on her group’s and others’ experience using the Hemodialysis Reliable Outflow (HeRO) graft (Merit Medical) to gain access to the superior vena cava (SVC), thus allowing for further upper extremity access options. The device has its limitations in patients with CVO, Dr. Wong noted, “but it can be an important tool for the dedicated access surgeon who is likely to be referred the most complicated patients who have run out of just about every other option.”

The Food and Drug Administration approved the HeRO graft for CVO in 2008, but a recent pooled analysis (Eur J Vasc Endovasc Surg. 2015;50[1]:108-13), which showed a 1-year primary patency rate of 22% and a secondary patency rate of 60%, may provide clarity on how the device can be used to treat CVO in end-stage renal disease (ESRD) patients when the care team desires an alternative to femoral arteriovenous graft, Dr. Wong said. “The 1-year primary patency rate overall was not very good, but with aggressive thrombectomy programs the 1-year patency rate was decent,” she said.

The pooled analysis involved eight series from 2009 to 2015, but the largest series, which involved 164 patients, reported primary and secondary patency rates of 48.8% and 90.8%, respectively (Eur J Vasc Endovasc Surg. 2012;44[1]:93-9). “Patency for these alternative accesses may not be quite what we can achieve with standard upper-extremity access,” Dr. Wong said, “but these patients do not have the standard access as an option.”

Dr. Wong explained where the HeRO fits into the existing vascular practice. “The current data suggest that we should try to exhaust all traditional upper extremity access options before considering anything else, but the HeRO could be considered as an acceptable option for suitable patients,” she said. However, to achieve those outcomes, “you need to have an aggressive thrombectomy program.”

HeRO may be an option for salvage of an existing arm access, plagued by recalcitrant CVO, while still preserving the femoral sites and for future hemodialysis access and/or renal transplantation, Dr. Wong said.

The HeRO also has been used in alternative configurations, taking advantage of axillary or subclavian routes to the SVC when both internal jugular veins are occluded. Dr. Wong has used the femoral route to the inferior vena cava (IVC) for salvaging the femoral AV graft in which iliofemoral venous outflow has been compromised.

Anatomically, the patient must be able to accept a large-bore (19-Fr) access catheter into the central vein. Physiologically, the patient must be able to maintain patency of the long, low-resistance HeRO circuit, which can be up to 50 cm in length, she said. The protocol at Dr. Wong’s institution recommends an inflow arterial diameter of at least 3 mm, along with a left ventricular ejection fraction of 20% or greater and a minimum systolic blood pressure of 100 mm Hg for HeRO on the right side, and possibly higher when coming from the left.

Chronic hypotension is a frequent disqualifier, although some of these patients may benefit from midodrine hydrochloride, she said. In any event, a review of medications and consultation with nephrology and the dialysis unit are mandatory elements of patient screening. “I usually request hemodialysis run sheets from the last three sessions to see what systolic blood pressure excursion is like over the course of treatment,” she said.

The basic principles of hemo-access care are important when considering the HeRO for CVO patients, Dr. Wong said. These include site/side preservation, catheter avoidance and “not to burn any bridges” for future access. “Individualization of care and careful patient selection are probably the best bets if you’re just starting out,” she said. “Choose good patients before resorting to HeRO as the last option for a fairly marginal candidate.”

Dr. Wong had no relevant financial relationships to disclose.

CHICAGO – Catheter dependence is often the final option available for hemodialysis patients who have exhausted upper extremity access because of central venous obstruction. But an alternative device that combines a standard expanded polytetrafluoroethylene (ePTFE) arterial graft component with an entirely internalized central venous catheter component may provide an additional option that can help avoid catheters in selected patients, according to pooled results reported at a symposium on vascular surgery sponsored by Northwestern University.

Virginia L. Wong, MD, of University Hospitals Cleveland Medical Center, reported on her group’s and others’ experience using the Hemodialysis Reliable Outflow (HeRO) graft (Merit Medical) to gain access to the superior vena cava (SVC), thus allowing for further upper extremity access options. The device has its limitations in patients with CVO, Dr. Wong noted, “but it can be an important tool for the dedicated access surgeon who is likely to be referred the most complicated patients who have run out of just about every other option.”

