Combining clopidogrel and aspirin following a small stroke or minor stroke symptoms reduces the risk of a new stroke, heart attack, or other ischemic event within 90 days, say researchers from the National Institute of Neurological Disorders and Stroke.

In POINT (Platelet-Oriented Inhibition in New TIA and minor ischemic stroke), an international clinical trial, 5% of the combination therapy group and 6.5% of the aspirin-only group had an ischemic event within 90 days. The benefit of the combination was concentrated in the first 2 weeks, while the risk of bleeding was constant over 90 days, says Walter Koroshetz, MD, director of NINDS, thus the treatment may be most valuable in acute management of a minor ischemic stroke or TIA.

The study was stopped early not only because the combination therapy was more effective than aspirin alone in preventing severe strokes, but also due to the risk of severe hemorrhage. The combination therapy was associated with an increase in major bleeding, although many of the episodes were not fatal and occurred outside the brain: 0.9% of the combination group had a major hemorrhage, compared with 0.4% of the aspirin-only group.

 “Overall, the risk of severe bleeding was very small,” says lead investigator S. Claiborne Johnston, MD, PhD, “but it was not zero.”

Combining clopidogrel and aspirin following a small stroke or minor stroke symptoms reduces the risk of a new stroke, heart attack, or other ischemic event within 90 days, say researchers from the National Institute of Neurological Disorders and Stroke.

In POINT (Platelet-Oriented Inhibition in New TIA and minor ischemic stroke), an international clinical trial, 5% of the combination therapy group and 6.5% of the aspirin-only group had an ischemic event within 90 days. The benefit of the combination was concentrated in the first 2 weeks, while the risk of bleeding was constant over 90 days, says Walter Koroshetz, MD, director of NINDS, thus the treatment may be most valuable in acute management of a minor ischemic stroke or TIA.

The study was stopped early not only because the combination therapy was more effective than aspirin alone in preventing severe strokes, but also due to the risk of severe hemorrhage. The combination therapy was associated with an increase in major bleeding, although many of the episodes were not fatal and occurred outside the brain: 0.9% of the combination group had a major hemorrhage, compared with 0.4% of the aspirin-only group.

 “Overall, the risk of severe bleeding was very small,” says lead investigator S. Claiborne Johnston, MD, PhD, “but it was not zero.”

Combining clopidogrel and aspirin following a small stroke or minor stroke symptoms reduces the risk of a new stroke, heart attack, or other ischemic event within 90 days, say researchers from the National Institute of Neurological Disorders and Stroke.

In POINT (Platelet-Oriented Inhibition in New TIA and minor ischemic stroke), an international clinical trial, 5% of the combination therapy group and 6.5% of the aspirin-only group had an ischemic event within 90 days. The benefit of the combination was concentrated in the first 2 weeks, while the risk of bleeding was constant over 90 days, says Walter Koroshetz, MD, director of NINDS, thus the treatment may be most valuable in acute management of a minor ischemic stroke or TIA.

The study was stopped early not only because the combination therapy was more effective than aspirin alone in preventing severe strokes, but also due to the risk of severe hemorrhage. The combination therapy was associated with an increase in major bleeding, although many of the episodes were not fatal and occurred outside the brain: 0.9% of the combination group had a major hemorrhage, compared with 0.4% of the aspirin-only group.

 “Overall, the risk of severe bleeding was very small,” says lead investigator S. Claiborne Johnston, MD, PhD, “but it was not zero.”

From the Harrison School of Pharmacy, Auburn University, Mobile, AL.

Abstract

• Objective: To summarize the literature relevant to managing dyslipidemia in the elderly and review recommendations for initiating lipid-lowering therapy.
• Methods: Review of the literature.
• Results: Statins are the most commonly utilized medication class for lipid-lowering in the general population, and they are recommended for primary prevention in patients between the ages of 40 to 75 with at least 1 risk factor for cardiovascular disease as well as for any patient needing secondary prevention. In the elderly, statins may be appropriate for both primary and secondary prevention if the benefits outweigh the risks. Based on the available evidence, it is safe to recommend statin therapy to elderly patients who require secondary prevention given the known benefits in reducing cardiovascular morbidity and mortality for patients up to the age of 80. For primary prevention, statin therapy may be beneficial, but one must carefully evaluate for comorbid conditions, life expectancy, concomitant medications, overall health status, frailty, and patient or family preference. Several other classes of lipid-lowering agents exist; however, there is not enough evidence for us to recommend use in the elderly population for cardiovascular risk reduction in either primary or secondary scenarios.
• Conclusion: Although clinical research in the elderly population is limited, evidence supports the use of statins in elderly patients for secondary prevention and in patients up to age 75 for primary prevention; however clinicians must use clinical judgement and take into consideration the patient’s situation regarding comorbidities, polypharmacy, and possible adverse effects. More high-quality evidence is necessary.

Key words: hyperlipidemia; geriatrics; elderly; patient-centered care; statin; cardiovascular disease.

The number of Americans age 65 years and older is projected to more than double, from 46 million today to over 98 million by 2060, and the 65-and-older age group’s share of the total population will rise to nearly 24% [1]. Life expectancy is now predicted to be > 20 years for women at age 65 and > 17 years for men at age 65 in many high-income countries, including the United States [2]. This demographic shift toward an older population will result in a higher burden of coronary heart disease and stroke, with atherosclerotic cardiovascular disease (ASCVD) prevalence and costs projected to increase substantially [3].

Among adults seeking medical care in the United States, roughly 95 million have a total cholesterol (TC) level of ≥ 200 mg/dL or more, and approximately 29 million have a TC > 240 mg/dL [4]. Cholesterol screening is important since most patients suffering from dyslipidemia are asymptomatic. Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Because of the complications associated with dyslipidemia, it is vital that patients are provided with primary and/or secondary prevention strategies to reduce the risk of cardiovascular disease (CVD) and protect high-risk patients from recurring events. A clinical controversy exists surrounding the elderly population, concerning whether or not clinicians should be providing lipid-lowering treatment to this group of individuals for dyslipidemia. The evidence is limited for patients over age 65, and even more so for the very elderly (> 80 years); therefore, it is necessary to review the available evidence to make an appropriate decision when it comes to managing dyslipidemia in the elderly population

Currently, HMG-CoA reductase inhibitors (statins) are the only known class of medications for the treatment of dyslipidemia that will prevent both primary and secondary cardiovascular (CV) events, including death. Statin intensity (Table 1) 

Guideline Recommendations

Current guidelines differ in their recommendations for treating dyslipidemia in the elderly population. In 2016, the Task Force for the Management of Dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) released updated guidelines for managing dyslipidemia. These guidelines recommend that older patients with established CVD be treated in the same way as younger patients because of the many benefits statin therapy demonstrated in clinical trials. They also suggest that statin therapy be started at a lower doses to achieve goals for primary prevention in the older population. In addition, CVD risk factors (hypertension, diabetes, dyslipidemia, smoking) should be addressed in this population to reduce CVD risk. They also acknowledged that primary prevention may not prolong life in the older adult, but treatment does reduce cardiovascular mortality and statin therapy is recommended to reduce the overall risk of CV morbidity in this population [11]. In contrast, The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines changed the management and treatment of dyslipidemia by highlighting “statin benefit groups” rather than recommending a treat-to-target goal as guidelines had done for many years. ACC/AHA recommends a moderate-intensity statin for patients > 75 years of age for secondary prevention versus the use of a high-intensity statin for patients who are between the ages of 40 and 75 based on the pooled cohort risk equation. In patients over age 75 with no history of CVD, no specific recommendation is available for the use of lipid-lowering therapy at this time [12]. ACC/AHA is expected to publish a new set of guidelines sometime in 2018 and they are projected to utilize lipid-lowering goals in combination with the pooled cohort equation to assess overall risk in patients with dyslipidemia.

The 2015 National Lipid Association (NLA) released “Part 1” guidelines for the management of dyslipidemia and then provided “Part 2” about a year later, which focuses on management for special populations. To summarize, the NLA guidelines recommend that elderly patients between the ages of 65 and 80 receive a high-intensity statin for secondary prevention after special consideration of the potential risks and benefits. In patients over the age of 80, NLA recommends a moderate-intensity statin for secondary prevention. For primary prevention, NLA recommends utilizing the pooled cohort risk equation to analyze patient characteristics, keeping in mind that age is a driving factor for increased risk of CVD and that the actual risk for developing a CV event may be “overestimated” if the patient has no other risk factors other than their age. When evaluating patients between the ages of 65 and 79 for primary prevention, NLA suggests following Part 1 of the guidelines. In Part 1, NLA recommends evaluating the patient’s characteristics and suggests a moderate- or high-intensity statin if the patient is considered “very high risk” or “high risk” and a moderate-intensity statin for patients who are considered “moderate risk”. For patients over the age of 80, they recommend utilizing a moderate- or a low-intensity statin depending on frailty status or if significant comorbidities or polypharmacy exist [13,14].

In 2017, the American Association of Clinical Endocrinologist (AACE) released guidelines for the management of dyslipidemia and CVD prevention. AACE recommends that patients over age 65 be screened for dyslipidemia, and those who have multiple risk factors, other than age, should be considered for treatment with lipid-lowering therapy. AACE focuses on specific target LDL-C levels as treatment goals [15].

In addition to statins, other lipid-lowering therapies are used to treat dyslipidemia. The 2016 American College of Cardiology (ACC) Task Force reported on the use of non-statin therapies for the management of dyslipidemia and prevention of clinical ASCVD [16]. The committee concluded that ezetimibe added to statin therapy, bile acid sequestrants as monotherapy, and niacin as monotherapy all have some benefit for the prevention of clinical ASCVD. These guidelines also discuss the use of PCSK-9 inhibitors and their potential to decrease the risk of clinical ASCVD, but trials are currently ongoing to determine actual benefit. These guidelines address special populations but they do not consider the elderly in their recommendations. Currently, the only special populations included are patients with heart failure, those on hemodialysis, women who are of childbearing age or pregnant, and those with autoimmune diseases [16]. The literature available for each individual medication is discussed in further detail below.

Evidence for Secondary Prevention

The benefits of statin therapy for secondary prevention in the elderly is more established than it is for primary prevention (Table 2). 

The ASCOT–LLA (Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm), published in 2003, evaluated the effect of atorvastatin 10 mg on reducing ASCVD events in moderate-risk patients between 40–79 years of age who had hypertension and normal or slightly elevated LDL-C levels, with at least 2 other risk factors for CVD (age > 55 years was considered a risk factor). The primary outcome was non-fatal MI including silent MI and fatal CHD. A significant reduction was seen in the primary endpoint. Over half of the study population was > 60 years of age, with a mean age of 63 years. In a post-hoc analysis, stroke prevention was found to be similar in patients who were > 70 years of age and those < 70 years of age [19].

One of the first trials to specifically analyze the impact of age on lipid-lowering therapy in secondary ASCVD prevention was the Scandinavian Simvastatin Survival Study (4S), published in 1994. They evaluated the effect of simvastatin 20 mg on CV-related mortality and morbidity in patients 35–70 years of age with hyperlipidemia and a history of angina or acute MI occurring > 6 months of the study starting. The primary outcome was all-cause mortality. The secondary endpoint was time to first major CV event, which included coronary death, non-fatal acute MI, resuscitated cardiac arrest, and silent MI. Simvastatin significantly reduced the primary outcome and CHD-related deaths. A subgroup analysis of the study population > 60 years of age showed that age made no significant impact on primary or secondary outcomes; however, investigators noted that these subgroup analyses had less statistical power than the population as a whole [20].

Published in 1998, the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) study evaluated the effects of pravastatin 40 mg daily on CHD-related mortality and overall mortality in patients with hyperlipidemia and clinical ASCVD (previous MI or unstable angina). The primary outcome observed was fatal CHD. Pravastatin significantly reduced the primary outcome, overall mortality, and pre-specified CV events. In a subgroup analysis, age group ( 65, and > 70 years) had no significant impact on the combined outcome of death from CHD and nonfatal MI; however, patients 65 to 70 years of age made up less than half of the study population [21].

The Cholesterol and Recurrent Events (CARE) trial, published in 1996, looked at the effect of pravastatin 40mg therapy for secondary ASCVD prevention following an MI in patients who had average cholesterol levels (defined as TC < 240 mg/dL and LDL-C 115–174 mg/dL). The primary endpoint assessed was time to fatal CHD or nonfatal MI. To meet statistical power they looked at subgroups for a broader outcome of a major coronary event (including fatal CHD, nonfatal MI, bypass surgery, and angioplasty). Pravastatin significantly reduced the primary outcome. The significant reduction in coronary events produced by pravastatin was noted to be significantly greater in women and in patients with higher pretreatment levels of LDL-C, but was not significantly impacted by age group (24–59 vs. 60–75 years) [22].

The Heart Protection Study (HPS), published in 2002, looked at the long-term effects of lowering LDL-C with simvastatin 40 mg in patients 40 to 80 years of age at high risk for mortality due to either vascular or nonvascular causes. The primary outcome assessed was all-cause mortality, with fatal or nonfatal vascular events as co-primary outcomes for subcategory analyses. Simvastatin significantly reduced both primary and co-primary outcomes, but there was no significant difference when they looked at nonvascular mortality between groups. Neither age nor baseline LDL levels were reported to have had a significant impact on outcomes. Over half the population was > 65 years of age, and about one-third of the population was > 70 years of age [23].

The PROVE-IT/TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) trial, published in 2004, compared pravastatin 40 mg (moderate-intensity) to atorvastatin 80 mg (high-intensity) for secondary ASCVD prevention in patients with recent acute coronary syndrome (ACS) 65 years of age and the mean age was 58 years [24].

The TNT (Treating to New Targets) trial, published in 2005, looked at secondary ASCVD prevention in regards to targeting LDL-C levels to < 100 mg/dL or < 70 mg/dL with atorvastatin 10 mg and atorvastatin 80 mg. Patients had stable coronary artery disease (CAD) and baseline LDL-C levels < 130 mg/dL. The primary endpoint was the occurrence of a CV event (CAD mortality, nonfatal MI not related to procedure, resuscitation after cardiac arrest, or fatal or nonfatal stroke). High-intensity atorvastatin (80 mg) significantly reduced the primary outcome. The mean age of the study population was approximately 61 years. The study reported no statistical interaction for age or sex in the primary outcome measure [25].

The Study Assessing Goals in the Elderly (SAGE), published in 2007, evaluated the effects of pravastatin 40 mg (moderate-intensity) vs atorvastatin 80 mg (high-intensity) on secondary ASCVD prevention in patients 65 to 85 years (mean age 72) with stable CHD, LDL-C 100–250 mg/dL, with at least 1 episode of myocardial ischemia with total ischemia duration > 3 minutes. The primary efficacy outcome observed was absolute change in total duration of myocardial ischemia on 48-hour ambulatory electrocardiographic monitoring from baseline to month 12. No significant difference was observed in efficacy between the two groups for the primary endpoint, but the intensive statin therapy group showed greater benefit respective to several secondary outcomes, including major acute CV events and death [26].

In summary, while these trials provide evidence that statin therapy is beneficial in a wide range of patients with clinical ASCVD and dyslipidemia, the trial data does not provide definitive guidance for treating elderly patients at this time. Given the small percentage of elderly patients that were included, some of the trial results reporting statistical significance in this age group hold less clinical significance. It appears that high-intensity statin therapy was more likely to effectively prevent clinical ASCVD and death than moderate-intensity statin therapy, but more evidence is needed regarding secondary prevention in patients over age 75.

Evidence for Primary Prevention

The PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) was published in 2002 to assess the efficacy of pravastatin in patients between the ages of 70 and 82 (mean age 75 years) with pre-existing vascular disease (coronary, cerebral, or peripheral) or at an elevated risk (smoking, hypertension, or diabetes). Patients were randomized to receive either placebo or pravastatin 40 mg (a moderate-intensity statin). They found that pravastatin therapy reduced the risk of the composite outcome of CHD-related death, nonfatal MI, and fatal or nonfatal stroke in this elderly population. A post-hoc analysis comparing primary versus secondary prevention groups found no significant differences between these subgroups [7].

Han et al recently conducted a post hoc secondary analysis of older participants (65 years and older) in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT-LLT). The intervention for ALLHAT-LLT was 40 mg pravastatin. They found no significant differences in all-cause mortality or cardiovascular outcomes between the pravastatin and usual care groups [27]

JUPITER (Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), published in 2008, examined the efficacy of rosuvastatin vs. placebo in low- to moderate-risk men 50 years and older and women 60 years and older using a composite outcome of MI, unstable angina, stroke, arterial revascularization, or CVD death. Rosuvastatin did significantly decrease the primary endpoint, however it did not reduce the risk of overall death [28]. A subgroup analysis was performed on the elderly (65–75 years) study participants in JUPITER demonstrating a significant risk reduction for the combined CV endpoint and a nonsignificant reduction of all-cause mortality [29].

CARDS (Collaborative Atorvastatin Diabetes Study), published in 2004, looked at statin use for primary prevention in high-risk patients with type 2 diabetes without high LDL-C, but they had to have at least 1 additional risk factor for CVD. The primary outcome was first acute CHD event (myocardial infarction including silent infarction, unstable angina, acute coronary heart disease death, resuscitated cardiac arrest), coronary revascularization procedures, or stroke. Atorvastatin 10 mg, a moderate-intensity statin, significantly decreased occurrence of the primary outcome [30]. A subgroup analysis was performed to evaluate patients specifically between the ages of 65 and 75 and found a similar outcome in the elderly with a significant reduction in first major CV event and stroke [31].

A recent study evaluating primary prevention in patients with an intermediate risk for CVD was the HOPE-3 (Heart Outcomes Prevention Evaluation), published in 2016. Two co-primary outcomes were evaluated: the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, while the second primary outcome also included revascularization, heart failure, and resuscitated cardiac arrest. Rosuvastatin significantly decreased occurrence of both co-primary endpoints. About half of the study populations was over the age of 65 with a median age of 71 [32].

In addition to these trials of primary prevention, summarized in Table 3, a meta-analysis was published in 2013 to assess whether statins reduce all-cause mortality and CV events in elderly people without established CV disease. 

As demonstrated by the above studies, it is evident that statins do help reduce the risk of CV events, regardless of statin intensity, but they do not consistently prevent death. However, the trials that did not demonstrate a significant outcome related to death utilized a moderate-intensity statin; if a high-intensity statin was used in those trials, there may have been a benefit [7,27]. More study is needed to evaluate the use of high-intensity statins in the elderly for the prevention of all-cause mortality and CV-related death.

Fortunately, the ongoing STAREE (STAtin Therapy for Reducing Events in the Elderly) study is looking specifically at the impact of statin therapy in adults 70 and older. Patients with a history of CVD or dementia are excluded. Results are set to be released in 2020 [34].

Risks of Using Statins in Older Adults

Statin use has been linked to a number of unwanted adverse effects.

Myalgia

Myalgia is variable but may occur in up to 25% of patients using statin therapy, and elderly patients typically experience more statin-associated myalgia than younger patients [35,36]. Elderly patients are more prone to decreased muscle mass and therefore may be at a higher risk of developing myalgia pain. Elderly patients are also utilizing more medications, leading to the potential for increased drug-drug interactions that could lead to myalgia. Elderly patients may also lose the function of drug metabolizing enzymes responsible for breaking down statin therapy, which may also increase the risk for statin-associated myalgia. One study demonstrated that elderly patients were more likely to discontinue statin therapy due to muscle pain and elderly patients reported more muscle side effects than their younger cohorts [37]. It is important to monitor for muscle pain and weakness in every patient. If they experience any myalgia, it is recommended to either lower the dose or discontinue the statin once it is determined to be statin-related. After myalgia resolves, therapy can be reinitiated at a lower dose or with a different statin if the patient is deemed high-risk. If creatine phosphokinase levels are greater than 10 times above the upper limit of normal, then discontinue the statin and wait for levels to return to normal. Re-initiation may be appropriate, but the the risks and benefits must be weighed. Simvastatin and atorvastatin are associated with higher rates of myalgia while pravastatin and rosuvastatin have the least myalgia pain associated with use [38,39].

Statin Intolerance

Statin intolerance, while not very common, is typically seen more often in special populations such as women, Asian patients, and the elderly. For a patient to be considered intolerant to statins, they need to have documented muscle symptoms or an elevated creatine phosphokinase level. Although not well defined, many clinicians consider improvement of symptoms with statin withdrawal as a diagnosis for statin intolerance. Typically patients are then rechallenged with 1 to 2 other statins and if still unable to tolerate, then different lipid-lowering therapies may be utilized [40]. In the elderly, it is important to rule out other causes for myalgia and monitor for significant drug interactions that may lead to muscle pain, particularly if the patient is requiring secondary prevention with statin therapy, before discontinuation.

Dementia

In 2012, the FDA issued a warning about the potential risk of cognitive impairment with the use of statins, which was based on case reports, not clinical trial data [41]. The NLA guidelines do not recommend baseline cognitive assessments prior to starting therapy and recommend that if patients do report cognitive impairment, other contributing factors and the risk associated with stopping statin therapy must be considered. Statin therapy may be discontinued to assess reversibility of symptoms, and if symptoms resolve, then it may be more beneficial to keep the patient off statin therapy. Clinicians may also consider lowering the dose or switching to another statin if they feel it is necessary for the patient to continue with a statin, particularly if the patient requires secondary prevention. Evidence suggests that statins are not associated with adverse effects on cognition and should not be withheld due to the potential for causing cognitive impairment alone [42]. The prevalence of cognitive impairment increases with age, so it is important for a clinician to rule out age-related processes or other disease states, such as Alzheimer’s, before discontinuation of previously tolerated statin therapy.

Renal Impairment

Kidney function must be evaluated prior to initiation of a statin in an elderly person as well as during the time the patient is taking a statin. Because statins are eliminated via the kidney, and because most elderly patients have decreased kidney function, the potential for drug build-up in the body is higher than in a younger patient and may lead to more adverse effects. Atorvastatin is the only option that does not require dose adjustment. All other statins should be adjusted based upon the level of renal impairment. The results from the SHARP study, published in 2011, showed that the combination of ezetimibe and simvastatin versus placebo significantly reduced ASCVD events in patients with moderate to severe chronic kidney disease, including those receiving dialysis. Specifically, this trial showed a significant reduction of ischemic events and occurrence of arterial revascularization procedures. Although the trial did not show a significant difference in incidence of MI or CHD-related mortality, the trial was not adequately powered to show differences in results among the individual ASCVD events and it is not clear whether the results can guide the use of statin therapy in all patients with chronic kidney disease [43]. Statins may be beneficial in renal insufficiency to lower LDL-C, but more studies are needed to assess CVD outcomes related to statin use in patients with a history of kidney disease [44].

Hepatic Function

Statins have been known to increase liver enzymes and in rare cases lead to liver injury, which typically has led to underutilization of therapy in clinical practice. Risk factors associated with this include preexisting hepatitis, advanced age, chronic alcohol use, and use of concomitant medications that may also cause hepatotoxicity, such as acetaminophen. When a statin-induced hepatic effect is suspected, it is important to first rule out other causes or disease states that may be undiagnosed. If no other cause can be found, clinicians may choose to reduce the statin dose, switch the statin, or discontinue the statin altogether if the risk outweighs the benefit. Additionally, statins do not have to be held in patients who have preexisting hepatic dysfunction if use is clearly indicated because the cardiovascular benefits typically outweigh the risks of causing liver injury. Clinical judgement is still warranted and patients with preexisting liver conditions should be monitored regularly [45].

Cost Considerations

Several studies have demonstrated that statin therapy, in the general population, is economical for both primary and secondary prevention of CVD [46,47]. The 4S study found simvastatin therapy to be cost-effective; for example, the cost per life year gained for a 70-year-old man with high chlesterol was $3800 [48]. In contrast, primary prevention in middle-aged men, based on the West of Scotland trial, averages about $35,000 per year of life gained [46]. In a 2015 study that utilized an established Markov simulation model, researchers studied adults 75 to 94 years and examined the cost-effectiveness of generic statins for primary prevention in this population. The authors estimated treating this population with statins over the next decade would be cost-effective. However, the researchers cautioned that the CV benefits and cost-effectiveness would be offset with even a modest increased risk of cognitive impairments or functional limitations. Statin use was not cost-effective in diabetes patients who did not have elevated LDL-C levels [49].

Non-Statin Therapies

Several other classes of medications are available for the management of hyperlipidemia; however, none of these lipid-lowering therapies have been found to reduce CVD events or mortality in the elderly population.

Ezetimibe

Ezetimibe blocks the absorption of intestinal cholesterol and is typically combined with statin therapy to lower LDL-C. Up until the IMPROVE-IT trial was published in 2015, ezetimibe did not have much use in clinical practice. This landmark trial was a large double-blind study that looked at secondary prevention in patients with ACS, comparing ezetimibe 10 mg and simvastatin 40 mg versus simvastatin 40 mg alone. The authors included patients over the age of 50 (mean age 64) with clinical ASCVD. They found that the addition of ezetimibe to simvastatin did reduce the primary composite outcome (CV mortality, major CV events, or nonfatal stroke) when compared to simvastatin alone [50]. This trial demonstrates clinical benefit with the addition of ezetimibe to statin therapy and adds additional evidence to support a target LDL-C of less than 70 mg/dL; however, the elderly population was not adequately represented in the study to allow extrapolation of these results to older patients.

PCSK-9 Inhibitors

The proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors are a newer class of monoclonal antibodies that were first approved by the US Food and Drug Administration in 2015. Alirocumab and evolocumab, both approved PCSK-9 inhibitors, bind to LDL receptors on the surface of hepatocytes and assist in the internalization of LDL receptors for lysosomal degradation. By inhibiting the binding of PCSK-9 to the LDL receptors, there is an overall increase in LDL receptors available on the cell surface to bind to LDL particles, thereby lowering LDL-C levels. Treatment with these agents are currently considered (in addition to diet and maximally tolerated statin therapy) in adult patients with heterozygous familial hypercholesterolemia or clinical ASCVD requiring further reduction in LDL-C. Two studies were published focusing on the use of PCSK-9 inhibitors: Open-label Study of Long-term Evaluation against LDL Cholesterol (OSLER) and the Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM). Overall, these studies demonstrated a 60% reduction of LDL-C among patients with high CVD risk on maximum-tolerated statin therapy. Furthermore, the ODYSSEY LONG TERM trial did find that the rate of major CVD adverse events was significantly lower with alirocumab added to maximum-tolerated statin therapy, with a hazard ratio of 0.52 [51].

One recent study of evolocumab, named the Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), enrolled patients between the ages of 40 and 85 with 1 major CV risk factor or 2 minor CV risk factors. The primary endpoint was a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. Evolocumab lowered major CV events by roughly 15% when added to statin therapy in patients who were at high risk for clinical ASCVD. The mean age of the patients in the trial was 63; however, it is unclear how many of the study participants were elderly [52].

Unfortunately, the studies discussed above do not represent the elderly population well and the agents have not been studied long-term to determine the effects of continued use beyond 2 years. Long-term outcome studies are currently underway; however, it is unknown at this time whether elderly patients are being considered in these studies. It is known that genetic variation of the PCSK-9 locus does lower LDL-C in the elderly but does not significantly lower their risk of vascular disease [51]. At this time, until further evidence is available, we do not recommend the use of PCSK-9 inhibitors in elderly patients.

Nicotinic Acid

Nicotinic acid (Niacin, Niacin ER), also known as vitamin B3, has been utilized for decades as a vitamin supplement, an anti-wrinkle agent, and is known to have neuroprotective effects. It has also been utilized for dyslipidemia and has had some benefits when used alone to decrease cardiovascular disease [53]. Unfortunately the Coronary Drug Project was completed in the 1980s and did not incorporate patients over the age of 64, therefore making the results difficult to apply to elderly patients today [54]. Other literature has been published in recent years to refute that study, claiming there is no additional benefit to using niacin for cardiovascular protection and these studies have included elderly patients. In the AIM-HIGH trial, published in 2011, approximately 46% of the patients were 65 or older. Patients who were previously taking statin therapy that had known cardiovascular disease were enrolled. Niacin added to simvastatin 40–80 mg lowered LDL-C, triglycerides, and increased HDL-C, but the addition of niacin was not proven to help lower the risk of cardiovascular events [55]. The HPS2-THRIVE study enrolled patients with known cardiovascular disease between the ages of 50 and 80 years and found no benefit in preventing CVD when adding niacin to statin therapy [56]. With its side effect profile, risk for increased glucose intolerance, and lack of evidence to demonstrate benefit for prevention of CV events, we do not recommend niacin for use in the elderly at this time.

Bile Acid Sequestrants

The ATP III guidelines [57] noted that when statins are not sufficient to lower high cholesterol, bile acid sequestrants also known as resins could be added. More recently, the 2016 ACC expert consensus on non-statin therapies for LDL-C lowering [16] stated resins may be considered in select circumstances as a second-line agent for adults with ezetimibe intolerance and with triglycerides

Fibrates

While fibrates (gemfibrozil, fenofibrate, clofibrate) have not been studied to demonstrate a reduction in CVD or CVD mortality in the elderly population, this medication class is beneficial in patients with hypertriglyceridemia to lower triglyceride levels and prevent pancreatitis. Fibrates are recommended for patients with triglyceride levels approaching 500 mg/dL. Fibrates can also increase high-density lipoproteins, which tend to be lower in the elderly population and considered a risk factor for CVD. Gemfibrozil is not recommended in combination with statin therapy due to an increased risk of myalgia. Fenofibrate is the drug of choice, particularly for diabetic patients with very uncontrolled triglyceride levels because it will not affect glucose levels [57]. At this time, we do not recommend the use of fibrates in the elderly population unless they are at risk for developing pancreatitis and have elevated triglyceride levels.

Patient-Centered Care

Evidence-based medicine can aid in making sound clinical decisions for proper patient care; however, treatment plans should consider the individual patient’s perspectives and needs, beliefs, expectations, and goals. In the elderly population, we must also consider factors such as finances, pill-burden, drug-drug interactions, physiological needs, comorbid disease states, and overall life expectancy. In addition, the elderly population is physiologically heterogeneous group and recommendations for therapy need to be individualized. Chronological age does not necessarily correspond to vascular age and risk factors for cardiovascular disease do not predict outcomes as well in the elderly as they do in younger patients. While older patients may view having to take 1 less medication as more important than preventing a heart attack or stroke at the age of 80, it is advisable to discuss all potential outcomes related to morbidity associated with the occurrence of an MI or stroke due to the lack of statin therapy. Additionally, pharmacists can play a vital role in evaluating elderly patients and their medication regimens. Elderly patients should undergo a medication reconciliation at each visit to evaluate drug-drug interactions, side effects, and potentially harmful medication combinations that may lead to increased adverse drug outcomes.

Conclusion

CHD increases with age, and most patients who have a CV event are more likely to die with advancing age. Based on the the limited available evidence, statin therapy is beneficial in the elderly population in reducing overall CV morbidity. We recommend beginning with with a moderate-intensity statin and adjusting accordingly. High-intensity statin therapy appears to be effective for elderly patients for secondary prevention, but clinicians should use clinical judgment and monitor for adverse events, particularly myalgia pain. At this time, we are unable to determine if non-statin therapies for the elderly would be beneficial and do not recommend their use unless the patient is at risk for pancreatitis, in which case a fenofibrate is recommended.

Corresponding author: Nicole A. Slater, PharmD, BCACP, Auburn University, Harrison School of Pharmacy, 650 Clinic Dr., Mobile, AL 36688.

Financial disclosures: None.

From the Harrison School of Pharmacy, Auburn University, Mobile, AL.

Abstract

• Objective: To summarize the literature relevant to managing dyslipidemia in the elderly and review recommendations for initiating lipid-lowering therapy.
• Methods: Review of the literature.
• Results: Statins are the most commonly utilized medication class for lipid-lowering in the general population, and they are recommended for primary prevention in patients between the ages of 40 to 75 with at least 1 risk factor for cardiovascular disease as well as for any patient needing secondary prevention. In the elderly, statins may be appropriate for both primary and secondary prevention if the benefits outweigh the risks. Based on the available evidence, it is safe to recommend statin therapy to elderly patients who require secondary prevention given the known benefits in reducing cardiovascular morbidity and mortality for patients up to the age of 80. For primary prevention, statin therapy may be beneficial, but one must carefully evaluate for comorbid conditions, life expectancy, concomitant medications, overall health status, frailty, and patient or family preference. Several other classes of lipid-lowering agents exist; however, there is not enough evidence for us to recommend use in the elderly population for cardiovascular risk reduction in either primary or secondary scenarios.
• Conclusion: Although clinical research in the elderly population is limited, evidence supports the use of statins in elderly patients for secondary prevention and in patients up to age 75 for primary prevention; however clinicians must use clinical judgement and take into consideration the patient’s situation regarding comorbidities, polypharmacy, and possible adverse effects. More high-quality evidence is necessary.

Key words: hyperlipidemia; geriatrics; elderly; patient-centered care; statin; cardiovascular disease.

The number of Americans age 65 years and older is projected to more than double, from 46 million today to over 98 million by 2060, and the 65-and-older age group’s share of the total population will rise to nearly 24% [1]. Life expectancy is now predicted to be > 20 years for women at age 65 and > 17 years for men at age 65 in many high-income countries, including the United States [2]. This demographic shift toward an older population will result in a higher burden of coronary heart disease and stroke, with atherosclerotic cardiovascular disease (ASCVD) prevalence and costs projected to increase substantially [3].

Among adults seeking medical care in the United States, roughly 95 million have a total cholesterol (TC) level of ≥ 200 mg/dL or more, and approximately 29 million have a TC > 240 mg/dL [4]. Cholesterol screening is important since most patients suffering from dyslipidemia are asymptomatic. Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Because of the complications associated with dyslipidemia, it is vital that patients are provided with primary and/or secondary prevention strategies to reduce the risk of cardiovascular disease (CVD) and protect high-risk patients from recurring events. A clinical controversy exists surrounding the elderly population, concerning whether or not clinicians should be providing lipid-lowering treatment to this group of individuals for dyslipidemia. The evidence is limited for patients over age 65, and even more so for the very elderly (> 80 years); therefore, it is necessary to review the available evidence to make an appropriate decision when it comes to managing dyslipidemia in the elderly population

Currently, HMG-CoA reductase inhibitors (statins) are the only known class of medications for the treatment of dyslipidemia that will prevent both primary and secondary cardiovascular (CV) events, including death. Statin intensity (Table 1) 

Guideline Recommendations

Current guidelines differ in their recommendations for treating dyslipidemia in the elderly population. In 2016, the Task Force for the Management of Dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) released updated guidelines for managing dyslipidemia. These guidelines recommend that older patients with established CVD be treated in the same way as younger patients because of the many benefits statin therapy demonstrated in clinical trials. They also suggest that statin therapy be started at a lower doses to achieve goals for primary prevention in the older population. In addition, CVD risk factors (hypertension, diabetes, dyslipidemia, smoking) should be addressed in this population to reduce CVD risk. They also acknowledged that primary prevention may not prolong life in the older adult, but treatment does reduce cardiovascular mortality and statin therapy is recommended to reduce the overall risk of CV morbidity in this population [11]. In contrast, The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines changed the management and treatment of dyslipidemia by highlighting “statin benefit groups” rather than recommending a treat-to-target goal as guidelines had done for many years. ACC/AHA recommends a moderate-intensity statin for patients > 75 years of age for secondary prevention versus the use of a high-intensity statin for patients who are between the ages of 40 and 75 based on the pooled cohort risk equation. In patients over age 75 with no history of CVD, no specific recommendation is available for the use of lipid-lowering therapy at this time [12]. ACC/AHA is expected to publish a new set of guidelines sometime in 2018 and they are projected to utilize lipid-lowering goals in combination with the pooled cohort equation to assess overall risk in patients with dyslipidemia.

The 2015 National Lipid Association (NLA) released “Part 1” guidelines for the management of dyslipidemia and then provided “Part 2” about a year later, which focuses on management for special populations. To summarize, the NLA guidelines recommend that elderly patients between the ages of 65 and 80 receive a high-intensity statin for secondary prevention after special consideration of the potential risks and benefits. In patients over the age of 80, NLA recommends a moderate-intensity statin for secondary prevention. For primary prevention, NLA recommends utilizing the pooled cohort risk equation to analyze patient characteristics, keeping in mind that age is a driving factor for increased risk of CVD and that the actual risk for developing a CV event may be “overestimated” if the patient has no other risk factors other than their age. When evaluating patients between the ages of 65 and 79 for primary prevention, NLA suggests following Part 1 of the guidelines. In Part 1, NLA recommends evaluating the patient’s characteristics and suggests a moderate- or high-intensity statin if the patient is considered “very high risk” or “high risk” and a moderate-intensity statin for patients who are considered “moderate risk”. For patients over the age of 80, they recommend utilizing a moderate- or a low-intensity statin depending on frailty status or if significant comorbidities or polypharmacy exist [13,14].

In 2017, the American Association of Clinical Endocrinologist (AACE) released guidelines for the management of dyslipidemia and CVD prevention. AACE recommends that patients over age 65 be screened for dyslipidemia, and those who have multiple risk factors, other than age, should be considered for treatment with lipid-lowering therapy. AACE focuses on specific target LDL-C levels as treatment goals [15].

In addition to statins, other lipid-lowering therapies are used to treat dyslipidemia. The 2016 American College of Cardiology (ACC) Task Force reported on the use of non-statin therapies for the management of dyslipidemia and prevention of clinical ASCVD [16]. The committee concluded that ezetimibe added to statin therapy, bile acid sequestrants as monotherapy, and niacin as monotherapy all have some benefit for the prevention of clinical ASCVD. These guidelines also discuss the use of PCSK-9 inhibitors and their potential to decrease the risk of clinical ASCVD, but trials are currently ongoing to determine actual benefit. These guidelines address special populations but they do not consider the elderly in their recommendations. Currently, the only special populations included are patients with heart failure, those on hemodialysis, women who are of childbearing age or pregnant, and those with autoimmune diseases [16]. The literature available for each individual medication is discussed in further detail below.

Evidence for Secondary Prevention

The benefits of statin therapy for secondary prevention in the elderly is more established than it is for primary prevention (Table 2). 

The ASCOT–LLA (Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm), published in 2003, evaluated the effect of atorvastatin 10 mg on reducing ASCVD events in moderate-risk patients between 40–79 years of age who had hypertension and normal or slightly elevated LDL-C levels, with at least 2 other risk factors for CVD (age > 55 years was considered a risk factor). The primary outcome was non-fatal MI including silent MI and fatal CHD. A significant reduction was seen in the primary endpoint. Over half of the study population was > 60 years of age, with a mean age of 63 years. In a post-hoc analysis, stroke prevention was found to be similar in patients who were > 70 years of age and those < 70 years of age [19].

One of the first trials to specifically analyze the impact of age on lipid-lowering therapy in secondary ASCVD prevention was the Scandinavian Simvastatin Survival Study (4S), published in 1994. They evaluated the effect of simvastatin 20 mg on CV-related mortality and morbidity in patients 35–70 years of age with hyperlipidemia and a history of angina or acute MI occurring > 6 months of the study starting. The primary outcome was all-cause mortality. The secondary endpoint was time to first major CV event, which included coronary death, non-fatal acute MI, resuscitated cardiac arrest, and silent MI. Simvastatin significantly reduced the primary outcome and CHD-related deaths. A subgroup analysis of the study population > 60 years of age showed that age made no significant impact on primary or secondary outcomes; however, investigators noted that these subgroup analyses had less statistical power than the population as a whole [20].