The Food and Drug Administration approved the HeRO graft for CVO in 2008, but a recent pooled analysis (Eur J Vasc Endovasc Surg. 2015;50[1]:108-13), which showed a 1-year primary patency rate of 22% and a secondary patency rate of 60%, may provide clarity on how the device can be used to treat CVO in end-stage renal disease (ESRD) patients when the care team desires an alternative to femoral arteriovenous graft, Dr. Wong said. “The 1-year primary patency rate overall was not very good, but with aggressive thrombectomy programs the 1-year patency rate was decent,” she said.

The pooled analysis involved eight series from 2009 to 2015, but the largest series, which involved 164 patients, reported primary and secondary patency rates of 48.8% and 90.8%, respectively (Eur J Vasc Endovasc Surg. 2012;44[1]:93-9). “Patency for these alternative accesses may not be quite what we can achieve with standard upper-extremity access,” Dr. Wong said, “but these patients do not have the standard access as an option.”

Dr. Wong explained where the HeRO fits into the existing vascular practice. “The current data suggest that we should try to exhaust all traditional upper extremity access options before considering anything else, but the HeRO could be considered as an acceptable option for suitable patients,” she said. However, to achieve those outcomes, “you need to have an aggressive thrombectomy program.”

HeRO may be an option for salvage of an existing arm access, plagued by recalcitrant CVO, while still preserving the femoral sites and for future hemodialysis access and/or renal transplantation, Dr. Wong said.

The HeRO also has been used in alternative configurations, taking advantage of axillary or subclavian routes to the SVC when both internal jugular veins are occluded. Dr. Wong has used the femoral route to the inferior vena cava (IVC) for salvaging the femoral AV graft in which iliofemoral venous outflow has been compromised.

Anatomically, the patient must be able to accept a large-bore (19-Fr) access catheter into the central vein. Physiologically, the patient must be able to maintain patency of the long, low-resistance HeRO circuit, which can be up to 50 cm in length, she said. The protocol at Dr. Wong’s institution recommends an inflow arterial diameter of at least 3 mm, along with a left ventricular ejection fraction of 20% or greater and a minimum systolic blood pressure of 100 mm Hg for HeRO on the right side, and possibly higher when coming from the left.

Chronic hypotension is a frequent disqualifier, although some of these patients may benefit from midodrine hydrochloride, she said. In any event, a review of medications and consultation with nephrology and the dialysis unit are mandatory elements of patient screening. “I usually request hemodialysis run sheets from the last three sessions to see what systolic blood pressure excursion is like over the course of treatment,” she said.

The basic principles of hemo-access care are important when considering the HeRO for CVO patients, Dr. Wong said. These include site/side preservation, catheter avoidance and “not to burn any bridges” for future access. “Individualization of care and careful patient selection are probably the best bets if you’re just starting out,” she said. “Choose good patients before resorting to HeRO as the last option for a fairly marginal candidate.”

Dr. Wong had no relevant financial relationships to disclose.

CHICAGO – Catheter dependence is often the final option available for hemodialysis patients who have exhausted upper extremity access because of central venous obstruction. But an alternative device that combines a standard expanded polytetrafluoroethylene (ePTFE) arterial graft component with an entirely internalized central venous catheter component may provide an additional option that can help avoid catheters in selected patients, according to pooled results reported at a symposium on vascular surgery sponsored by Northwestern University.

Virginia L. Wong, MD, of University Hospitals Cleveland Medical Center, reported on her group’s and others’ experience using the Hemodialysis Reliable Outflow (HeRO) graft (Merit Medical) to gain access to the superior vena cava (SVC), thus allowing for further upper extremity access options. The device has its limitations in patients with CVO, Dr. Wong noted, “but it can be an important tool for the dedicated access surgeon who is likely to be referred the most complicated patients who have run out of just about every other option.”