Published in 1998, the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) study evaluated the effects of pravastatin 40 mg daily on CHD-related mortality and overall mortality in patients with hyperlipidemia and clinical ASCVD (previous MI or unstable angina). The primary outcome observed was fatal CHD. Pravastatin significantly reduced the primary outcome, overall mortality, and pre-specified CV events. In a subgroup analysis, age group ( 65, and > 70 years) had no significant impact on the combined outcome of death from CHD and nonfatal MI; however, patients 65 to 70 years of age made up less than half of the study population [21].

The Cholesterol and Recurrent Events (CARE) trial, published in 1996, looked at the effect of pravastatin 40mg therapy for secondary ASCVD prevention following an MI in patients who had average cholesterol levels (defined as TC < 240 mg/dL and LDL-C 115–174 mg/dL). The primary endpoint assessed was time to fatal CHD or nonfatal MI. To meet statistical power they looked at subgroups for a broader outcome of a major coronary event (including fatal CHD, nonfatal MI, bypass surgery, and angioplasty). Pravastatin significantly reduced the primary outcome. The significant reduction in coronary events produced by pravastatin was noted to be significantly greater in women and in patients with higher pretreatment levels of LDL-C, but was not significantly impacted by age group (24–59 vs. 60–75 years) [22].

The Heart Protection Study (HPS), published in 2002, looked at the long-term effects of lowering LDL-C with simvastatin 40 mg in patients 40 to 80 years of age at high risk for mortality due to either vascular or nonvascular causes. The primary outcome assessed was all-cause mortality, with fatal or nonfatal vascular events as co-primary outcomes for subcategory analyses. Simvastatin significantly reduced both primary and co-primary outcomes, but there was no significant difference when they looked at nonvascular mortality between groups. Neither age nor baseline LDL levels were reported to have had a significant impact on outcomes. Over half the population was > 65 years of age, and about one-third of the population was > 70 years of age [23].

The PROVE-IT/TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) trial, published in 2004, compared pravastatin 40 mg (moderate-intensity) to atorvastatin 80 mg (high-intensity) for secondary ASCVD prevention in patients with recent acute coronary syndrome (ACS) 65 years of age and the mean age was 58 years [24].

The TNT (Treating to New Targets) trial, published in 2005, looked at secondary ASCVD prevention in regards to targeting LDL-C levels to < 100 mg/dL or < 70 mg/dL with atorvastatin 10 mg and atorvastatin 80 mg. Patients had stable coronary artery disease (CAD) and baseline LDL-C levels < 130 mg/dL. The primary endpoint was the occurrence of a CV event (CAD mortality, nonfatal MI not related to procedure, resuscitation after cardiac arrest, or fatal or nonfatal stroke). High-intensity atorvastatin (80 mg) significantly reduced the primary outcome. The mean age of the study population was approximately 61 years. The study reported no statistical interaction for age or sex in the primary outcome measure [25].

The Study Assessing Goals in the Elderly (SAGE), published in 2007, evaluated the effects of pravastatin 40 mg (moderate-intensity) vs atorvastatin 80 mg (high-intensity) on secondary ASCVD prevention in patients 65 to 85 years (mean age 72) with stable CHD, LDL-C 100–250 mg/dL, with at least 1 episode of myocardial ischemia with total ischemia duration > 3 minutes. The primary efficacy outcome observed was absolute change in total duration of myocardial ischemia on 48-hour ambulatory electrocardiographic monitoring from baseline to month 12. No significant difference was observed in efficacy between the two groups for the primary endpoint, but the intensive statin therapy group showed greater benefit respective to several secondary outcomes, including major acute CV events and death [26].

In summary, while these trials provide evidence that statin therapy is beneficial in a wide range of patients with clinical ASCVD and dyslipidemia, the trial data does not provide definitive guidance for treating elderly patients at this time. Given the small percentage of elderly patients that were included, some of the trial results reporting statistical significance in this age group hold less clinical significance. It appears that high-intensity statin therapy was more likely to effectively prevent clinical ASCVD and death than moderate-intensity statin therapy, but more evidence is needed regarding secondary prevention in patients over age 75.

Evidence for Primary Prevention

The PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) was published in 2002 to assess the efficacy of pravastatin in patients between the ages of 70 and 82 (mean age 75 years) with pre-existing vascular disease (coronary, cerebral, or peripheral) or at an elevated risk (smoking, hypertension, or diabetes). Patients were randomized to receive either placebo or pravastatin 40 mg (a moderate-intensity statin). They found that pravastatin therapy reduced the risk of the composite outcome of CHD-related death, nonfatal MI, and fatal or nonfatal stroke in this elderly population. A post-hoc analysis comparing primary versus secondary prevention groups found no significant differences between these subgroups [7].

Han et al recently conducted a post hoc secondary analysis of older participants (65 years and older) in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT-LLT). The intervention for ALLHAT-LLT was 40 mg pravastatin. They found no significant differences in all-cause mortality or cardiovascular outcomes between the pravastatin and usual care groups [27]

JUPITER (Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), published in 2008, examined the efficacy of rosuvastatin vs. placebo in low- to moderate-risk men 50 years and older and women 60 years and older using a composite outcome of MI, unstable angina, stroke, arterial revascularization, or CVD death. Rosuvastatin did significantly decrease the primary endpoint, however it did not reduce the risk of overall death [28]. A subgroup analysis was performed on the elderly (65–75 years) study participants in JUPITER demonstrating a significant risk reduction for the combined CV endpoint and a nonsignificant reduction of all-cause mortality [29].

CARDS (Collaborative Atorvastatin Diabetes Study), published in 2004, looked at statin use for primary prevention in high-risk patients with type 2 diabetes without high LDL-C, but they had to have at least 1 additional risk factor for CVD. The primary outcome was first acute CHD event (myocardial infarction including silent infarction, unstable angina, acute coronary heart disease death, resuscitated cardiac arrest), coronary revascularization procedures, or stroke. Atorvastatin 10 mg, a moderate-intensity statin, significantly decreased occurrence of the primary outcome [30]. A subgroup analysis was performed to evaluate patients specifically between the ages of 65 and 75 and found a similar outcome in the elderly with a significant reduction in first major CV event and stroke [31].

A recent study evaluating primary prevention in patients with an intermediate risk for CVD was the HOPE-3 (Heart Outcomes Prevention Evaluation), published in 2016. Two co-primary outcomes were evaluated: the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, while the second primary outcome also included revascularization, heart failure, and resuscitated cardiac arrest. Rosuvastatin significantly decreased occurrence of both co-primary endpoints. About half of the study populations was over the age of 65 with a median age of 71 [32].

In addition to these trials of primary prevention, summarized in Table 3, a meta-analysis was published in 2013 to assess whether statins reduce all-cause mortality and CV events in elderly people without established CV disease. 

As demonstrated by the above studies, it is evident that statins do help reduce the risk of CV events, regardless of statin intensity, but they do not consistently prevent death. However, the trials that did not demonstrate a significant outcome related to death utilized a moderate-intensity statin; if a high-intensity statin was used in those trials, there may have been a benefit [7,27]. More study is needed to evaluate the use of high-intensity statins in the elderly for the prevention of all-cause mortality and CV-related death.

Fortunately, the ongoing STAREE (STAtin Therapy for Reducing Events in the Elderly) study is looking specifically at the impact of statin therapy in adults 70 and older. Patients with a history of CVD or dementia are excluded. Results are set to be released in 2020 [34].

Risks of Using Statins in Older Adults

Statin use has been linked to a number of unwanted adverse effects.

Myalgia

Myalgia is variable but may occur in up to 25% of patients using statin therapy, and elderly patients typically experience more statin-associated myalgia than younger patients [35,36]. Elderly patients are more prone to decreased muscle mass and therefore may be at a higher risk of developing myalgia pain. Elderly patients are also utilizing more medications, leading to the potential for increased drug-drug interactions that could lead to myalgia. Elderly patients may also lose the function of drug metabolizing enzymes responsible for breaking down statin therapy, which may also increase the risk for statin-associated myalgia. One study demonstrated that elderly patients were more likely to discontinue statin therapy due to muscle pain and elderly patients reported more muscle side effects than their younger cohorts [37]. It is important to monitor for muscle pain and weakness in every patient. If they experience any myalgia, it is recommended to either lower the dose or discontinue the statin once it is determined to be statin-related. After myalgia resolves, therapy can be reinitiated at a lower dose or with a different statin if the patient is deemed high-risk. If creatine phosphokinase levels are greater than 10 times above the upper limit of normal, then discontinue the statin and wait for levels to return to normal. Re-initiation may be appropriate, but the the risks and benefits must be weighed. Simvastatin and atorvastatin are associated with higher rates of myalgia while pravastatin and rosuvastatin have the least myalgia pain associated with use [38,39].

Statin Intolerance

Statin intolerance, while not very common, is typically seen more often in special populations such as women, Asian patients, and the elderly. For a patient to be considered intolerant to statins, they need to have documented muscle symptoms or an elevated creatine phosphokinase level. Although not well defined, many clinicians consider improvement of symptoms with statin withdrawal as a diagnosis for statin intolerance. Typically patients are then rechallenged with 1 to 2 other statins and if still unable to tolerate, then different lipid-lowering therapies may be utilized [40]. In the elderly, it is important to rule out other causes for myalgia and monitor for significant drug interactions that may lead to muscle pain, particularly if the patient is requiring secondary prevention with statin therapy, before discontinuation.

Dementia

In 2012, the FDA issued a warning about the potential risk of cognitive impairment with the use of statins, which was based on case reports, not clinical trial data [41]. The NLA guidelines do not recommend baseline cognitive assessments prior to starting therapy and recommend that if patients do report cognitive impairment, other contributing factors and the risk associated with stopping statin therapy must be considered. Statin therapy may be discontinued to assess reversibility of symptoms, and if symptoms resolve, then it may be more beneficial to keep the patient off statin therapy. Clinicians may also consider lowering the dose or switching to another statin if they feel it is necessary for the patient to continue with a statin, particularly if the patient requires secondary prevention. Evidence suggests that statins are not associated with adverse effects on cognition and should not be withheld due to the potential for causing cognitive impairment alone [42]. The prevalence of cognitive impairment increases with age, so it is important for a clinician to rule out age-related processes or other disease states, such as Alzheimer’s, before discontinuation of previously tolerated statin therapy.

Renal Impairment

Kidney function must be evaluated prior to initiation of a statin in an elderly person as well as during the time the patient is taking a statin. Because statins are eliminated via the kidney, and because most elderly patients have decreased kidney function, the potential for drug build-up in the body is higher than in a younger patient and may lead to more adverse effects. Atorvastatin is the only option that does not require dose adjustment. All other statins should be adjusted based upon the level of renal impairment. The results from the SHARP study, published in 2011, showed that the combination of ezetimibe and simvastatin versus placebo significantly reduced ASCVD events in patients with moderate to severe chronic kidney disease, including those receiving dialysis. Specifically, this trial showed a significant reduction of ischemic events and occurrence of arterial revascularization procedures. Although the trial did not show a significant difference in incidence of MI or CHD-related mortality, the trial was not adequately powered to show differences in results among the individual ASCVD events and it is not clear whether the results can guide the use of statin therapy in all patients with chronic kidney disease [43]. Statins may be beneficial in renal insufficiency to lower LDL-C, but more studies are needed to assess CVD outcomes related to statin use in patients with a history of kidney disease [44].

Hepatic Function

Statins have been known to increase liver enzymes and in rare cases lead to liver injury, which typically has led to underutilization of therapy in clinical practice. Risk factors associated with this include preexisting hepatitis, advanced age, chronic alcohol use, and use of concomitant medications that may also cause hepatotoxicity, such as acetaminophen. When a statin-induced hepatic effect is suspected, it is important to first rule out other causes or disease states that may be undiagnosed. If no other cause can be found, clinicians may choose to reduce the statin dose, switch the statin, or discontinue the statin altogether if the risk outweighs the benefit. Additionally, statins do not have to be held in patients who have preexisting hepatic dysfunction if use is clearly indicated because the cardiovascular benefits typically outweigh the risks of causing liver injury. Clinical judgement is still warranted and patients with preexisting liver conditions should be monitored regularly [45].

Cost Considerations

Several studies have demonstrated that statin therapy, in the general population, is economical for both primary and secondary prevention of CVD [46,47]. The 4S study found simvastatin therapy to be cost-effective; for example, the cost per life year gained for a 70-year-old man with high chlesterol was $3800 [48]. In contrast, primary prevention in middle-aged men, based on the West of Scotland trial, averages about $35,000 per year of life gained [46]. In a 2015 study that utilized an established Markov simulation model, researchers studied adults 75 to 94 years and examined the cost-effectiveness of generic statins for primary prevention in this population. The authors estimated treating this population with statins over the next decade would be cost-effective. However, the researchers cautioned that the CV benefits and cost-effectiveness would be offset with even a modest increased risk of cognitive impairments or functional limitations. Statin use was not cost-effective in diabetes patients who did not have elevated LDL-C levels [49].

Non-Statin Therapies

Several other classes of medications are available for the management of hyperlipidemia; however, none of these lipid-lowering therapies have been found to reduce CVD events or mortality in the elderly population.

Ezetimibe

Ezetimibe blocks the absorption of intestinal cholesterol and is typically combined with statin therapy to lower LDL-C. Up until the IMPROVE-IT trial was published in 2015, ezetimibe did not have much use in clinical practice. This landmark trial was a large double-blind study that looked at secondary prevention in patients with ACS, comparing ezetimibe 10 mg and simvastatin 40 mg versus simvastatin 40 mg alone. The authors included patients over the age of 50 (mean age 64) with clinical ASCVD. They found that the addition of ezetimibe to simvastatin did reduce the primary composite outcome (CV mortality, major CV events, or nonfatal stroke) when compared to simvastatin alone [50]. This trial demonstrates clinical benefit with the addition of ezetimibe to statin therapy and adds additional evidence to support a target LDL-C of less than 70 mg/dL; however, the elderly population was not adequately represented in the study to allow extrapolation of these results to older patients.

PCSK-9 Inhibitors

The proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors are a newer class of monoclonal antibodies that were first approved by the US Food and Drug Administration in 2015. Alirocumab and evolocumab, both approved PCSK-9 inhibitors, bind to LDL receptors on the surface of hepatocytes and assist in the internalization of LDL receptors for lysosomal degradation. By inhibiting the binding of PCSK-9 to the LDL receptors, there is an overall increase in LDL receptors available on the cell surface to bind to LDL particles, thereby lowering LDL-C levels. Treatment with these agents are currently considered (in addition to diet and maximally tolerated statin therapy) in adult patients with heterozygous familial hypercholesterolemia or clinical ASCVD requiring further reduction in LDL-C. Two studies were published focusing on the use of PCSK-9 inhibitors: Open-label Study of Long-term Evaluation against LDL Cholesterol (OSLER) and the Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM). Overall, these studies demonstrated a 60% reduction of LDL-C among patients with high CVD risk on maximum-tolerated statin therapy. Furthermore, the ODYSSEY LONG TERM trial did find that the rate of major CVD adverse events was significantly lower with alirocumab added to maximum-tolerated statin therapy, with a hazard ratio of 0.52 [51].

One recent study of evolocumab, named the Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), enrolled patients between the ages of 40 and 85 with 1 major CV risk factor or 2 minor CV risk factors. The primary endpoint was a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. Evolocumab lowered major CV events by roughly 15% when added to statin therapy in patients who were at high risk for clinical ASCVD. The mean age of the patients in the trial was 63; however, it is unclear how many of the study participants were elderly [52].

Unfortunately, the studies discussed above do not represent the elderly population well and the agents have not been studied long-term to determine the effects of continued use beyond 2 years. Long-term outcome studies are currently underway; however, it is unknown at this time whether elderly patients are being considered in these studies. It is known that genetic variation of the PCSK-9 locus does lower LDL-C in the elderly but does not significantly lower their risk of vascular disease [51]. At this time, until further evidence is available, we do not recommend the use of PCSK-9 inhibitors in elderly patients.

Nicotinic Acid

Nicotinic acid (Niacin, Niacin ER), also known as vitamin B3, has been utilized for decades as a vitamin supplement, an anti-wrinkle agent, and is known to have neuroprotective effects. It has also been utilized for dyslipidemia and has had some benefits when used alone to decrease cardiovascular disease [53]. Unfortunately the Coronary Drug Project was completed in the 1980s and did not incorporate patients over the age of 64, therefore making the results difficult to apply to elderly patients today [54]. Other literature has been published in recent years to refute that study, claiming there is no additional benefit to using niacin for cardiovascular protection and these studies have included elderly patients. In the AIM-HIGH trial, published in 2011, approximately 46% of the patients were 65 or older. Patients who were previously taking statin therapy that had known cardiovascular disease were enrolled. Niacin added to simvastatin 40–80 mg lowered LDL-C, triglycerides, and increased HDL-C, but the addition of niacin was not proven to help lower the risk of cardiovascular events [55]. The HPS2-THRIVE study enrolled patients with known cardiovascular disease between the ages of 50 and 80 years and found no benefit in preventing CVD when adding niacin to statin therapy [56]. With its side effect profile, risk for increased glucose intolerance, and lack of evidence to demonstrate benefit for prevention of CV events, we do not recommend niacin for use in the elderly at this time.

Bile Acid Sequestrants

The ATP III guidelines [57] noted that when statins are not sufficient to lower high cholesterol, bile acid sequestrants also known as resins could be added. More recently, the 2016 ACC expert consensus on non-statin therapies for LDL-C lowering [16] stated resins may be considered in select circumstances as a second-line agent for adults with ezetimibe intolerance and with triglycerides

Fibrates

While fibrates (gemfibrozil, fenofibrate, clofibrate) have not been studied to demonstrate a reduction in CVD or CVD mortality in the elderly population, this medication class is beneficial in patients with hypertriglyceridemia to lower triglyceride levels and prevent pancreatitis. Fibrates are recommended for patients with triglyceride levels approaching 500 mg/dL. Fibrates can also increase high-density lipoproteins, which tend to be lower in the elderly population and considered a risk factor for CVD. Gemfibrozil is not recommended in combination with statin therapy due to an increased risk of myalgia. Fenofibrate is the drug of choice, particularly for diabetic patients with very uncontrolled triglyceride levels because it will not affect glucose levels [57]. At this time, we do not recommend the use of fibrates in the elderly population unless they are at risk for developing pancreatitis and have elevated triglyceride levels.

Patient-Centered Care

Evidence-based medicine can aid in making sound clinical decisions for proper patient care; however, treatment plans should consider the individual patient’s perspectives and needs, beliefs, expectations, and goals. In the elderly population, we must also consider factors such as finances, pill-burden, drug-drug interactions, physiological needs, comorbid disease states, and overall life expectancy. In addition, the elderly population is physiologically heterogeneous group and recommendations for therapy need to be individualized. Chronological age does not necessarily correspond to vascular age and risk factors for cardiovascular disease do not predict outcomes as well in the elderly as they do in younger patients. While older patients may view having to take 1 less medication as more important than preventing a heart attack or stroke at the age of 80, it is advisable to discuss all potential outcomes related to morbidity associated with the occurrence of an MI or stroke due to the lack of statin therapy. Additionally, pharmacists can play a vital role in evaluating elderly patients and their medication regimens. Elderly patients should undergo a medication reconciliation at each visit to evaluate drug-drug interactions, side effects, and potentially harmful medication combinations that may lead to increased adverse drug outcomes.

Conclusion

CHD increases with age, and most patients who have a CV event are more likely to die with advancing age. Based on the the limited available evidence, statin therapy is beneficial in the elderly population in reducing overall CV morbidity. We recommend beginning with with a moderate-intensity statin and adjusting accordingly. High-intensity statin therapy appears to be effective for elderly patients for secondary prevention, but clinicians should use clinical judgment and monitor for adverse events, particularly myalgia pain. At this time, we are unable to determine if non-statin therapies for the elderly would be beneficial and do not recommend their use unless the patient is at risk for pancreatitis, in which case a fenofibrate is recommended.

Corresponding author: Nicole A. Slater, PharmD, BCACP, Auburn University, Harrison School of Pharmacy, 650 Clinic Dr., Mobile, AL 36688.

Financial disclosures: None.

From the Harrison School of Pharmacy, Auburn University, Mobile, AL.

Abstract

• Objective: To summarize the literature relevant to managing dyslipidemia in the elderly and review recommendations for initiating lipid-lowering therapy.
• Methods: Review of the literature.
• Results: Statins are the most commonly utilized medication class for lipid-lowering in the general population, and they are recommended for primary prevention in patients between the ages of 40 to 75 with at least 1 risk factor for cardiovascular disease as well as for any patient needing secondary prevention. In the elderly, statins may be appropriate for both primary and secondary prevention if the benefits outweigh the risks. Based on the available evidence, it is safe to recommend statin therapy to elderly patients who require secondary prevention given the known benefits in reducing cardiovascular morbidity and mortality for patients up to the age of 80. For primary prevention, statin therapy may be beneficial, but one must carefully evaluate for comorbid conditions, life expectancy, concomitant medications, overall health status, frailty, and patient or family preference. Several other classes of lipid-lowering agents exist; however, there is not enough evidence for us to recommend use in the elderly population for cardiovascular risk reduction in either primary or secondary scenarios.
• Conclusion: Although clinical research in the elderly population is limited, evidence supports the use of statins in elderly patients for secondary prevention and in patients up to age 75 for primary prevention; however clinicians must use clinical judgement and take into consideration the patient’s situation regarding comorbidities, polypharmacy, and possible adverse effects. More high-quality evidence is necessary.

Key words: hyperlipidemia; geriatrics; elderly; patient-centered care; statin; cardiovascular disease.

The number of Americans age 65 years and older is projected to more than double, from 46 million today to over 98 million by 2060, and the 65-and-older age group’s share of the total population will rise to nearly 24% [1]. Life expectancy is now predicted to be > 20 years for women at age 65 and > 17 years for men at age 65 in many high-income countries, including the United States [2]. This demographic shift toward an older population will result in a higher burden of coronary heart disease and stroke, with atherosclerotic cardiovascular disease (ASCVD) prevalence and costs projected to increase substantially [3].

Among adults seeking medical care in the United States, roughly 95 million have a total cholesterol (TC) level of ≥ 200 mg/dL or more, and approximately 29 million have a TC > 240 mg/dL [4]. Cholesterol screening is important since most patients suffering from dyslipidemia are asymptomatic. Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Because of the complications associated with dyslipidemia, it is vital that patients are provided with primary and/or secondary prevention strategies to reduce the risk of cardiovascular disease (CVD) and protect high-risk patients from recurring events. A clinical controversy exists surrounding the elderly population, concerning whether or not clinicians should be providing lipid-lowering treatment to this group of individuals for dyslipidemia. The evidence is limited for patients over age 65, and even more so for the very elderly (> 80 years); therefore, it is necessary to review the available evidence to make an appropriate decision when it comes to managing dyslipidemia in the elderly population

Currently, HMG-CoA reductase inhibitors (statins) are the only known class of medications for the treatment of dyslipidemia that will prevent both primary and secondary cardiovascular (CV) events, including death. Statin intensity (Table 1) 

Guideline Recommendations

Current guidelines differ in their recommendations for treating dyslipidemia in the elderly population. In 2016, the Task Force for the Management of Dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) released updated guidelines for managing dyslipidemia. These guidelines recommend that older patients with established CVD be treated in the same way as younger patients because of the many benefits statin therapy demonstrated in clinical trials. They also suggest that statin therapy be started at a lower doses to achieve goals for primary prevention in the older population. In addition, CVD risk factors (hypertension, diabetes, dyslipidemia, smoking) should be addressed in this population to reduce CVD risk. They also acknowledged that primary prevention may not prolong life in the older adult, but treatment does reduce cardiovascular mortality and statin therapy is recommended to reduce the overall risk of CV morbidity in this population [11]. In contrast, The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines changed the management and treatment of dyslipidemia by highlighting “statin benefit groups” rather than recommending a treat-to-target goal as guidelines had done for many years. ACC/AHA recommends a moderate-intensity statin for patients > 75 years of age for secondary prevention versus the use of a high-intensity statin for patients who are between the ages of 40 and 75 based on the pooled cohort risk equation. In patients over age 75 with no history of CVD, no specific recommendation is available for the use of lipid-lowering therapy at this time [12]. ACC/AHA is expected to publish a new set of guidelines sometime in 2018 and they are projected to utilize lipid-lowering goals in combination with the pooled cohort equation to assess overall risk in patients with dyslipidemia.

The 2015 National Lipid Association (NLA) released “Part 1” guidelines for the management of dyslipidemia and then provided “Part 2” about a year later, which focuses on management for special populations. To summarize, the NLA guidelines recommend that elderly patients between the ages of 65 and 80 receive a high-intensity statin for secondary prevention after special consideration of the potential risks and benefits. In patients over the age of 80, NLA recommends a moderate-intensity statin for secondary prevention. For primary prevention, NLA recommends utilizing the pooled cohort risk equation to analyze patient characteristics, keeping in mind that age is a driving factor for increased risk of CVD and that the actual risk for developing a CV event may be “overestimated” if the patient has no other risk factors other than their age. When evaluating patients between the ages of 65 and 79 for primary prevention, NLA suggests following Part 1 of the guidelines. In Part 1, NLA recommends evaluating the patient’s characteristics and suggests a moderate- or high-intensity statin if the patient is considered “very high risk” or “high risk” and a moderate-intensity statin for patients who are considered “moderate risk”. For patients over the age of 80, they recommend utilizing a moderate- or a low-intensity statin depending on frailty status or if significant comorbidities or polypharmacy exist [13,14].

In 2017, the American Association of Clinical Endocrinologist (AACE) released guidelines for the management of dyslipidemia and CVD prevention. AACE recommends that patients over age 65 be screened for dyslipidemia, and those who have multiple risk factors, other than age, should be considered for treatment with lipid-lowering therapy. AACE focuses on specific target LDL-C levels as treatment goals [15].

In addition to statins, other lipid-lowering therapies are used to treat dyslipidemia. The 2016 American College of Cardiology (ACC) Task Force reported on the use of non-statin therapies for the management of dyslipidemia and prevention of clinical ASCVD [16]. The committee concluded that ezetimibe added to statin therapy, bile acid sequestrants as monotherapy, and niacin as monotherapy all have some benefit for the prevention of clinical ASCVD. These guidelines also discuss the use of PCSK-9 inhibitors and their potential to decrease the risk of clinical ASCVD, but trials are currently ongoing to determine actual benefit. These guidelines address special populations but they do not consider the elderly in their recommendations. Currently, the only special populations included are patients with heart failure, those on hemodialysis, women who are of childbearing age or pregnant, and those with autoimmune diseases [16]. The literature available for each individual medication is discussed in further detail below.

Evidence for Secondary Prevention

The benefits of statin therapy for secondary prevention in the elderly is more established than it is for primary prevention (Table 2). 

The ASCOT–LLA (Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm), published in 2003, evaluated the effect of atorvastatin 10 mg on reducing ASCVD events in moderate-risk patients between 40–79 years of age who had hypertension and normal or slightly elevated LDL-C levels, with at least 2 other risk factors for CVD (age > 55 years was considered a risk factor). The primary outcome was non-fatal MI including silent MI and fatal CHD. A significant reduction was seen in the primary endpoint. Over half of the study population was > 60 years of age, with a mean age of 63 years. In a post-hoc analysis, stroke prevention was found to be similar in patients who were > 70 years of age and those < 70 years of age [19].

One of the first trials to specifically analyze the impact of age on lipid-lowering therapy in secondary ASCVD prevention was the Scandinavian Simvastatin Survival Study (4S), published in 1994. They evaluated the effect of simvastatin 20 mg on CV-related mortality and morbidity in patients 35–70 years of age with hyperlipidemia and a history of angina or acute MI occurring > 6 months of the study starting. The primary outcome was all-cause mortality. The secondary endpoint was time to first major CV event, which included coronary death, non-fatal acute MI, resuscitated cardiac arrest, and silent MI. Simvastatin significantly reduced the primary outcome and CHD-related deaths. A subgroup analysis of the study population > 60 years of age showed that age made no significant impact on primary or secondary outcomes; however, investigators noted that these subgroup analyses had less statistical power than the population as a whole [20].

Published in 1998, the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) study evaluated the effects of pravastatin 40 mg daily on CHD-related mortality and overall mortality in patients with hyperlipidemia and clinical ASCVD (previous MI or unstable angina). The primary outcome observed was fatal CHD. Pravastatin significantly reduced the primary outcome, overall mortality, and pre-specified CV events. In a subgroup analysis, age group ( 65, and > 70 years) had no significant impact on the combined outcome of death from CHD and nonfatal MI; however, patients 65 to 70 years of age made up less than half of the study population [21].

The Cholesterol and Recurrent Events (CARE) trial, published in 1996, looked at the effect of pravastatin 40mg therapy for secondary ASCVD prevention following an MI in patients who had average cholesterol levels (defined as TC < 240 mg/dL and LDL-C 115–174 mg/dL). The primary endpoint assessed was time to fatal CHD or nonfatal MI. To meet statistical power they looked at subgroups for a broader outcome of a major coronary event (including fatal CHD, nonfatal MI, bypass surgery, and angioplasty). Pravastatin significantly reduced the primary outcome. The significant reduction in coronary events produced by pravastatin was noted to be significantly greater in women and in patients with higher pretreatment levels of LDL-C, but was not significantly impacted by age group (24–59 vs. 60–75 years) [22].

The Heart Protection Study (HPS), published in 2002, looked at the long-term effects of lowering LDL-C with simvastatin 40 mg in patients 40 to 80 years of age at high risk for mortality due to either vascular or nonvascular causes. The primary outcome assessed was all-cause mortality, with fatal or nonfatal vascular events as co-primary outcomes for subcategory analyses. Simvastatin significantly reduced both primary and co-primary outcomes, but there was no significant difference when they looked at nonvascular mortality between groups. Neither age nor baseline LDL levels were reported to have had a significant impact on outcomes. Over half the population was > 65 years of age, and about one-third of the population was > 70 years of age [23].

The PROVE-IT/TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) trial, published in 2004, compared pravastatin 40 mg (moderate-intensity) to atorvastatin 80 mg (high-intensity) for secondary ASCVD prevention in patients with recent acute coronary syndrome (ACS) 65 years of age and the mean age was 58 years [24].

The TNT (Treating to New Targets) trial, published in 2005, looked at secondary ASCVD prevention in regards to targeting LDL-C levels to < 100 mg/dL or < 70 mg/dL with atorvastatin 10 mg and atorvastatin 80 mg. Patients had stable coronary artery disease (CAD) and baseline LDL-C levels < 130 mg/dL. The primary endpoint was the occurrence of a CV event (CAD mortality, nonfatal MI not related to procedure, resuscitation after cardiac arrest, or fatal or nonfatal stroke). High-intensity atorvastatin (80 mg) significantly reduced the primary outcome. The mean age of the study population was approximately 61 years. The study reported no statistical interaction for age or sex in the primary outcome measure [25].

The Study Assessing Goals in the Elderly (SAGE), published in 2007, evaluated the effects of pravastatin 40 mg (moderate-intensity) vs atorvastatin 80 mg (high-intensity) on secondary ASCVD prevention in patients 65 to 85 years (mean age 72) with stable CHD, LDL-C 100–250 mg/dL, with at least 1 episode of myocardial ischemia with total ischemia duration > 3 minutes. The primary efficacy outcome observed was absolute change in total duration of myocardial ischemia on 48-hour ambulatory electrocardiographic monitoring from baseline to month 12. No significant difference was observed in efficacy between the two groups for the primary endpoint, but the intensive statin therapy group showed greater benefit respective to several secondary outcomes, including major acute CV events and death [26].

In summary, while these trials provide evidence that statin therapy is beneficial in a wide range of patients with clinical ASCVD and dyslipidemia, the trial data does not provide definitive guidance for treating elderly patients at this time. Given the small percentage of elderly patients that were included, some of the trial results reporting statistical significance in this age group hold less clinical significance. It appears that high-intensity statin therapy was more likely to effectively prevent clinical ASCVD and death than moderate-intensity statin therapy, but more evidence is needed regarding secondary prevention in patients over age 75.

Evidence for Primary Prevention

The PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) was published in 2002 to assess the efficacy of pravastatin in patients between the ages of 70 and 82 (mean age 75 years) with pre-existing vascular disease (coronary, cerebral, or peripheral) or at an elevated risk (smoking, hypertension, or diabetes). Patients were randomized to receive either placebo or pravastatin 40 mg (a moderate-intensity statin). They found that pravastatin therapy reduced the risk of the composite outcome of CHD-related death, nonfatal MI, and fatal or nonfatal stroke in this elderly population. A post-hoc analysis comparing primary versus secondary prevention groups found no significant differences between these subgroups [7].

Han et al recently conducted a post hoc secondary analysis of older participants (65 years and older) in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT-LLT). The intervention for ALLHAT-LLT was 40 mg pravastatin. They found no significant differences in all-cause mortality or cardiovascular outcomes between the pravastatin and usual care groups [27]

JUPITER (Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), published in 2008, examined the efficacy of rosuvastatin vs. placebo in low- to moderate-risk men 50 years and older and women 60 years and older using a composite outcome of MI, unstable angina, stroke, arterial revascularization, or CVD death. Rosuvastatin did significantly decrease the primary endpoint, however it did not reduce the risk of overall death [28]. A subgroup analysis was performed on the elderly (65–75 years) study participants in JUPITER demonstrating a significant risk reduction for the combined CV endpoint and a nonsignificant reduction of all-cause mortality [29].

CARDS (Collaborative Atorvastatin Diabetes Study), published in 2004, looked at statin use for primary prevention in high-risk patients with type 2 diabetes without high LDL-C, but they had to have at least 1 additional risk factor for CVD. The primary outcome was first acute CHD event (myocardial infarction including silent infarction, unstable angina, acute coronary heart disease death, resuscitated cardiac arrest), coronary revascularization procedures, or stroke. Atorvastatin 10 mg, a moderate-intensity statin, significantly decreased occurrence of the primary outcome [30]. A subgroup analysis was performed to evaluate patients specifically between the ages of 65 and 75 and found a similar outcome in the elderly with a significant reduction in first major CV event and stroke [31].

A recent study evaluating primary prevention in patients with an intermediate risk for CVD was the HOPE-3 (Heart Outcomes Prevention Evaluation), published in 2016. Two co-primary outcomes were evaluated: the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, while the second primary outcome also included revascularization, heart failure, and resuscitated cardiac arrest. Rosuvastatin significantly decreased occurrence of both co-primary endpoints. About half of the study populations was over the age of 65 with a median age of 71 [32].

In addition to these trials of primary prevention, summarized in Table 3, a meta-analysis was published in 2013 to assess whether statins reduce all-cause mortality and CV events in elderly people without established CV disease. 

As demonstrated by the above studies, it is evident that statins do help reduce the risk of CV events, regardless of statin intensity, but they do not consistently prevent death. However, the trials that did not demonstrate a significant outcome related to death utilized a moderate-intensity statin; if a high-intensity statin was used in those trials, there may have been a benefit [7,27]. More study is needed to evaluate the use of high-intensity statins in the elderly for the prevention of all-cause mortality and CV-related death.

Fortunately, the ongoing STAREE (STAtin Therapy for Reducing Events in the Elderly) study is looking specifically at the impact of statin therapy in adults 70 and older. Patients with a history of CVD or dementia are excluded. Results are set to be released in 2020 [34].

Risks of Using Statins in Older Adults

Statin use has been linked to a number of unwanted adverse effects.

Myalgia

Myalgia is variable but may occur in up to 25% of patients using statin therapy, and elderly patients typically experience more statin-associated myalgia than younger patients [35,36]. Elderly patients are more prone to decreased muscle mass and therefore may be at a higher risk of developing myalgia pain. Elderly patients are also utilizing more medications, leading to the potential for increased drug-drug interactions that could lead to myalgia. Elderly patients may also lose the function of drug metabolizing enzymes responsible for breaking down statin therapy, which may also increase the risk for statin-associated myalgia. One study demonstrated that elderly patients were more likely to discontinue statin therapy due to muscle pain and elderly patients reported more muscle side effects than their younger cohorts [37]. It is important to monitor for muscle pain and weakness in every patient. If they experience any myalgia, it is recommended to either lower the dose or discontinue the statin once it is determined to be statin-related. After myalgia resolves, therapy can be reinitiated at a lower dose or with a different statin if the patient is deemed high-risk. If creatine phosphokinase levels are greater than 10 times above the upper limit of normal, then discontinue the statin and wait for levels to return to normal. Re-initiation may be appropriate, but the the risks and benefits must be weighed. Simvastatin and atorvastatin are associated with higher rates of myalgia while pravastatin and rosuvastatin have the least myalgia pain associated with use [38,39].

Statin Intolerance

Statin intolerance, while not very common, is typically seen more often in special populations such as women, Asian patients, and the elderly. For a patient to be considered intolerant to statins, they need to have documented muscle symptoms or an elevated creatine phosphokinase level. Although not well defined, many clinicians consider improvement of symptoms with statin withdrawal as a diagnosis for statin intolerance. Typically patients are then rechallenged with 1 to 2 other statins and if still unable to tolerate, then different lipid-lowering therapies may be utilized [40]. In the elderly, it is important to rule out other causes for myalgia and monitor for significant drug interactions that may lead to muscle pain, particularly if the patient is requiring secondary prevention with statin therapy, before discontinuation.

Dementia

In 2012, the FDA issued a warning about the potential risk of cognitive impairment with the use of statins, which was based on case reports, not clinical trial data [41]. The NLA guidelines do not recommend baseline cognitive assessments prior to starting therapy and recommend that if patients do report cognitive impairment, other contributing factors and the risk associated with stopping statin therapy must be considered. Statin therapy may be discontinued to assess reversibility of symptoms, and if symptoms resolve, then it may be more beneficial to keep the patient off statin therapy. Clinicians may also consider lowering the dose or switching to another statin if they feel it is necessary for the patient to continue with a statin, particularly if the patient requires secondary prevention. Evidence suggests that statins are not associated with adverse effects on cognition and should not be withheld due to the potential for causing cognitive impairment alone [42]. The prevalence of cognitive impairment increases with age, so it is important for a clinician to rule out age-related processes or other disease states, such as Alzheimer’s, before discontinuation of previously tolerated statin therapy.

Renal Impairment

Kidney function must be evaluated prior to initiation of a statin in an elderly person as well as during the time the patient is taking a statin. Because statins are eliminated via the kidney, and because most elderly patients have decreased kidney function, the potential for drug build-up in the body is higher than in a younger patient and may lead to more adverse effects. Atorvastatin is the only option that does not require dose adjustment. All other statins should be adjusted based upon the level of renal impairment. The results from the SHARP study, published in 2011, showed that the combination of ezetimibe and simvastatin versus placebo significantly reduced ASCVD events in patients with moderate to severe chronic kidney disease, including those receiving dialysis. Specifically, this trial showed a significant reduction of ischemic events and occurrence of arterial revascularization procedures. Although the trial did not show a significant difference in incidence of MI or CHD-related mortality, the trial was not adequately powered to show differences in results among the individual ASCVD events and it is not clear whether the results can guide the use of statin therapy in all patients with chronic kidney disease [43]. Statins may be beneficial in renal insufficiency to lower LDL-C, but more studies are needed to assess CVD outcomes related to statin use in patients with a history of kidney disease [44].

Hepatic Function

Statins have been known to increase liver enzymes and in rare cases lead to liver injury, which typically has led to underutilization of therapy in clinical practice. Risk factors associated with this include preexisting hepatitis, advanced age, chronic alcohol use, and use of concomitant medications that may also cause hepatotoxicity, such as acetaminophen. When a statin-induced hepatic effect is suspected, it is important to first rule out other causes or disease states that may be undiagnosed. If no other cause can be found, clinicians may choose to reduce the statin dose, switch the statin, or discontinue the statin altogether if the risk outweighs the benefit. Additionally, statins do not have to be held in patients who have preexisting hepatic dysfunction if use is clearly indicated because the cardiovascular benefits typically outweigh the risks of causing liver injury. Clinical judgement is still warranted and patients with preexisting liver conditions should be monitored regularly [45].