The Food and Drug Administration approved the HeRO graft for CVO in 2008, but a recent pooled analysis (Eur J Vasc Endovasc Surg. 2015;50[1]:108-13), which showed a 1-year primary patency rate of 22% and a secondary patency rate of 60%, may provide clarity on how the device can be used to treat CVO in end-stage renal disease (ESRD) patients when the care team desires an alternative to femoral arteriovenous graft, Dr. Wong said. “The 1-year primary patency rate overall was not very good, but with aggressive thrombectomy programs the 1-year patency rate was decent,” she said.

The pooled analysis involved eight series from 2009 to 2015, but the largest series, which involved 164 patients, reported primary and secondary patency rates of 48.8% and 90.8%, respectively (Eur J Vasc Endovasc Surg. 2012;44[1]:93-9). “Patency for these alternative accesses may not be quite what we can achieve with standard upper-extremity access,” Dr. Wong said, “but these patients do not have the standard access as an option.”

Dr. Wong explained where the HeRO fits into the existing vascular practice. “The current data suggest that we should try to exhaust all traditional upper extremity access options before considering anything else, but the HeRO could be considered as an acceptable option for suitable patients,” she said. However, to achieve those outcomes, “you need to have an aggressive thrombectomy program.”

HeRO may be an option for salvage of an existing arm access, plagued by recalcitrant CVO, while still preserving the femoral sites and for future hemodialysis access and/or renal transplantation, Dr. Wong said.

The HeRO also has been used in alternative configurations, taking advantage of axillary or subclavian routes to the SVC when both internal jugular veins are occluded. Dr. Wong has used the femoral route to the inferior vena cava (IVC) for salvaging the femoral AV graft in which iliofemoral venous outflow has been compromised.

Anatomically, the patient must be able to accept a large-bore (19-Fr) access catheter into the central vein. Physiologically, the patient must be able to maintain patency of the long, low-resistance HeRO circuit, which can be up to 50 cm in length, she said. The protocol at Dr. Wong’s institution recommends an inflow arterial diameter of at least 3 mm, along with a left ventricular ejection fraction of 20% or greater and a minimum systolic blood pressure of 100 mm Hg for HeRO on the right side, and possibly higher when coming from the left.

Chronic hypotension is a frequent disqualifier, although some of these patients may benefit from midodrine hydrochloride, she said. In any event, a review of medications and consultation with nephrology and the dialysis unit are mandatory elements of patient screening. “I usually request hemodialysis run sheets from the last three sessions to see what systolic blood pressure excursion is like over the course of treatment,” she said.

The basic principles of hemo-access care are important when considering the HeRO for CVO patients, Dr. Wong said. These include site/side preservation, catheter avoidance and “not to burn any bridges” for future access. “Individualization of care and careful patient selection are probably the best bets if you’re just starting out,” she said. “Choose good patients before resorting to HeRO as the last option for a fairly marginal candidate.”

Dr. Wong had no relevant financial relationships to disclose.

CHICAGO – Bioresorbable scaffolds, new drugs, adjuvant interventions, and stem and progenitor cell therapy will change how vascular surgeons treat peripheral artery disease in the next 5 years, so they must embrace these emerging treatments or run the risk of being displaced by other specialists, according to a presentation at a symposium on vascular surgery sponsored by Northwestern University.

“Vascular surgeons must position their practices to be the nexus for the evaluation and treatment of the patient and proactively engage in the critical trials of these new technologies,” said Patrick J. Geraghty, MD, of Washington University, St. Louis. “If our specialty fails to adapt to new treatment options, we risk getting sidelined as critical limb ischemia (CLI) treatment moves into a multimodality model.”

CHICAGO – Bioresorbable scaffolds, new drugs, adjuvant interventions, and stem and progenitor cell therapy will change how vascular surgeons treat peripheral artery disease in the next 5 years, so they must embrace these emerging treatments or run the risk of being displaced by other specialists, according to a presentation at a symposium on vascular surgery sponsored by Northwestern University.