Cost Considerations

Several studies have demonstrated that statin therapy, in the general population, is economical for both primary and secondary prevention of CVD [46,47]. The 4S study found simvastatin therapy to be cost-effective; for example, the cost per life year gained for a 70-year-old man with high chlesterol was $3800 [48]. In contrast, primary prevention in middle-aged men, based on the West of Scotland trial, averages about $35,000 per year of life gained [46]. In a 2015 study that utilized an established Markov simulation model, researchers studied adults 75 to 94 years and examined the cost-effectiveness of generic statins for primary prevention in this population. The authors estimated treating this population with statins over the next decade would be cost-effective. However, the researchers cautioned that the CV benefits and cost-effectiveness would be offset with even a modest increased risk of cognitive impairments or functional limitations. Statin use was not cost-effective in diabetes patients who did not have elevated LDL-C levels [49].

Non-Statin Therapies

Several other classes of medications are available for the management of hyperlipidemia; however, none of these lipid-lowering therapies have been found to reduce CVD events or mortality in the elderly population.

Ezetimibe

Ezetimibe blocks the absorption of intestinal cholesterol and is typically combined with statin therapy to lower LDL-C. Up until the IMPROVE-IT trial was published in 2015, ezetimibe did not have much use in clinical practice. This landmark trial was a large double-blind study that looked at secondary prevention in patients with ACS, comparing ezetimibe 10 mg and simvastatin 40 mg versus simvastatin 40 mg alone. The authors included patients over the age of 50 (mean age 64) with clinical ASCVD. They found that the addition of ezetimibe to simvastatin did reduce the primary composite outcome (CV mortality, major CV events, or nonfatal stroke) when compared to simvastatin alone [50]. This trial demonstrates clinical benefit with the addition of ezetimibe to statin therapy and adds additional evidence to support a target LDL-C of less than 70 mg/dL; however, the elderly population was not adequately represented in the study to allow extrapolation of these results to older patients.

PCSK-9 Inhibitors

The proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors are a newer class of monoclonal antibodies that were first approved by the US Food and Drug Administration in 2015. Alirocumab and evolocumab, both approved PCSK-9 inhibitors, bind to LDL receptors on the surface of hepatocytes and assist in the internalization of LDL receptors for lysosomal degradation. By inhibiting the binding of PCSK-9 to the LDL receptors, there is an overall increase in LDL receptors available on the cell surface to bind to LDL particles, thereby lowering LDL-C levels. Treatment with these agents are currently considered (in addition to diet and maximally tolerated statin therapy) in adult patients with heterozygous familial hypercholesterolemia or clinical ASCVD requiring further reduction in LDL-C. Two studies were published focusing on the use of PCSK-9 inhibitors: Open-label Study of Long-term Evaluation against LDL Cholesterol (OSLER) and the Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM). Overall, these studies demonstrated a 60% reduction of LDL-C among patients with high CVD risk on maximum-tolerated statin therapy. Furthermore, the ODYSSEY LONG TERM trial did find that the rate of major CVD adverse events was significantly lower with alirocumab added to maximum-tolerated statin therapy, with a hazard ratio of 0.52 [51].

One recent study of evolocumab, named the Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), enrolled patients between the ages of 40 and 85 with 1 major CV risk factor or 2 minor CV risk factors. The primary endpoint was a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. Evolocumab lowered major CV events by roughly 15% when added to statin therapy in patients who were at high risk for clinical ASCVD. The mean age of the patients in the trial was 63; however, it is unclear how many of the study participants were elderly [52].

Unfortunately, the studies discussed above do not represent the elderly population well and the agents have not been studied long-term to determine the effects of continued use beyond 2 years. Long-term outcome studies are currently underway; however, it is unknown at this time whether elderly patients are being considered in these studies. It is known that genetic variation of the PCSK-9 locus does lower LDL-C in the elderly but does not significantly lower their risk of vascular disease [51]. At this time, until further evidence is available, we do not recommend the use of PCSK-9 inhibitors in elderly patients.

Nicotinic Acid

Nicotinic acid (Niacin, Niacin ER), also known as vitamin B3, has been utilized for decades as a vitamin supplement, an anti-wrinkle agent, and is known to have neuroprotective effects. It has also been utilized for dyslipidemia and has had some benefits when used alone to decrease cardiovascular disease [53]. Unfortunately the Coronary Drug Project was completed in the 1980s and did not incorporate patients over the age of 64, therefore making the results difficult to apply to elderly patients today [54]. Other literature has been published in recent years to refute that study, claiming there is no additional benefit to using niacin for cardiovascular protection and these studies have included elderly patients. In the AIM-HIGH trial, published in 2011, approximately 46% of the patients were 65 or older. Patients who were previously taking statin therapy that had known cardiovascular disease were enrolled. Niacin added to simvastatin 40–80 mg lowered LDL-C, triglycerides, and increased HDL-C, but the addition of niacin was not proven to help lower the risk of cardiovascular events [55]. The HPS2-THRIVE study enrolled patients with known cardiovascular disease between the ages of 50 and 80 years and found no benefit in preventing CVD when adding niacin to statin therapy [56]. With its side effect profile, risk for increased glucose intolerance, and lack of evidence to demonstrate benefit for prevention of CV events, we do not recommend niacin for use in the elderly at this time.

Bile Acid Sequestrants

The ATP III guidelines [57] noted that when statins are not sufficient to lower high cholesterol, bile acid sequestrants also known as resins could be added. More recently, the 2016 ACC expert consensus on non-statin therapies for LDL-C lowering [16] stated resins may be considered in select circumstances as a second-line agent for adults with ezetimibe intolerance and with triglycerides

Fibrates

While fibrates (gemfibrozil, fenofibrate, clofibrate) have not been studied to demonstrate a reduction in CVD or CVD mortality in the elderly population, this medication class is beneficial in patients with hypertriglyceridemia to lower triglyceride levels and prevent pancreatitis. Fibrates are recommended for patients with triglyceride levels approaching 500 mg/dL. Fibrates can also increase high-density lipoproteins, which tend to be lower in the elderly population and considered a risk factor for CVD. Gemfibrozil is not recommended in combination with statin therapy due to an increased risk of myalgia. Fenofibrate is the drug of choice, particularly for diabetic patients with very uncontrolled triglyceride levels because it will not affect glucose levels [57]. At this time, we do not recommend the use of fibrates in the elderly population unless they are at risk for developing pancreatitis and have elevated triglyceride levels.

Patient-Centered Care

Evidence-based medicine can aid in making sound clinical decisions for proper patient care; however, treatment plans should consider the individual patient’s perspectives and needs, beliefs, expectations, and goals. In the elderly population, we must also consider factors such as finances, pill-burden, drug-drug interactions, physiological needs, comorbid disease states, and overall life expectancy. In addition, the elderly population is physiologically heterogeneous group and recommendations for therapy need to be individualized. Chronological age does not necessarily correspond to vascular age and risk factors for cardiovascular disease do not predict outcomes as well in the elderly as they do in younger patients. While older patients may view having to take 1 less medication as more important than preventing a heart attack or stroke at the age of 80, it is advisable to discuss all potential outcomes related to morbidity associated with the occurrence of an MI or stroke due to the lack of statin therapy. Additionally, pharmacists can play a vital role in evaluating elderly patients and their medication regimens. Elderly patients should undergo a medication reconciliation at each visit to evaluate drug-drug interactions, side effects, and potentially harmful medication combinations that may lead to increased adverse drug outcomes.

Conclusion

CHD increases with age, and most patients who have a CV event are more likely to die with advancing age. Based on the the limited available evidence, statin therapy is beneficial in the elderly population in reducing overall CV morbidity. We recommend beginning with with a moderate-intensity statin and adjusting accordingly. High-intensity statin therapy appears to be effective for elderly patients for secondary prevention, but clinicians should use clinical judgment and monitor for adverse events, particularly myalgia pain. At this time, we are unable to determine if non-statin therapies for the elderly would be beneficial and do not recommend their use unless the patient is at risk for pancreatitis, in which case a fenofibrate is recommended.

Corresponding author: Nicole A. Slater, PharmD, BCACP, Auburn University, Harrison School of Pharmacy, 650 Clinic Dr., Mobile, AL 36688.

Financial disclosures: None.

From the Department of Psychiatry, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

Abstract

• Objective: To provide a review of emergency department (ED)-based psychosocial interventions that support adult patients with an identified suicide risk towards a goal of reducing subsequent suicidal behavior through the period after discharge, which is known to be a time of high risk for suicidal behavior.
• Methods: Non-systematic review of the literature.
• Results: Multiple methods of engaging patients after discharge from the ED have been shown to reduce subsequent suicidal behaviors. These methods include sending caring letters in the mail, facilitating supportive phone conversations, case management, and protocols that combine different services. Overall, the existing literature is insufficient to recommend widespread adoption of any individual strategy or protocol. However, providing psychosocial and emotional support to patients with an identified suicide risk after they are discharged from the ED is feasible and may reduce subsequent suicidal behaviors. Templates for providing supportive outreach using different modalities now exist, and these may help guide the ongoing development and widespread adoption of more effective and cost-effective solutions.
• Conclusion: Many ED–based interventions that provide enhanced support to patients with suicide risk after they are discharged have demonstrated a potential to reduce the risk of future suicidal behavior.

Key words: suicide; emergency department.

Despite the fact that emergency department (ED) providers often feel unprepared to manage suicide risk, patients with significant suicide risk frequently receive care in EDs, whether or not they have sustained physical injuries resulting from suicidal behavior [1,2]. Patients make greater than 400,000 visits to EDs in the United States each year for suicidal and self-injurious behaviors (suicide attempts and self-injurious behaviors are typically coded in ways that make them indistinguishable from each other in retrospective analyses) [3], and it is estimated that 6% to 10% of all patients in EDs endorse suicidal ideation when asked, regardless of their original chief complaints [4]. Meanwhile, suicide has become the 10th leading cause of death in the United States [5], and the Joint Commission has charged all accredited health care organizations with providing comprehensive treatment to suicidal patients, which may range from immediately containing an acute risk to ensuring continuity of care in follow-up [5].

When an acute suicide risk is identified in the ED, the provider’s immediate next steps should be to place the patient in a safe area under constant observation and to provide an emergency assessment [5,6]. Although psychiatric consultation and/or psychiatric admission may follow this assessment, suicide risk does not require admission in all cases; and some patients with suicide risk may be discharged to an outpatient setting even without receiving a psychiatric consultation [1]. Regardless of whether an outpatient disposition from the ED is appropriate, however, the period that immediately follows discharge is a time of high risk for repeated suicidal behavior and suicide death [7–9], and only 30% to 50% of patients who are discharged from EDs after a self-harm incident actually keep a follow-up mental health appointment [9,10]. Therefore, any support given to patients through this transition out of the emergency care setting could be especially high-yield.

The Joint Commission recommends that all patients with suicidal ideation receive, at minimum, a referral to treatment, telephone numbers for local and national crisis support resources (including the National Suicide Prevention Lifeline 1-800-273-TALK), collaborative safety planning, and counseling to restrict access to lethal means upon discharge [5]. However, some programs have demonstrated the capacity to provide enhanced support to patients beyond discharge from the ED, with some success in reducing the rates of subsequent suicidal behaviors. This non-systematic review describes interventions that can be initiated in the context of an ED encounter with the purpose of reducing future suicidal behavior among adult patients. They are primarily psychosocial rather than clinical. Clinical interventions that apply psychotherapy [11–13] psychopharmacology [14], and specialized inpatient treatments [15] have been studied as well but are beyond the scope of this review.

[polldaddy:10107269]

Interventions to Support Patients At Risk of Suicide After Discharge from the ED

Brief Contact Interventions

The idea that maintaining written correspondence with patients who have a known suicide risk after discharge can reduce subsequent suicide rates originated with a study of psychiatric inpatients conducted by Motto and Bostrom, in which patients who had been admitted for depression but had declined outpatient treatment were randomly assigned to periodically receive letters containing supportive messages from staff members over a period of 5 years [16]. This study remarkably found that these so-called brief contact interventions (BCIs), which were personalized to each recipient but did not contain psychotherapy per se, were associated with a reduced rate of suicide throughout the duration of the program compared with no written contacts [16].

BCIs have since been adapted to other communication formats and have been studied in patients who were discharged directly from the ED after an evaluation of suicide risk or suicidal behavior. Typically, BCIs consist of short, supportive messages that are delivered at regular intervals (often once every 1–2 months) over a period of 1 to 5 years [17,18]. They notably do not contain psychotherapy content, although they may reinforce coping strategies or remind recipients of how to access help if needed [17,19]. They may arrive as postcards [20,21], letters [22], telephone outreach [23–25], or a combination of modalities [26].

Protocols that rely on BCIs alone vary in their structure and have yielded mixed results [18]. A meta-analysis of 12 BCI protocols conducted by Milner et al found that, overall, BCIs administered after a presentation to the ED for self-harm have been associated with a significant reduction in repeat suicide attempts per recipient but not in total suicide deaths [27]. Milner’s group did not recommend large-scale promotion of BCIs based on the inadequacy of data so far, but suggested that this strategy may yet show promise upon further study [27]. A key advantage of BCIs is that they are inexpensive to implement, particularly if they do not include a telephone outreach component [28]. Thus, even if the potential benefit to patients is small, administering BCIs can be cost-effective [28].

It should not come as a surprise, therefore, that the potential for incorporation of BCIs into mobile smartphone technology is currently under investigation. Individuals who own mobile phones typically keep them on their persons and turned on continuously, and thus this is a reliable platform for maintaining contact with a wide range of patients in real-time [17,29]. Developers of at least 2 BCI smartphone programs that rely on mobile text messaging have published their protocols [17,30]. However, whether these programs will succeed in meaningfully reducing suicide rates remains to be determined by future research.

Green Cards

Morgan et al conducted a study in the United Kingdom in which individuals who presented to EDs after a self-harm event received a “green card,” which contained encouraging messages about seeking help and provided contact information for emergency services with 24-hour availability [31]. The green card also facilitated access to a crisis admission if necessary. The green card was distributed first in the ED and a second time by mail 3 weeks later. No suicides occurred in either the intervention or control group, which received usual care, and no statistically significant differences in suicide reattempt rate were found between groups after 1 year [31].

Evans et al studied an updated version of the green card intervention in which the green card facilitated access to an on-call psychiatrist with 24-hour availability by telephone [32]. The updated card included encouraging messages about seeking help similar to the original green card described by Morgan; however, the psychiatry consultation via telephone replaced the offer of hospital admission [32]. This second trial of green cards also failed to show a reduction in the rate of suicide reattempts among green card recipients at 6 months and 1 year [32,33].

Brief Intervention and Contact

The World Health Organization’s Brief Intervention and Contact (BIC) protocol is a standardized, multi-step suicide prevention program that has been studied primarily in patients who present to EDs after a suicide attempt in middle-income countries [34]. BIC includes a 1-hour information session that is administered shortly prior to discharge, and subsequently provides 9 follow-up contact interventions at specified intervals over an 18-month period. Unlike in a typical BCI, the contacts in BIC are conducted by a clinician either face-to-face or over the phone and include standardized assessments of the patient’s condition, although they still do not include psychotherapy. BIC has been shown to reduce suicide attempts, suicide deaths, or both in India [34–36], Iran [34,36,37], China [34,36], Brazil [34,36], and Sri Lanka [34,36] but was not found to directly improve clinical outcomes in a study conducted in French Polynesia [38]. A meta-analysis conducted by Riblet et al concluded that BIC is effective in reducing suicide risk overall [39].

ED-SAFE

The Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) protocol was validated in 8 EDs in 7 states in the US that did not already provide psychiatric services internally [40]. Under this model, all patients in the ED receive a screening for suicide risk, and those with an initial positive screen receive a secondary screen administered by the ED physician, a self-administered safety plan, and a series of up to 11 phone contacts over the following year that are administered by trained mental health clinicians in a central location. The ED-SAFE phone contacts follow the Coping Long Term with Active Suicide Program (CLASP) protocol [41] and provide support around safety planning and treatment engagement. They have the capacity to engage the patients’ significant others directly if a significant other is available and the patient chooses to involve that person.

In a single multicenter study, ED-SAFE reduced the absolute risk of suicide attempt by 5%, and the relative risk by 20% compared to usual treatment [40]. An intermediate phase of the study compared the universal suicide screening alone (ie, without the safety plan or follow-up contacts) with usual care and did not find this to improve outcomes [40].

Case Management

Kawanishi et al conducted a randomized controlled trial of assertive case management, the ACTION-J study, for patients with psychiatric diagnoses who presented with self-harm to 17 participating EDs in Japan [42]. In the ACTION-J study, case managers were mental health clinicians who provided clinical evaluations, treatment planning, encouragement, and care coordination over the course of 7 scheduled face-to-face or phone contacts in the first 18 months, and additional contacts at 6-month intervals until the completion of the trial (up to a total of 5 years) [43]. The comparison intervention, enhanced usual care, consisted of psychoeducation provided at the time of the encounter in the ED without case management services. The assertive case management intervention was associated with a decrease in suicidal behavior in the first 6 months but not for the duration of the study, except in women, for whom the benefit lasted the full 18 months [42]. A subsequent analysis also found a decrease in the total number of self-harm episodes per person-year compared to enhanced usual care, although there was not a difference in the number of participants who experienced a repeat self-harm episode [43]. The benefit was most strongly pronounced among patients who had presented with an index suicide attempt [43].

Morthorst et al applied an alternative case management model for the assertive intervention for deliberate self harm (AID) trial, which took place in Denmark [44]. Participants were aged 12 and older and could have been recruited from medical or pediatric inpatient units as well as the ED after a self-harm event. AID employed psychiatric nurses to provide crisis intervention, crisis planning, problem solving, motivational support, family mediation, and assistance with keeping appointments over a period of 6 months following discharge. Outreach took place over the phone, by text message, in participants’ homes, in cafes, and at health and social services appointments. The intervention required at least 4 contacts, although additional contacts could be made if appropriate. In comparison with a control group, in which participants received only usual care (which included ready access to short-term psychotherapy), the AID intervention was not associated with statistically significant differences in recurrent suicidal behaviors [44]. Subgroup analyses examining adult participants aged 20–39 and 40 and older also did not find differences in recurrent suicidal behavior between groups [44].

The Baerum Model and OPAC

A municipal suicide prevention team that provides comprehensive social services to suicide attempters has operated in Baerum, Norway, since 1983 [45]. Under the Baerum model, patients who attempt suicide, can be discharged from the general hospital without psychiatric admission, and are determined to have a high level of need for support are connected by a hospital-based suicide prevention team to a community-based team consisting of nurses and a consulting psychologist, who subsequently engage patients in own their homes and through follow-up phone calls. The services they provide include care coordination, encouragement, activation of social networks, psychological first-aid, and counseling focused on problem-solving. The ostensible goal of the suicide prevention team is to provide a bridge between inpatient medical care and outpatient mental health treatment; however, the intervention lasts approximately 1 year regardless of whether the patient connects with a treatment program [45].

A retrospective comparison of outcomes between recipients of the original Baerum program and non-recipients failed to find a difference in suicide attempts or suicide deaths between groups [45]. However, this was not a controlled study, and suicide attempters were preferentially referred to the program based on whether they had a higher level of need at baseline. Hvid and Wang adapted this model to patients who presented to EDs and general hospitals in Amager, Denmark [46] and have since conducted a series of randomized controlled trials comparing their adaptation to usual care. The Danish version of the Baerum model, renamed OPAC (for “outreach, problem solving, adherence, continuity”), provides similar case management and counseling services but for a maximum of 6 months. In their studies, OPAC significantly reduced the number of patients with a repeat suicide attempt and the total number of repeat suicide attempts at a 1-year interval, and this effect on total number of suicide attempts was sustained at 5 years [47,48]. Although the OPAC protocol begins with a patient’s presentation to the ED, the intervention is initiated after admission to the general hospital. Therefore, while this may inspire a model that provides similar services directly from the ED to patients who do not require general hospital admission, the existing model is not entirely based in the ED.

Discussion

The needs of suicidal patients are often multidimensional, and in some cases their risks are driven by psychosocial problems in addition to, or instead of, medically modifiable psychiatric conditions [49]. However, developing an ED-based program to support patients who are at risk of suicide after they are discharged from the ED is possible. Many such programs that provide or facilitate caring contacts, family support, case management, and/or treatment engagement with discharged patients have demonstrated that similar strategies may have the potential to impact future suicidal behavior. Nonetheless, it would be a stretch to say that all hospital systems should immediately begin doing so.

A new post-discharge support program is an investment of financial resources, personnel, and sometimes technology. Successful delivery of support or messages in any format requires that the intended recipient be able to receive it via reliable access to a working address, telephone number, or electronic device. Nonetheless, programs that rely on BCIs alone (excluding those conducted via telephone) cost relatively little to implement and thus would require a smaller investment than programs that require synchronous telephone or face-to-face contacts with staff in addition to or instead of BCIs. Costs for synchronous programs will also vary depending on the frequency and duration of contacts and the licensure and training required of the staff who provide them.

A trend toward better outcomes associating with more resource-intensive programs is easy to imagine but has not been definitively demonstrated. The wide variation between protocols in all types of programs makes comparisons between those that do and do not include synchronous contacts, and between types of synchronous contacts, difficult. Meanwhile, the low cost of BCIs alone could increase their attractiveness as an investment regardless of the magnitude of outcome improvement.

Denchev et al constructed a cost/benefit comparison model that included the postcard BCI study conducted by Carter et al [20], the telephone outreach study conducted by Vaiva et al [23], and a study of cognitive behavioral therapy (CBT) [11], all of which showed a clinical benefit. This model relied upon some numeric estimations and did not account for variation in outcomes between individual studies of each intervention strategy. However, it concluded that both telephone outreach and CBT were likely to be cost-prohibitive compared to asynchronous BCIs, which were associated with a reduction in costs overall [28].

Conclusion

There remains much to learn regarding how best to reduce suicide risk among adult patients in the period after discharge from the ED, during which patients with an identified suicide risk are known to be vulnerable. However, providing psychosocial and emotional support to patients with an identified suicide risk after they are discharged from the ED is feasible and may reduce subsequent suicidal behaviors. Templates for providing supportive outreach using different modalities now exist, and these may help guide the ongoing development and widespread adoption of more effective and cost-effective solutions.

Corresponding author: David S. Kroll, MD, [email protected].

Financial disclosure: Dr. Kroll has received research funding from Brigham and Women’s Hospital to study and develop technological solutions for supporting suicidal patients after discharge from the emergency department. He has additionally received research funding and a speaking honorarium from Avasure.

From the Department of Psychiatry, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

Abstract

• Objective: To provide a review of emergency department (ED)-based psychosocial interventions that support adult patients with an identified suicide risk towards a goal of reducing subsequent suicidal behavior through the period after discharge, which is known to be a time of high risk for suicidal behavior.
• Methods: Non-systematic review of the literature.
• Results: Multiple methods of engaging patients after discharge from the ED have been shown to reduce subsequent suicidal behaviors. These methods include sending caring letters in the mail, facilitating supportive phone conversations, case management, and protocols that combine different services. Overall, the existing literature is insufficient to recommend widespread adoption of any individual strategy or protocol. However, providing psychosocial and emotional support to patients with an identified suicide risk after they are discharged from the ED is feasible and may reduce subsequent suicidal behaviors. Templates for providing supportive outreach using different modalities now exist, and these may help guide the ongoing development and widespread adoption of more effective and cost-effective solutions.
• Conclusion: Many ED–based interventions that provide enhanced support to patients with suicide risk after they are discharged have demonstrated a potential to reduce the risk of future suicidal behavior.

Key words: suicide; emergency department.

Despite the fact that emergency department (ED) providers often feel unprepared to manage suicide risk, patients with significant suicide risk frequently receive care in EDs, whether or not they have sustained physical injuries resulting from suicidal behavior [1,2]. Patients make greater than 400,000 visits to EDs in the United States each year for suicidal and self-injurious behaviors (suicide attempts and self-injurious behaviors are typically coded in ways that make them indistinguishable from each other in retrospective analyses) [3], and it is estimated that 6% to 10% of all patients in EDs endorse suicidal ideation when asked, regardless of their original chief complaints [4]. Meanwhile, suicide has become the 10th leading cause of death in the United States [5], and the Joint Commission has charged all accredited health care organizations with providing comprehensive treatment to suicidal patients, which may range from immediately containing an acute risk to ensuring continuity of care in follow-up [5].

When an acute suicide risk is identified in the ED, the provider’s immediate next steps should be to place the patient in a safe area under constant observation and to provide an emergency assessment [5,6]. Although psychiatric consultation and/or psychiatric admission may follow this assessment, suicide risk does not require admission in all cases; and some patients with suicide risk may be discharged to an outpatient setting even without receiving a psychiatric consultation [1]. Regardless of whether an outpatient disposition from the ED is appropriate, however, the period that immediately follows discharge is a time of high risk for repeated suicidal behavior and suicide death [7–9], and only 30% to 50% of patients who are discharged from EDs after a self-harm incident actually keep a follow-up mental health appointment [9,10]. Therefore, any support given to patients through this transition out of the emergency care setting could be especially high-yield.

The Joint Commission recommends that all patients with suicidal ideation receive, at minimum, a referral to treatment, telephone numbers for local and national crisis support resources (including the National Suicide Prevention Lifeline 1-800-273-TALK), collaborative safety planning, and counseling to restrict access to lethal means upon discharge [5]. However, some programs have demonstrated the capacity to provide enhanced support to patients beyond discharge from the ED, with some success in reducing the rates of subsequent suicidal behaviors. This non-systematic review describes interventions that can be initiated in the context of an ED encounter with the purpose of reducing future suicidal behavior among adult patients. They are primarily psychosocial rather than clinical. Clinical interventions that apply psychotherapy [11–13] psychopharmacology [14], and specialized inpatient treatments [15] have been studied as well but are beyond the scope of this review.

[polldaddy:10107269]

Interventions to Support Patients At Risk of Suicide After Discharge from the ED

Brief Contact Interventions

The idea that maintaining written correspondence with patients who have a known suicide risk after discharge can reduce subsequent suicide rates originated with a study of psychiatric inpatients conducted by Motto and Bostrom, in which patients who had been admitted for depression but had declined outpatient treatment were randomly assigned to periodically receive letters containing supportive messages from staff members over a period of 5 years [16]. This study remarkably found that these so-called brief contact interventions (BCIs), which were personalized to each recipient but did not contain psychotherapy per se, were associated with a reduced rate of suicide throughout the duration of the program compared with no written contacts [16].

BCIs have since been adapted to other communication formats and have been studied in patients who were discharged directly from the ED after an evaluation of suicide risk or suicidal behavior. Typically, BCIs consist of short, supportive messages that are delivered at regular intervals (often once every 1–2 months) over a period of 1 to 5 years [17,18]. They notably do not contain psychotherapy content, although they may reinforce coping strategies or remind recipients of how to access help if needed [17,19]. They may arrive as postcards [20,21], letters [22], telephone outreach [23–25], or a combination of modalities [26].

Protocols that rely on BCIs alone vary in their structure and have yielded mixed results [18]. A meta-analysis of 12 BCI protocols conducted by Milner et al found that, overall, BCIs administered after a presentation to the ED for self-harm have been associated with a significant reduction in repeat suicide attempts per recipient but not in total suicide deaths [27]. Milner’s group did not recommend large-scale promotion of BCIs based on the inadequacy of data so far, but suggested that this strategy may yet show promise upon further study [27]. A key advantage of BCIs is that they are inexpensive to implement, particularly if they do not include a telephone outreach component [28]. Thus, even if the potential benefit to patients is small, administering BCIs can be cost-effective [28].

It should not come as a surprise, therefore, that the potential for incorporation of BCIs into mobile smartphone technology is currently under investigation. Individuals who own mobile phones typically keep them on their persons and turned on continuously, and thus this is a reliable platform for maintaining contact with a wide range of patients in real-time [17,29]. Developers of at least 2 BCI smartphone programs that rely on mobile text messaging have published their protocols [17,30]. However, whether these programs will succeed in meaningfully reducing suicide rates remains to be determined by future research.

Green Cards

Morgan et al conducted a study in the United Kingdom in which individuals who presented to EDs after a self-harm event received a “green card,” which contained encouraging messages about seeking help and provided contact information for emergency services with 24-hour availability [31]. The green card also facilitated access to a crisis admission if necessary. The green card was distributed first in the ED and a second time by mail 3 weeks later. No suicides occurred in either the intervention or control group, which received usual care, and no statistically significant differences in suicide reattempt rate were found between groups after 1 year [31].

Evans et al studied an updated version of the green card intervention in which the green card facilitated access to an on-call psychiatrist with 24-hour availability by telephone [32]. The updated card included encouraging messages about seeking help similar to the original green card described by Morgan; however, the psychiatry consultation via telephone replaced the offer of hospital admission [32]. This second trial of green cards also failed to show a reduction in the rate of suicide reattempts among green card recipients at 6 months and 1 year [32,33].

Brief Intervention and Contact

The World Health Organization’s Brief Intervention and Contact (BIC) protocol is a standardized, multi-step suicide prevention program that has been studied primarily in patients who present to EDs after a suicide attempt in middle-income countries [34]. BIC includes a 1-hour information session that is administered shortly prior to discharge, and subsequently provides 9 follow-up contact interventions at specified intervals over an 18-month period. Unlike in a typical BCI, the contacts in BIC are conducted by a clinician either face-to-face or over the phone and include standardized assessments of the patient’s condition, although they still do not include psychotherapy. BIC has been shown to reduce suicide attempts, suicide deaths, or both in India [34–36], Iran [34,36,37], China [34,36], Brazil [34,36], and Sri Lanka [34,36] but was not found to directly improve clinical outcomes in a study conducted in French Polynesia [38]. A meta-analysis conducted by Riblet et al concluded that BIC is effective in reducing suicide risk overall [39].

ED-SAFE

The Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) protocol was validated in 8 EDs in 7 states in the US that did not already provide psychiatric services internally [40]. Under this model, all patients in the ED receive a screening for suicide risk, and those with an initial positive screen receive a secondary screen administered by the ED physician, a self-administered safety plan, and a series of up to 11 phone contacts over the following year that are administered by trained mental health clinicians in a central location. The ED-SAFE phone contacts follow the Coping Long Term with Active Suicide Program (CLASP) protocol [41] and provide support around safety planning and treatment engagement. They have the capacity to engage the patients’ significant others directly if a significant other is available and the patient chooses to involve that person.

In a single multicenter study, ED-SAFE reduced the absolute risk of suicide attempt by 5%, and the relative risk by 20% compared to usual treatment [40]. An intermediate phase of the study compared the universal suicide screening alone (ie, without the safety plan or follow-up contacts) with usual care and did not find this to improve outcomes [40].

Case Management

Kawanishi et al conducted a randomized controlled trial of assertive case management, the ACTION-J study, for patients with psychiatric diagnoses who presented with self-harm to 17 participating EDs in Japan [42]. In the ACTION-J study, case managers were mental health clinicians who provided clinical evaluations, treatment planning, encouragement, and care coordination over the course of 7 scheduled face-to-face or phone contacts in the first 18 months, and additional contacts at 6-month intervals until the completion of the trial (up to a total of 5 years) [43]. The comparison intervention, enhanced usual care, consisted of psychoeducation provided at the time of the encounter in the ED without case management services. The assertive case management intervention was associated with a decrease in suicidal behavior in the first 6 months but not for the duration of the study, except in women, for whom the benefit lasted the full 18 months [42]. A subsequent analysis also found a decrease in the total number of self-harm episodes per person-year compared to enhanced usual care, although there was not a difference in the number of participants who experienced a repeat self-harm episode [43]. The benefit was most strongly pronounced among patients who had presented with an index suicide attempt [43].

Morthorst et al applied an alternative case management model for the assertive intervention for deliberate self harm (AID) trial, which took place in Denmark [44]. Participants were aged 12 and older and could have been recruited from medical or pediatric inpatient units as well as the ED after a self-harm event. AID employed psychiatric nurses to provide crisis intervention, crisis planning, problem solving, motivational support, family mediation, and assistance with keeping appointments over a period of 6 months following discharge. Outreach took place over the phone, by text message, in participants’ homes, in cafes, and at health and social services appointments. The intervention required at least 4 contacts, although additional contacts could be made if appropriate. In comparison with a control group, in which participants received only usual care (which included ready access to short-term psychotherapy), the AID intervention was not associated with statistically significant differences in recurrent suicidal behaviors [44]. Subgroup analyses examining adult participants aged 20–39 and 40 and older also did not find differences in recurrent suicidal behavior between groups [44].

The Baerum Model and OPAC

A municipal suicide prevention team that provides comprehensive social services to suicide attempters has operated in Baerum, Norway, since 1983 [45]. Under the Baerum model, patients who attempt suicide, can be discharged from the general hospital without psychiatric admission, and are determined to have a high level of need for support are connected by a hospital-based suicide prevention team to a community-based team consisting of nurses and a consulting psychologist, who subsequently engage patients in own their homes and through follow-up phone calls. The services they provide include care coordination, encouragement, activation of social networks, psychological first-aid, and counseling focused on problem-solving. The ostensible goal of the suicide prevention team is to provide a bridge between inpatient medical care and outpatient mental health treatment; however, the intervention lasts approximately 1 year regardless of whether the patient connects with a treatment program [45].

A retrospective comparison of outcomes between recipients of the original Baerum program and non-recipients failed to find a difference in suicide attempts or suicide deaths between groups [45]. However, this was not a controlled study, and suicide attempters were preferentially referred to the program based on whether they had a higher level of need at baseline. Hvid and Wang adapted this model to patients who presented to EDs and general hospitals in Amager, Denmark [46] and have since conducted a series of randomized controlled trials comparing their adaptation to usual care. The Danish version of the Baerum model, renamed OPAC (for “outreach, problem solving, adherence, continuity”), provides similar case management and counseling services but for a maximum of 6 months. In their studies, OPAC significantly reduced the number of patients with a repeat suicide attempt and the total number of repeat suicide attempts at a 1-year interval, and this effect on total number of suicide attempts was sustained at 5 years [47,48]. Although the OPAC protocol begins with a patient’s presentation to the ED, the intervention is initiated after admission to the general hospital. Therefore, while this may inspire a model that provides similar services directly from the ED to patients who do not require general hospital admission, the existing model is not entirely based in the ED.

Discussion

The needs of suicidal patients are often multidimensional, and in some cases their risks are driven by psychosocial problems in addition to, or instead of, medically modifiable psychiatric conditions [49]. However, developing an ED-based program to support patients who are at risk of suicide after they are discharged from the ED is possible. Many such programs that provide or facilitate caring contacts, family support, case management, and/or treatment engagement with discharged patients have demonstrated that similar strategies may have the potential to impact future suicidal behavior. Nonetheless, it would be a stretch to say that all hospital systems should immediately begin doing so.

A new post-discharge support program is an investment of financial resources, personnel, and sometimes technology. Successful delivery of support or messages in any format requires that the intended recipient be able to receive it via reliable access to a working address, telephone number, or electronic device. Nonetheless, programs that rely on BCIs alone (excluding those conducted via telephone) cost relatively little to implement and thus would require a smaller investment than programs that require synchronous telephone or face-to-face contacts with staff in addition to or instead of BCIs. Costs for synchronous programs will also vary depending on the frequency and duration of contacts and the licensure and training required of the staff who provide them.

A trend toward better outcomes associating with more resource-intensive programs is easy to imagine but has not been definitively demonstrated. The wide variation between protocols in all types of programs makes comparisons between those that do and do not include synchronous contacts, and between types of synchronous contacts, difficult. Meanwhile, the low cost of BCIs alone could increase their attractiveness as an investment regardless of the magnitude of outcome improvement.

Denchev et al constructed a cost/benefit comparison model that included the postcard BCI study conducted by Carter et al [20], the telephone outreach study conducted by Vaiva et al [23], and a study of cognitive behavioral therapy (CBT) [11], all of which showed a clinical benefit. This model relied upon some numeric estimations and did not account for variation in outcomes between individual studies of each intervention strategy. However, it concluded that both telephone outreach and CBT were likely to be cost-prohibitive compared to asynchronous BCIs, which were associated with a reduction in costs overall [28].

Conclusion

There remains much to learn regarding how best to reduce suicide risk among adult patients in the period after discharge from the ED, during which patients with an identified suicide risk are known to be vulnerable. However, providing psychosocial and emotional support to patients with an identified suicide risk after they are discharged from the ED is feasible and may reduce subsequent suicidal behaviors. Templates for providing supportive outreach using different modalities now exist, and these may help guide the ongoing development and widespread adoption of more effective and cost-effective solutions.

Corresponding author: David S. Kroll, MD, [email protected].

Financial disclosure: Dr. Kroll has received research funding from Brigham and Women’s Hospital to study and develop technological solutions for supporting suicidal patients after discharge from the emergency department. He has additionally received research funding and a speaking honorarium from Avasure.

From the Department of Psychiatry, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

Abstract

• Objective: To provide a review of emergency department (ED)-based psychosocial interventions that support adult patients with an identified suicide risk towards a goal of reducing subsequent suicidal behavior through the period after discharge, which is known to be a time of high risk for suicidal behavior.
• Methods: Non-systematic review of the literature.
• Results: Multiple methods of engaging patients after discharge from the ED have been shown to reduce subsequent suicidal behaviors. These methods include sending caring letters in the mail, facilitating supportive phone conversations, case management, and protocols that combine different services. Overall, the existing literature is insufficient to recommend widespread adoption of any individual strategy or protocol. However, providing psychosocial and emotional support to patients with an identified suicide risk after they are discharged from the ED is feasible and may reduce subsequent suicidal behaviors. Templates for providing supportive outreach using different modalities now exist, and these may help guide the ongoing development and widespread adoption of more effective and cost-effective solutions.
• Conclusion: Many ED–based interventions that provide enhanced support to patients with suicide risk after they are discharged have demonstrated a potential to reduce the risk of future suicidal behavior.

Key words: suicide; emergency department.

Despite the fact that emergency department (ED) providers often feel unprepared to manage suicide risk, patients with significant suicide risk frequently receive care in EDs, whether or not they have sustained physical injuries resulting from suicidal behavior [1,2]. Patients make greater than 400,000 visits to EDs in the United States each year for suicidal and self-injurious behaviors (suicide attempts and self-injurious behaviors are typically coded in ways that make them indistinguishable from each other in retrospective analyses) [3], and it is estimated that 6% to 10% of all patients in EDs endorse suicidal ideation when asked, regardless of their original chief complaints [4]. Meanwhile, suicide has become the 10th leading cause of death in the United States [5], and the Joint Commission has charged all accredited health care organizations with providing comprehensive treatment to suicidal patients, which may range from immediately containing an acute risk to ensuring continuity of care in follow-up [5].

When an acute suicide risk is identified in the ED, the provider’s immediate next steps should be to place the patient in a safe area under constant observation and to provide an emergency assessment [5,6]. Although psychiatric consultation and/or psychiatric admission may follow this assessment, suicide risk does not require admission in all cases; and some patients with suicide risk may be discharged to an outpatient setting even without receiving a psychiatric consultation [1]. Regardless of whether an outpatient disposition from the ED is appropriate, however, the period that immediately follows discharge is a time of high risk for repeated suicidal behavior and suicide death [7–9], and only 30% to 50% of patients who are discharged from EDs after a self-harm incident actually keep a follow-up mental health appointment [9,10]. Therefore, any support given to patients through this transition out of the emergency care setting could be especially high-yield.