“Vascular surgeons must position their practices to be the nexus for the evaluation and treatment of the patient and proactively engage in the critical trials of these new technologies,” said Patrick J. Geraghty, MD, of Washington University, St. Louis. “If our specialty fails to adapt to new treatment options, we risk getting sidelined as critical limb ischemia (CLI) treatment moves into a multimodality model.”

CHICAGO – Bioresorbable scaffolds, new drugs, adjuvant interventions, and stem and progenitor cell therapy will change how vascular surgeons treat peripheral artery disease in the next 5 years, so they must embrace these emerging treatments or run the risk of being displaced by other specialists, according to a presentation at a symposium on vascular surgery sponsored by Northwestern University.

“Vascular surgeons must position their practices to be the nexus for the evaluation and treatment of the patient and proactively engage in the critical trials of these new technologies,” said Patrick J. Geraghty, MD, of Washington University, St. Louis. “If our specialty fails to adapt to new treatment options, we risk getting sidelined as critical limb ischemia (CLI) treatment moves into a multimodality model.”

CHICAGO – New data have shown that fibromuscular dysplasia is associated with high rates of dissection and/or aneurysm, and emerging recommendations call for routine imaging early on in the diagnosis of FMD to monitor for these vascular events, a researcher who developed those recommendations reported at a symposium on vascular surgery sponsored by Northwestern University.

“Given the very high rate of aneurysms in this population, it is now recommended that all patients with FMD should undergo at least one-time head-to pelvis imaging with CT angiography or MR angiography to screen for the presence of an aneurysm or to identify other areas of FMD involvement,” said Daniella Kadian-Dodov, MD, of Icahn School of Medicine at Mount Sinai in New York (J Am Coll Cardiol. 2016;68:176-85).

CHICAGO – New data have shown that fibromuscular dysplasia is associated with high rates of dissection and/or aneurysm, and emerging recommendations call for routine imaging early on in the diagnosis of FMD to monitor for these vascular events, a researcher who developed those recommendations reported at a symposium on vascular surgery sponsored by Northwestern University.

“Given the very high rate of aneurysms in this population, it is now recommended that all patients with FMD should undergo at least one-time head-to pelvis imaging with CT angiography or MR angiography to screen for the presence of an aneurysm or to identify other areas of FMD involvement,” said Daniella Kadian-Dodov, MD, of Icahn School of Medicine at Mount Sinai in New York (J Am Coll Cardiol. 2016;68:176-85).

CHICAGO – New data have shown that fibromuscular dysplasia is associated with high rates of dissection and/or aneurysm, and emerging recommendations call for routine imaging early on in the diagnosis of FMD to monitor for these vascular events, a researcher who developed those recommendations reported at a symposium on vascular surgery sponsored by Northwestern University.

“Given the very high rate of aneurysms in this population, it is now recommended that all patients with FMD should undergo at least one-time head-to pelvis imaging with CT angiography or MR angiography to screen for the presence of an aneurysm or to identify other areas of FMD involvement,” said Daniella Kadian-Dodov, MD, of Icahn School of Medicine at Mount Sinai in New York (J Am Coll Cardiol. 2016;68:176-85).

NEW ORLEANS – High-intensity statin therapy in patients with peripheral artery disease was associated with significant reductions in amputations as well as mortality during up to 5 years of follow-up in the first large study to examine the relationship, Shipra Arya, MD, reported at the American Heart Association scientific sessions.

Low- or moderate-intensity statin therapy also improved survival compared to no statin, albeit to a significantly lesser magnitude than high-intensity therapy. But high- and low/intermediate-intensity statins were similarly effective in reducing amputation risk, according to Dr. Arya, a vascular surgeon at Emory University in Atlanta.

bjancin@frontlinemedcom.com

NEW ORLEANS – High-intensity statin therapy in patients with peripheral artery disease was associated with significant reductions in amputations as well as mortality during up to 5 years of follow-up in the first large study to examine the relationship, Shipra Arya, MD, reported at the American Heart Association scientific sessions.