The Joint Commission recommends that all patients with suicidal ideation receive, at minimum, a referral to treatment, telephone numbers for local and national crisis support resources (including the National Suicide Prevention Lifeline 1-800-273-TALK), collaborative safety planning, and counseling to restrict access to lethal means upon discharge [5]. However, some programs have demonstrated the capacity to provide enhanced support to patients beyond discharge from the ED, with some success in reducing the rates of subsequent suicidal behaviors. This non-systematic review describes interventions that can be initiated in the context of an ED encounter with the purpose of reducing future suicidal behavior among adult patients. They are primarily psychosocial rather than clinical. Clinical interventions that apply psychotherapy [11–13] psychopharmacology [14], and specialized inpatient treatments [15] have been studied as well but are beyond the scope of this review.

[polldaddy:10107269]

Interventions to Support Patients At Risk of Suicide After Discharge from the ED

Brief Contact Interventions

The idea that maintaining written correspondence with patients who have a known suicide risk after discharge can reduce subsequent suicide rates originated with a study of psychiatric inpatients conducted by Motto and Bostrom, in which patients who had been admitted for depression but had declined outpatient treatment were randomly assigned to periodically receive letters containing supportive messages from staff members over a period of 5 years [16]. This study remarkably found that these so-called brief contact interventions (BCIs), which were personalized to each recipient but did not contain psychotherapy per se, were associated with a reduced rate of suicide throughout the duration of the program compared with no written contacts [16].

BCIs have since been adapted to other communication formats and have been studied in patients who were discharged directly from the ED after an evaluation of suicide risk or suicidal behavior. Typically, BCIs consist of short, supportive messages that are delivered at regular intervals (often once every 1–2 months) over a period of 1 to 5 years [17,18]. They notably do not contain psychotherapy content, although they may reinforce coping strategies or remind recipients of how to access help if needed [17,19]. They may arrive as postcards [20,21], letters [22], telephone outreach [23–25], or a combination of modalities [26].

Protocols that rely on BCIs alone vary in their structure and have yielded mixed results [18]. A meta-analysis of 12 BCI protocols conducted by Milner et al found that, overall, BCIs administered after a presentation to the ED for self-harm have been associated with a significant reduction in repeat suicide attempts per recipient but not in total suicide deaths [27]. Milner’s group did not recommend large-scale promotion of BCIs based on the inadequacy of data so far, but suggested that this strategy may yet show promise upon further study [27]. A key advantage of BCIs is that they are inexpensive to implement, particularly if they do not include a telephone outreach component [28]. Thus, even if the potential benefit to patients is small, administering BCIs can be cost-effective [28].

It should not come as a surprise, therefore, that the potential for incorporation of BCIs into mobile smartphone technology is currently under investigation. Individuals who own mobile phones typically keep them on their persons and turned on continuously, and thus this is a reliable platform for maintaining contact with a wide range of patients in real-time [17,29]. Developers of at least 2 BCI smartphone programs that rely on mobile text messaging have published their protocols [17,30]. However, whether these programs will succeed in meaningfully reducing suicide rates remains to be determined by future research.

Green Cards

Morgan et al conducted a study in the United Kingdom in which individuals who presented to EDs after a self-harm event received a “green card,” which contained encouraging messages about seeking help and provided contact information for emergency services with 24-hour availability [31]. The green card also facilitated access to a crisis admission if necessary. The green card was distributed first in the ED and a second time by mail 3 weeks later. No suicides occurred in either the intervention or control group, which received usual care, and no statistically significant differences in suicide reattempt rate were found between groups after 1 year [31].

Evans et al studied an updated version of the green card intervention in which the green card facilitated access to an on-call psychiatrist with 24-hour availability by telephone [32]. The updated card included encouraging messages about seeking help similar to the original green card described by Morgan; however, the psychiatry consultation via telephone replaced the offer of hospital admission [32]. This second trial of green cards also failed to show a reduction in the rate of suicide reattempts among green card recipients at 6 months and 1 year [32,33].

Brief Intervention and Contact

The World Health Organization’s Brief Intervention and Contact (BIC) protocol is a standardized, multi-step suicide prevention program that has been studied primarily in patients who present to EDs after a suicide attempt in middle-income countries [34]. BIC includes a 1-hour information session that is administered shortly prior to discharge, and subsequently provides 9 follow-up contact interventions at specified intervals over an 18-month period. Unlike in a typical BCI, the contacts in BIC are conducted by a clinician either face-to-face or over the phone and include standardized assessments of the patient’s condition, although they still do not include psychotherapy. BIC has been shown to reduce suicide attempts, suicide deaths, or both in India [34–36], Iran [34,36,37], China [34,36], Brazil [34,36], and Sri Lanka [34,36] but was not found to directly improve clinical outcomes in a study conducted in French Polynesia [38]. A meta-analysis conducted by Riblet et al concluded that BIC is effective in reducing suicide risk overall [39].

ED-SAFE

The Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) protocol was validated in 8 EDs in 7 states in the US that did not already provide psychiatric services internally [40]. Under this model, all patients in the ED receive a screening for suicide risk, and those with an initial positive screen receive a secondary screen administered by the ED physician, a self-administered safety plan, and a series of up to 11 phone contacts over the following year that are administered by trained mental health clinicians in a central location. The ED-SAFE phone contacts follow the Coping Long Term with Active Suicide Program (CLASP) protocol [41] and provide support around safety planning and treatment engagement. They have the capacity to engage the patients’ significant others directly if a significant other is available and the patient chooses to involve that person.

In a single multicenter study, ED-SAFE reduced the absolute risk of suicide attempt by 5%, and the relative risk by 20% compared to usual treatment [40]. An intermediate phase of the study compared the universal suicide screening alone (ie, without the safety plan or follow-up contacts) with usual care and did not find this to improve outcomes [40].

Case Management

Kawanishi et al conducted a randomized controlled trial of assertive case management, the ACTION-J study, for patients with psychiatric diagnoses who presented with self-harm to 17 participating EDs in Japan [42]. In the ACTION-J study, case managers were mental health clinicians who provided clinical evaluations, treatment planning, encouragement, and care coordination over the course of 7 scheduled face-to-face or phone contacts in the first 18 months, and additional contacts at 6-month intervals until the completion of the trial (up to a total of 5 years) [43]. The comparison intervention, enhanced usual care, consisted of psychoeducation provided at the time of the encounter in the ED without case management services. The assertive case management intervention was associated with a decrease in suicidal behavior in the first 6 months but not for the duration of the study, except in women, for whom the benefit lasted the full 18 months [42]. A subsequent analysis also found a decrease in the total number of self-harm episodes per person-year compared to enhanced usual care, although there was not a difference in the number of participants who experienced a repeat self-harm episode [43]. The benefit was most strongly pronounced among patients who had presented with an index suicide attempt [43].

Morthorst et al applied an alternative case management model for the assertive intervention for deliberate self harm (AID) trial, which took place in Denmark [44]. Participants were aged 12 and older and could have been recruited from medical or pediatric inpatient units as well as the ED after a self-harm event. AID employed psychiatric nurses to provide crisis intervention, crisis planning, problem solving, motivational support, family mediation, and assistance with keeping appointments over a period of 6 months following discharge. Outreach took place over the phone, by text message, in participants’ homes, in cafes, and at health and social services appointments. The intervention required at least 4 contacts, although additional contacts could be made if appropriate. In comparison with a control group, in which participants received only usual care (which included ready access to short-term psychotherapy), the AID intervention was not associated with statistically significant differences in recurrent suicidal behaviors [44]. Subgroup analyses examining adult participants aged 20–39 and 40 and older also did not find differences in recurrent suicidal behavior between groups [44].

The Baerum Model and OPAC

A municipal suicide prevention team that provides comprehensive social services to suicide attempters has operated in Baerum, Norway, since 1983 [45]. Under the Baerum model, patients who attempt suicide, can be discharged from the general hospital without psychiatric admission, and are determined to have a high level of need for support are connected by a hospital-based suicide prevention team to a community-based team consisting of nurses and a consulting psychologist, who subsequently engage patients in own their homes and through follow-up phone calls. The services they provide include care coordination, encouragement, activation of social networks, psychological first-aid, and counseling focused on problem-solving. The ostensible goal of the suicide prevention team is to provide a bridge between inpatient medical care and outpatient mental health treatment; however, the intervention lasts approximately 1 year regardless of whether the patient connects with a treatment program [45].

A retrospective comparison of outcomes between recipients of the original Baerum program and non-recipients failed to find a difference in suicide attempts or suicide deaths between groups [45]. However, this was not a controlled study, and suicide attempters were preferentially referred to the program based on whether they had a higher level of need at baseline. Hvid and Wang adapted this model to patients who presented to EDs and general hospitals in Amager, Denmark [46] and have since conducted a series of randomized controlled trials comparing their adaptation to usual care. The Danish version of the Baerum model, renamed OPAC (for “outreach, problem solving, adherence, continuity”), provides similar case management and counseling services but for a maximum of 6 months. In their studies, OPAC significantly reduced the number of patients with a repeat suicide attempt and the total number of repeat suicide attempts at a 1-year interval, and this effect on total number of suicide attempts was sustained at 5 years [47,48]. Although the OPAC protocol begins with a patient’s presentation to the ED, the intervention is initiated after admission to the general hospital. Therefore, while this may inspire a model that provides similar services directly from the ED to patients who do not require general hospital admission, the existing model is not entirely based in the ED.

Discussion

The needs of suicidal patients are often multidimensional, and in some cases their risks are driven by psychosocial problems in addition to, or instead of, medically modifiable psychiatric conditions [49]. However, developing an ED-based program to support patients who are at risk of suicide after they are discharged from the ED is possible. Many such programs that provide or facilitate caring contacts, family support, case management, and/or treatment engagement with discharged patients have demonstrated that similar strategies may have the potential to impact future suicidal behavior. Nonetheless, it would be a stretch to say that all hospital systems should immediately begin doing so.

A new post-discharge support program is an investment of financial resources, personnel, and sometimes technology. Successful delivery of support or messages in any format requires that the intended recipient be able to receive it via reliable access to a working address, telephone number, or electronic device. Nonetheless, programs that rely on BCIs alone (excluding those conducted via telephone) cost relatively little to implement and thus would require a smaller investment than programs that require synchronous telephone or face-to-face contacts with staff in addition to or instead of BCIs. Costs for synchronous programs will also vary depending on the frequency and duration of contacts and the licensure and training required of the staff who provide them.

A trend toward better outcomes associating with more resource-intensive programs is easy to imagine but has not been definitively demonstrated. The wide variation between protocols in all types of programs makes comparisons between those that do and do not include synchronous contacts, and between types of synchronous contacts, difficult. Meanwhile, the low cost of BCIs alone could increase their attractiveness as an investment regardless of the magnitude of outcome improvement.

Denchev et al constructed a cost/benefit comparison model that included the postcard BCI study conducted by Carter et al [20], the telephone outreach study conducted by Vaiva et al [23], and a study of cognitive behavioral therapy (CBT) [11], all of which showed a clinical benefit. This model relied upon some numeric estimations and did not account for variation in outcomes between individual studies of each intervention strategy. However, it concluded that both telephone outreach and CBT were likely to be cost-prohibitive compared to asynchronous BCIs, which were associated with a reduction in costs overall [28].

Conclusion

There remains much to learn regarding how best to reduce suicide risk among adult patients in the period after discharge from the ED, during which patients with an identified suicide risk are known to be vulnerable. However, providing psychosocial and emotional support to patients with an identified suicide risk after they are discharged from the ED is feasible and may reduce subsequent suicidal behaviors. Templates for providing supportive outreach using different modalities now exist, and these may help guide the ongoing development and widespread adoption of more effective and cost-effective solutions.

Corresponding author: David S. Kroll, MD, [email protected].

Financial disclosure: Dr. Kroll has received research funding from Brigham and Women’s Hospital to study and develop technological solutions for supporting suicidal patients after discharge from the emergency department. He has additionally received research funding and a speaking honorarium from Avasure.

Study Overview

Objective. To evaluate the efficacy of an intervention targeting both patients and clinicians intended to increase goals-of-care conversations.

Design. Multicenter cluster-randomized controlled trial.

Setting and participants. Clinicians (physicians or nurse practitioners) were recruited between February 2014 and November 2015 from 2 large health centers in the Pacific Northwest and were eligible if they provided primary or specialty care and had at least 5 eligible patients in their panels. Using the electronic health record (EHR) and clinic schedules, study staff identified and contacted (via mail or telephone) consecutive patients cared for by participating clinicians between March 2014 and May 2016 with the following eligibility criteria: age 18 years or older, 2 or more visits with the clinician in the last 18 months, and 1 or more qualifying conditions. Qualifying conditions included (1) metastatic cancer or inoperable lung cancer; (2) COPD with FEV₁ values below 35% of that predicted or oxygen dependence, restrictive lung disease with a total lung capacity below 50% of that predicted, or cystic fibrosis with FEV₁ below 30% of that predicted; (3) New York Heart Association class III or IV heart failure, pulmonary arterial hypertension, or left ventricular assist device or implantable cardioverter defibrillator implant; 4) cirrhosis or end-stage liver disease; (5) dialysis-dependent renal failure and diabetes; (6) age 75 or older with one or more life-limiting chronic illness; (7) age 90 or older; (8) hospitalization in the last 18 months with a life-limiting illness; (9) Charlson comorbidity index of 6 or higher. The qualifying criteria were selected to identify a median survival of approximately 2 years, suggesting relevance of goals-of-care discussions.

Intervention. The intervention was the patient-specific Jumpstart-Tips intervention, intended to prime clinicians and patients for a brief discussion of goals of care during a routine clinic visit. Patients in the intervention group received a survey to assess their preferences, barriers and facilitators for communication about end-of-life care. Survey responses were used to (1) generate an abstracted version of the patient’s preferences, (2) identify the most important communication barrier or facilitator, and (3) provide communication tips based on curricular materials from VitalTalk (http://vitaltalk.org) tailored to patient responses. The 1-page communication guide, called Jumpstart-Tips, was sent to clinicians 1 or 2 days prior to the target clinic visit date. Patients also received 1-page patient-specific Jumpstart-Tips forms, which summarized their survey responses and provided suggestions for having a goals-of-care conversation with the clinician. Patients in the control group completed the same surveys, but no information was provided to the patients or clinicians. Clinicians were randomly assigned in a 1:1 ratio to intervention or enhanced usual care.

Main outcome measures. The primary outcome was patient-reported occurrence of goals-of-care communication, which was evaluated using a validated dichotomous survey item. Other outcomes included clinician documentation of a goals-of-care conversation in the medical record, patient-reported quality of communication (measured using Quality of Communication questionnaire) at 2 weeks, patient reports of goal-concordant care at 3 months, and patient-reported symptoms of depression and anxiety at 3 and 6 months. All analyses included covariate adjustment for the baseline measure of the outcome and adjustment for other variables found to confound the association between randomization group and outcome.

Main results. Of 485 potentially eligible clinicians, 65 clinicians were randomized to the intervention group and 69 were randomized to the control group. Of these 132 clinicians, 124 had patients participating in the study: 537 out of 917 eligible patients enrolled, with 249 allocated to intervention and 288 to usual care.

Patients in the intervention group were more likely to report a goals-of-care conversation with their provider among all patients (74%, n = 137 vs 31%, n = 66; P n = 112 vs 28%, n = 44; P n = 140 vs 17%, n = 45; P n = 114 vs 17%, n = 34; P
Patients in the intervention group also reported higher quality ratings of goals-of-care conversations at the target visit (mean values, 4.6 v 2.1, P = 0.01, on the 4-indicator construct). Additionally, intervention members reported statistically significant higher ratings on 3 of the 7 individual quality-of-communication survey items.

Patient-assessed goal concordant care did not increase significantly overall (70% vs 57%; P = 0.08) but did increase for patients with stable goals between 3-month follow-up and last prior assessment (73% vs 57%; P = 0.03). Symptoms of depression or anxiety were not different between groups at 3 or 6 months.

Conclusion. The Jumpstart-Tips intervention was associated with an increase in patient reports and clinician documentation of goals-of-care communication. Increased patient-reported goal-concordant care among patients with stable goals was also associated with the intervention. Statistical significance was not detected for changes in depression or anxiety as a result of the intervention. The impact on goals-of-care discussion between patients and caregivers is suggestive of enhanced patient-centered care; however, further studies are needed to evaluate whether this communication is associated with changes in health care delivery.

Commentary

Previous research has shown that patients with serious illness who discuss their goals-of-care fare better in terms of quality of life and reducing intensity of care at the end-of-life [1]. However, providers often fail to or inadequately discuss goals of care with seriously ill patients [2,3]. This contributes to the lack of concordance between patient wishes, particularly related to end-of-life care, and clinical plans of care [4,5]. Addressing this gap between care provided and care desired, as well as providing high-quality, patient-centered care is needed.

Access to palliative care providers (who are trained to address these priorities) in the outpatient setting lags, despite an increase in specialists [6,7]. Thus, primary and specialty care providers in the outpatient setting are best positioned to align their care strategy with the goals of their patients. However, there have been limited results in showing that goals-of-care communication can be improved within the practice setting [8,9]. A randomized clinical trial among hospitalized seniors at the end-of-life showed an association where those who received advanced care planning with had improved quality of life, reduced care at dying, and reduced psychological distress among family [10]. However, in another randomized trial, simulation-based communication training compared with usual education among internal medicine and nurse practitioner trainees did not improve quality of communication about end-of-life care or quality of end-of-life care but was associated with a small increase in patients’ depressive symptoms [11]. A recent 2018 literature review of strategies used to facilitate the discussion of advance care planning with older adults in primary care settings identified effective interventions, including delivering education using various delivery methods, computer-generated triggers for primary care physicians (PCPs), inclusion of multidisciplinary professionals for content delivery, and patient preparation for PCP visit [12].

This article adds to the literature by demonstrating the feasibility and impact of implementing an intervention to increase communication about goals of care and end-of-life care. Further, this study highlights how communication that is bilateral, predetermined, and structured can be integrated into primary care. Strengths of the study include the use of randomization; deployment of validated survey tools; and confirmatory factor analysis to assess whether the survey variables are consistent with the hypothesized constructs. In addition, study staff were blinded when extracting data from the EHR record around discussions and documentation of goals-of-care conversations during patient visits. However, several limitations are present. There may be limited generalizability as the study was performed at low-scale, across one region as well as selection bias among clinicians participating in the study. Clinicians were not blinded of their assignment, which may have influenced their behaviors to discuss and document goals-of-care conversations.

Applications for Clinical Practice

Increasing quality communication around the end of life and understanding of a patient’s goals is important. Good communication can facilitate the development of a comprehensive treatment plan that is medically sound and concordant with the patient’s wishes and values. Clinicians and practices should consider adopting approaches to communication priming and accurate documentation, including: (1) incorporating/automating Jumpstart-Tips forms into practice (and tailoring as needed); (2) identifying similar education material that can serve as a primer for patients; (3) creating a pre-visit form for patients/caregivers to document and inform the clinician of their goals prior to the visit; (4) incorporating a standard EHR note to document and update goals-of-care discussion at each visit; and (5) more broadly encouraging (or providing training for) clinicians to practice bilateral communications with patients during visits.

—Ronald Sanchez, MPH, and Katrina F. Mateo, MPH

Study Overview

Objective. To evaluate the efficacy of an intervention targeting both patients and clinicians intended to increase goals-of-care conversations.

Design. Multicenter cluster-randomized controlled trial.