Low- or moderate-intensity statin therapy also improved survival compared to no statin, albeit to a significantly lesser magnitude than high-intensity therapy. But high- and low/intermediate-intensity statins were similarly effective in reducing amputation risk, according to Dr. Arya, a vascular surgeon at Emory University in Atlanta.

bjancin@frontlinemedcom.com

NEW ORLEANS – High-intensity statin therapy in patients with peripheral artery disease was associated with significant reductions in amputations as well as mortality during up to 5 years of follow-up in the first large study to examine the relationship, Shipra Arya, MD, reported at the American Heart Association scientific sessions.

Low- or moderate-intensity statin therapy also improved survival compared to no statin, albeit to a significantly lesser magnitude than high-intensity therapy. But high- and low/intermediate-intensity statins were similarly effective in reducing amputation risk, according to Dr. Arya, a vascular surgeon at Emory University in Atlanta.

bjancin@frontlinemedcom.com

CHICAGO – As Medicare ratchets up penalties for readmissions and hospitals scrutinize procedures such as carotid interventions and lower extremity bypass that have traditionally high readmission rates, a four-phase model that assesses readmission risks could help vascular surgeons and their institutions keep patients from returning after vascular procedures, according to a presentation at a symposium on vascular surgery sponsored by Northwestern University.

“The rate of readmissions for vascular surgery is 50% higher than all other surgical interventions,” said Karen Ho, MD, of Northwestern University, Chicago. She noted that the reported readmission rates for abdominal aortic aneurysm (AAA) repair were 13.3% for endovascular and 12.8% for open (Ann Surg. 2012;256:595-605). For carotid endarterectomy (CEA), a large study reported a readmission rate of 9.6% (J Am Coll Cardiol. 2015;65:1398-1408), while a sampling of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database showed a 30-day readmission rate of 16.5% for lower extremity bypass (J Vasc Surg. 2014;60:1266-74).

CHICAGO – As Medicare ratchets up penalties for readmissions and hospitals scrutinize procedures such as carotid interventions and lower extremity bypass that have traditionally high readmission rates, a four-phase model that assesses readmission risks could help vascular surgeons and their institutions keep patients from returning after vascular procedures, according to a presentation at a symposium on vascular surgery sponsored by Northwestern University.

“The rate of readmissions for vascular surgery is 50% higher than all other surgical interventions,” said Karen Ho, MD, of Northwestern University, Chicago. She noted that the reported readmission rates for abdominal aortic aneurysm (AAA) repair were 13.3% for endovascular and 12.8% for open (Ann Surg. 2012;256:595-605). For carotid endarterectomy (CEA), a large study reported a readmission rate of 9.6% (J Am Coll Cardiol. 2015;65:1398-1408), while a sampling of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database showed a 30-day readmission rate of 16.5% for lower extremity bypass (J Vasc Surg. 2014;60:1266-74).

CHICAGO – As Medicare ratchets up penalties for readmissions and hospitals scrutinize procedures such as carotid interventions and lower extremity bypass that have traditionally high readmission rates, a four-phase model that assesses readmission risks could help vascular surgeons and their institutions keep patients from returning after vascular procedures, according to a presentation at a symposium on vascular surgery sponsored by Northwestern University.

“The rate of readmissions for vascular surgery is 50% higher than all other surgical interventions,” said Karen Ho, MD, of Northwestern University, Chicago. She noted that the reported readmission rates for abdominal aortic aneurysm (AAA) repair were 13.3% for endovascular and 12.8% for open (Ann Surg. 2012;256:595-605). For carotid endarterectomy (CEA), a large study reported a readmission rate of 9.6% (J Am Coll Cardiol. 2015;65:1398-1408), while a sampling of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database showed a 30-day readmission rate of 16.5% for lower extremity bypass (J Vasc Surg. 2014;60:1266-74).

Salvage limbs at all costs

Aggressive limb salvage in people with diabetes leads to an overall reduction in cost not only economically, but also from the patient’s perspective. The vast majority of diabetic patients with critical ischemia are actually good candidates for limb salvage. Tragically, many of these patients are never referred for evaluation for limb salvage because of misconceptions about the pathophysiology of the disease.

An argument against limb salvage is that primary amputation prevents or shortens the course of wound care and enables patients to become ambulatory, albeit with a prosthesis, faster. However, in the modern era of vascular surgery, revascularization can be performed successfully with minimal mortality and excellent rates of limb salvage, especially when it’s done within a team-based approach.

Dr. Trissa A. Babrowski is an assistant professor of surgery, specializing in vascular surgery and endovascular therapy, at the University of Chicago Heart and Vascular Center. She had no financial relationships to disclose.

Primary amputation can be OK

I am not an amputationalist. I do practice limb salvage. In fact I’m probably the most aggressive limb salvage surgeon in my hospital. But primary amputation is a completely acceptable option for a selected group of patients with diabetes. We should not try to do limb salvage “at all costs.”

I do not find this to be a contradictory position. In fact, I think it adds credence to my support of limb salvage that I think primary amputation can be OK. In all honesty, there are very few things in life that should be done at all costs.

Dr. Timothy J. Nypaver is head of vascular surgery at Henry Ford Hospital, Detroit. He had no financial relationships to disclose.

Salvage limbs at all costs

Aggressive limb salvage in people with diabetes leads to an overall reduction in cost not only economically, but also from the patient’s perspective. The vast majority of diabetic patients with critical ischemia are actually good candidates for limb salvage. Tragically, many of these patients are never referred for evaluation for limb salvage because of misconceptions about the pathophysiology of the disease.

An argument against limb salvage is that primary amputation prevents or shortens the course of wound care and enables patients to become ambulatory, albeit with a prosthesis, faster. However, in the modern era of vascular surgery, revascularization can be performed successfully with minimal mortality and excellent rates of limb salvage, especially when it’s done within a team-based approach.

Dr. Trissa A. Babrowski is an assistant professor of surgery, specializing in vascular surgery and endovascular therapy, at the University of Chicago Heart and Vascular Center. She had no financial relationships to disclose.

Primary amputation can be OK

I am not an amputationalist. I do practice limb salvage. In fact I’m probably the most aggressive limb salvage surgeon in my hospital. But primary amputation is a completely acceptable option for a selected group of patients with diabetes. We should not try to do limb salvage “at all costs.”

I do not find this to be a contradictory position. In fact, I think it adds credence to my support of limb salvage that I think primary amputation can be OK. In all honesty, there are very few things in life that should be done at all costs.

Dr. Timothy J. Nypaver is head of vascular surgery at Henry Ford Hospital, Detroit. He had no financial relationships to disclose.

Salvage limbs at all costs

Aggressive limb salvage in people with diabetes leads to an overall reduction in cost not only economically, but also from the patient’s perspective. The vast majority of diabetic patients with critical ischemia are actually good candidates for limb salvage. Tragically, many of these patients are never referred for evaluation for limb salvage because of misconceptions about the pathophysiology of the disease.

An argument against limb salvage is that primary amputation prevents or shortens the course of wound care and enables patients to become ambulatory, albeit with a prosthesis, faster. However, in the modern era of vascular surgery, revascularization can be performed successfully with minimal mortality and excellent rates of limb salvage, especially when it’s done within a team-based approach.

Dr. Trissa A. Babrowski is an assistant professor of surgery, specializing in vascular surgery and endovascular therapy, at the University of Chicago Heart and Vascular Center. She had no financial relationships to disclose.

Primary amputation can be OK

I am not an amputationalist. I do practice limb salvage. In fact I’m probably the most aggressive limb salvage surgeon in my hospital. But primary amputation is a completely acceptable option for a selected group of patients with diabetes. We should not try to do limb salvage “at all costs.”

I do not find this to be a contradictory position. In fact, I think it adds credence to my support of limb salvage that I think primary amputation can be OK. In all honesty, there are very few things in life that should be done at all costs.

Dr. Timothy J. Nypaver is head of vascular surgery at Henry Ford Hospital, Detroit. He had no financial relationships to disclose.