Setting and participants. Clinicians (physicians or nurse practitioners) were recruited between February 2014 and November 2015 from 2 large health centers in the Pacific Northwest and were eligible if they provided primary or specialty care and had at least 5 eligible patients in their panels. Using the electronic health record (EHR) and clinic schedules, study staff identified and contacted (via mail or telephone) consecutive patients cared for by participating clinicians between March 2014 and May 2016 with the following eligibility criteria: age 18 years or older, 2 or more visits with the clinician in the last 18 months, and 1 or more qualifying conditions. Qualifying conditions included (1) metastatic cancer or inoperable lung cancer; (2) COPD with FEV₁ values below 35% of that predicted or oxygen dependence, restrictive lung disease with a total lung capacity below 50% of that predicted, or cystic fibrosis with FEV₁ below 30% of that predicted; (3) New York Heart Association class III or IV heart failure, pulmonary arterial hypertension, or left ventricular assist device or implantable cardioverter defibrillator implant; 4) cirrhosis or end-stage liver disease; (5) dialysis-dependent renal failure and diabetes; (6) age 75 or older with one or more life-limiting chronic illness; (7) age 90 or older; (8) hospitalization in the last 18 months with a life-limiting illness; (9) Charlson comorbidity index of 6 or higher. The qualifying criteria were selected to identify a median survival of approximately 2 years, suggesting relevance of goals-of-care discussions.

Intervention. The intervention was the patient-specific Jumpstart-Tips intervention, intended to prime clinicians and patients for a brief discussion of goals of care during a routine clinic visit. Patients in the intervention group received a survey to assess their preferences, barriers and facilitators for communication about end-of-life care. Survey responses were used to (1) generate an abstracted version of the patient’s preferences, (2) identify the most important communication barrier or facilitator, and (3) provide communication tips based on curricular materials from VitalTalk (http://vitaltalk.org) tailored to patient responses. The 1-page communication guide, called Jumpstart-Tips, was sent to clinicians 1 or 2 days prior to the target clinic visit date. Patients also received 1-page patient-specific Jumpstart-Tips forms, which summarized their survey responses and provided suggestions for having a goals-of-care conversation with the clinician. Patients in the control group completed the same surveys, but no information was provided to the patients or clinicians. Clinicians were randomly assigned in a 1:1 ratio to intervention or enhanced usual care.

Main outcome measures. The primary outcome was patient-reported occurrence of goals-of-care communication, which was evaluated using a validated dichotomous survey item. Other outcomes included clinician documentation of a goals-of-care conversation in the medical record, patient-reported quality of communication (measured using Quality of Communication questionnaire) at 2 weeks, patient reports of goal-concordant care at 3 months, and patient-reported symptoms of depression and anxiety at 3 and 6 months. All analyses included covariate adjustment for the baseline measure of the outcome and adjustment for other variables found to confound the association between randomization group and outcome.

Main results. Of 485 potentially eligible clinicians, 65 clinicians were randomized to the intervention group and 69 were randomized to the control group. Of these 132 clinicians, 124 had patients participating in the study: 537 out of 917 eligible patients enrolled, with 249 allocated to intervention and 288 to usual care.

Patients in the intervention group were more likely to report a goals-of-care conversation with their provider among all patients (74%, n = 137 vs 31%, n = 66; P n = 112 vs 28%, n = 44; P n = 140 vs 17%, n = 45; P n = 114 vs 17%, n = 34; P
Patients in the intervention group also reported higher quality ratings of goals-of-care conversations at the target visit (mean values, 4.6 v 2.1, P = 0.01, on the 4-indicator construct). Additionally, intervention members reported statistically significant higher ratings on 3 of the 7 individual quality-of-communication survey items.

Patient-assessed goal concordant care did not increase significantly overall (70% vs 57%; P = 0.08) but did increase for patients with stable goals between 3-month follow-up and last prior assessment (73% vs 57%; P = 0.03). Symptoms of depression or anxiety were not different between groups at 3 or 6 months.

Conclusion. The Jumpstart-Tips intervention was associated with an increase in patient reports and clinician documentation of goals-of-care communication. Increased patient-reported goal-concordant care among patients with stable goals was also associated with the intervention. Statistical significance was not detected for changes in depression or anxiety as a result of the intervention. The impact on goals-of-care discussion between patients and caregivers is suggestive of enhanced patient-centered care; however, further studies are needed to evaluate whether this communication is associated with changes in health care delivery.

Commentary

Previous research has shown that patients with serious illness who discuss their goals-of-care fare better in terms of quality of life and reducing intensity of care at the end-of-life [1]. However, providers often fail to or inadequately discuss goals of care with seriously ill patients [2,3]. This contributes to the lack of concordance between patient wishes, particularly related to end-of-life care, and clinical plans of care [4,5]. Addressing this gap between care provided and care desired, as well as providing high-quality, patient-centered care is needed.

Access to palliative care providers (who are trained to address these priorities) in the outpatient setting lags, despite an increase in specialists [6,7]. Thus, primary and specialty care providers in the outpatient setting are best positioned to align their care strategy with the goals of their patients. However, there have been limited results in showing that goals-of-care communication can be improved within the practice setting [8,9]. A randomized clinical trial among hospitalized seniors at the end-of-life showed an association where those who received advanced care planning with had improved quality of life, reduced care at dying, and reduced psychological distress among family [10]. However, in another randomized trial, simulation-based communication training compared with usual education among internal medicine and nurse practitioner trainees did not improve quality of communication about end-of-life care or quality of end-of-life care but was associated with a small increase in patients’ depressive symptoms [11]. A recent 2018 literature review of strategies used to facilitate the discussion of advance care planning with older adults in primary care settings identified effective interventions, including delivering education using various delivery methods, computer-generated triggers for primary care physicians (PCPs), inclusion of multidisciplinary professionals for content delivery, and patient preparation for PCP visit [12].

This article adds to the literature by demonstrating the feasibility and impact of implementing an intervention to increase communication about goals of care and end-of-life care. Further, this study highlights how communication that is bilateral, predetermined, and structured can be integrated into primary care. Strengths of the study include the use of randomization; deployment of validated survey tools; and confirmatory factor analysis to assess whether the survey variables are consistent with the hypothesized constructs. In addition, study staff were blinded when extracting data from the EHR record around discussions and documentation of goals-of-care conversations during patient visits. However, several limitations are present. There may be limited generalizability as the study was performed at low-scale, across one region as well as selection bias among clinicians participating in the study. Clinicians were not blinded of their assignment, which may have influenced their behaviors to discuss and document goals-of-care conversations.

Applications for Clinical Practice

Increasing quality communication around the end of life and understanding of a patient’s goals is important. Good communication can facilitate the development of a comprehensive treatment plan that is medically sound and concordant with the patient’s wishes and values. Clinicians and practices should consider adopting approaches to communication priming and accurate documentation, including: (1) incorporating/automating Jumpstart-Tips forms into practice (and tailoring as needed); (2) identifying similar education material that can serve as a primer for patients; (3) creating a pre-visit form for patients/caregivers to document and inform the clinician of their goals prior to the visit; (4) incorporating a standard EHR note to document and update goals-of-care discussion at each visit; and (5) more broadly encouraging (or providing training for) clinicians to practice bilateral communications with patients during visits.

—Ronald Sanchez, MPH, and Katrina F. Mateo, MPH

Study Overview

Objective. To evaluate the efficacy of an intervention targeting both patients and clinicians intended to increase goals-of-care conversations.

Design. Multicenter cluster-randomized controlled trial.

Setting and participants. Clinicians (physicians or nurse practitioners) were recruited between February 2014 and November 2015 from 2 large health centers in the Pacific Northwest and were eligible if they provided primary or specialty care and had at least 5 eligible patients in their panels. Using the electronic health record (EHR) and clinic schedules, study staff identified and contacted (via mail or telephone) consecutive patients cared for by participating clinicians between March 2014 and May 2016 with the following eligibility criteria: age 18 years or older, 2 or more visits with the clinician in the last 18 months, and 1 or more qualifying conditions. Qualifying conditions included (1) metastatic cancer or inoperable lung cancer; (2) COPD with FEV₁ values below 35% of that predicted or oxygen dependence, restrictive lung disease with a total lung capacity below 50% of that predicted, or cystic fibrosis with FEV₁ below 30% of that predicted; (3) New York Heart Association class III or IV heart failure, pulmonary arterial hypertension, or left ventricular assist device or implantable cardioverter defibrillator implant; 4) cirrhosis or end-stage liver disease; (5) dialysis-dependent renal failure and diabetes; (6) age 75 or older with one or more life-limiting chronic illness; (7) age 90 or older; (8) hospitalization in the last 18 months with a life-limiting illness; (9) Charlson comorbidity index of 6 or higher. The qualifying criteria were selected to identify a median survival of approximately 2 years, suggesting relevance of goals-of-care discussions.

Intervention. The intervention was the patient-specific Jumpstart-Tips intervention, intended to prime clinicians and patients for a brief discussion of goals of care during a routine clinic visit. Patients in the intervention group received a survey to assess their preferences, barriers and facilitators for communication about end-of-life care. Survey responses were used to (1) generate an abstracted version of the patient’s preferences, (2) identify the most important communication barrier or facilitator, and (3) provide communication tips based on curricular materials from VitalTalk (http://vitaltalk.org) tailored to patient responses. The 1-page communication guide, called Jumpstart-Tips, was sent to clinicians 1 or 2 days prior to the target clinic visit date. Patients also received 1-page patient-specific Jumpstart-Tips forms, which summarized their survey responses and provided suggestions for having a goals-of-care conversation with the clinician. Patients in the control group completed the same surveys, but no information was provided to the patients or clinicians. Clinicians were randomly assigned in a 1:1 ratio to intervention or enhanced usual care.

Main outcome measures. The primary outcome was patient-reported occurrence of goals-of-care communication, which was evaluated using a validated dichotomous survey item. Other outcomes included clinician documentation of a goals-of-care conversation in the medical record, patient-reported quality of communication (measured using Quality of Communication questionnaire) at 2 weeks, patient reports of goal-concordant care at 3 months, and patient-reported symptoms of depression and anxiety at 3 and 6 months. All analyses included covariate adjustment for the baseline measure of the outcome and adjustment for other variables found to confound the association between randomization group and outcome.

Main results. Of 485 potentially eligible clinicians, 65 clinicians were randomized to the intervention group and 69 were randomized to the control group. Of these 132 clinicians, 124 had patients participating in the study: 537 out of 917 eligible patients enrolled, with 249 allocated to intervention and 288 to usual care.

Patients in the intervention group were more likely to report a goals-of-care conversation with their provider among all patients (74%, n = 137 vs 31%, n = 66; P n = 112 vs 28%, n = 44; P n = 140 vs 17%, n = 45; P n = 114 vs 17%, n = 34; P
Patients in the intervention group also reported higher quality ratings of goals-of-care conversations at the target visit (mean values, 4.6 v 2.1, P = 0.01, on the 4-indicator construct). Additionally, intervention members reported statistically significant higher ratings on 3 of the 7 individual quality-of-communication survey items.

Patient-assessed goal concordant care did not increase significantly overall (70% vs 57%; P = 0.08) but did increase for patients with stable goals between 3-month follow-up and last prior assessment (73% vs 57%; P = 0.03). Symptoms of depression or anxiety were not different between groups at 3 or 6 months.

Conclusion. The Jumpstart-Tips intervention was associated with an increase in patient reports and clinician documentation of goals-of-care communication. Increased patient-reported goal-concordant care among patients with stable goals was also associated with the intervention. Statistical significance was not detected for changes in depression or anxiety as a result of the intervention. The impact on goals-of-care discussion between patients and caregivers is suggestive of enhanced patient-centered care; however, further studies are needed to evaluate whether this communication is associated with changes in health care delivery.

Commentary

Previous research has shown that patients with serious illness who discuss their goals-of-care fare better in terms of quality of life and reducing intensity of care at the end-of-life [1]. However, providers often fail to or inadequately discuss goals of care with seriously ill patients [2,3]. This contributes to the lack of concordance between patient wishes, particularly related to end-of-life care, and clinical plans of care [4,5]. Addressing this gap between care provided and care desired, as well as providing high-quality, patient-centered care is needed.

Access to palliative care providers (who are trained to address these priorities) in the outpatient setting lags, despite an increase in specialists [6,7]. Thus, primary and specialty care providers in the outpatient setting are best positioned to align their care strategy with the goals of their patients. However, there have been limited results in showing that goals-of-care communication can be improved within the practice setting [8,9]. A randomized clinical trial among hospitalized seniors at the end-of-life showed an association where those who received advanced care planning with had improved quality of life, reduced care at dying, and reduced psychological distress among family [10]. However, in another randomized trial, simulation-based communication training compared with usual education among internal medicine and nurse practitioner trainees did not improve quality of communication about end-of-life care or quality of end-of-life care but was associated with a small increase in patients’ depressive symptoms [11]. A recent 2018 literature review of strategies used to facilitate the discussion of advance care planning with older adults in primary care settings identified effective interventions, including delivering education using various delivery methods, computer-generated triggers for primary care physicians (PCPs), inclusion of multidisciplinary professionals for content delivery, and patient preparation for PCP visit [12].

This article adds to the literature by demonstrating the feasibility and impact of implementing an intervention to increase communication about goals of care and end-of-life care. Further, this study highlights how communication that is bilateral, predetermined, and structured can be integrated into primary care. Strengths of the study include the use of randomization; deployment of validated survey tools; and confirmatory factor analysis to assess whether the survey variables are consistent with the hypothesized constructs. In addition, study staff were blinded when extracting data from the EHR record around discussions and documentation of goals-of-care conversations during patient visits. However, several limitations are present. There may be limited generalizability as the study was performed at low-scale, across one region as well as selection bias among clinicians participating in the study. Clinicians were not blinded of their assignment, which may have influenced their behaviors to discuss and document goals-of-care conversations.

Applications for Clinical Practice

Increasing quality communication around the end of life and understanding of a patient’s goals is important. Good communication can facilitate the development of a comprehensive treatment plan that is medically sound and concordant with the patient’s wishes and values. Clinicians and practices should consider adopting approaches to communication priming and accurate documentation, including: (1) incorporating/automating Jumpstart-Tips forms into practice (and tailoring as needed); (2) identifying similar education material that can serve as a primer for patients; (3) creating a pre-visit form for patients/caregivers to document and inform the clinician of their goals prior to the visit; (4) incorporating a standard EHR note to document and update goals-of-care discussion at each visit; and (5) more broadly encouraging (or providing training for) clinicians to practice bilateral communications with patients during visits.

—Ronald Sanchez, MPH, and Katrina F. Mateo, MPH

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To assess usability and patient perceptions of the sarilumab auto-injector device  (“sarilumab pen”) among patients with moderate-to-severe rheumatoid arthritis (RA).

Design. 12-week, randomized, parallel-group usability study.

Setting and participants. The study was conducted at 53 centers in 6 countries. Inclusion criteria were a diagnosis of RA (as defined by American College of Rheumatology/ European League Against Rheumatism 2010 Criteria) of ≥ 3-month disease duration, willing and able to self inject, continuous treatment with 1 or a combination of nonbiologic disease modifying antirheumatic drugs (except leflunomide in combination with methotrexate); and moderatly to severely active RA, defined as 4/66 swollen joint, 4/68 tender joints, and high-sensitivity C-reactive protein (hsCRP) measurement ≥ 4 mg/L. Exclusion criteria were age

Patients were randomized 1:1:1:1 to sarilumamb 150 or 200 mg every 2 weeks administered by single-use, disposable, prefilled pen or pre-filled syringe. Randomization method was not reported.

Main outcomes measures. The primary endpoint was number of “product technical failures” (PTFs). Patients randomized to the pen were given a diary that had questions related to their ability to remove the cap, start the injection, and complete the injection. Participants were asked to answer the questions each time they used the pen. If the response was “no” to any of the 3 questions, this was considered a “product technical complaint” (PTC). PTCs that had a validated technical cause based on pen evaluation and analysis were considered PTFs.

In addition, patient perceptions and satisfaction with the pen were assessed via questionnaire. At baseline, patients were asked about injections and prior experience with self-injection, and at 12 weeks they were asked about their experiences in using the pen. Other outcomes assessed included adverse events and pharmokinetic parameters.

Results. 217 participants were enrolled: 108 patients were in the pen group (56 randomized to 150 mg and 52 randomized to 200 mg) and 109 were in the syringe group (53 randomized to 150 mg and 56 randomized to 200 mg). Completion rates were similar among groups. Sixteen patients discontinued due to treatment-emergent adverse events. There were no PTFs. There was one PTC, in which the user accidently bumped the pen, which expelled the drug onto the floor.

At baseline, before the first injection, the majority of patients reported that they were not afraid of needles (58%), had past experience with self-injections (55%), and were either “very confident” or “extremely confident” regarding self-injections (55%). After the 12-week assessment phase, when asked about their overall level of satisfaction, 98% of patients reported they were “satisfied” or “very satisfied” with the sarilumab pen.

Treatment emergent adverse events occurred in 66% of patients, with no clinically meaningful differences leading to discontinuation in the pen and syringe groups. The most common adverse events were infections and neutropenia.

Conclusion. Patients successfully completed self-injections with the sarilumab pen and found it easy to use.

Commentary

Rheumatoid arthritis (RA) is a common immune-mediated disease characterized by chronically progressive inflammation and destruction of joints and associated structures, resulting in significant morbidity, mortality, and disability. Improved understanding of RA disease pathogenesis in recent years has led to the development of new biologic treatments designed to target specific elements of the RA inflammatory response.

Sarilumab is an interleukin-6 blocker that was approved in the US in 2017 for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. While a syringe form of this drug is currently available, at the time of this writing the pen has not yet been released.

In this real-world usability study sponsored by Sanofi, there were no technical difficulties with using the pen. Most patients thought the pen was easy or very easy to use, and safety and effeicacy appeared to be generally comparable between the pen and syringe. The pen also offers safety protection features that prevent needlestick injury.

The authors of the current study noted that results from previous studies have shown that patients with RA favor treatment devices that are easy to use, convenient, less painful, and take less time to use, and patients have demonstrated a preference for autoinjector devices over more conventional methods of treatment administration [1–3], such as syringes. Pens have been well accepted for the treatment of other chronic health conditions, including diabetes mellitus, migraine headaches, and growth hormone deficiency, and subcutaneous administration of a tumor necrosis factor (TNF) inhibitor via pen has also been accepted for the treatment of RA [1]. As RA requires lifelong treatment, the use of a pen that is ergonomically designed to take into account the manual dexterity issues relevant to this patient population could potentially enhance compliance.

Applications for Clinical Practice

A prefilled pen was well accepted and associated with favorable patient perceptions, indicating that this delivery system may be a viable option for RA patients who are prescribed sarilumab.

Study Overview

Objective. To assess usability and patient perceptions of the sarilumab auto-injector device  (“sarilumab pen”) among patients with moderate-to-severe rheumatoid arthritis (RA).

Design. 12-week, randomized, parallel-group usability study.

Setting and participants. The study was conducted at 53 centers in 6 countries. Inclusion criteria were a diagnosis of RA (as defined by American College of Rheumatology/ European League Against Rheumatism 2010 Criteria) of ≥ 3-month disease duration, willing and able to self inject, continuous treatment with 1 or a combination of nonbiologic disease modifying antirheumatic drugs (except leflunomide in combination with methotrexate); and moderatly to severely active RA, defined as 4/66 swollen joint, 4/68 tender joints, and high-sensitivity C-reactive protein (hsCRP) measurement ≥ 4 mg/L. Exclusion criteria were age

Patients were randomized 1:1:1:1 to sarilumamb 150 or 200 mg every 2 weeks administered by single-use, disposable, prefilled pen or pre-filled syringe. Randomization method was not reported.

Main outcomes measures. The primary endpoint was number of “product technical failures” (PTFs). Patients randomized to the pen were given a diary that had questions related to their ability to remove the cap, start the injection, and complete the injection. Participants were asked to answer the questions each time they used the pen. If the response was “no” to any of the 3 questions, this was considered a “product technical complaint” (PTC). PTCs that had a validated technical cause based on pen evaluation and analysis were considered PTFs.

In addition, patient perceptions and satisfaction with the pen were assessed via questionnaire. At baseline, patients were asked about injections and prior experience with self-injection, and at 12 weeks they were asked about their experiences in using the pen. Other outcomes assessed included adverse events and pharmokinetic parameters.

Results. 217 participants were enrolled: 108 patients were in the pen group (56 randomized to 150 mg and 52 randomized to 200 mg) and 109 were in the syringe group (53 randomized to 150 mg and 56 randomized to 200 mg). Completion rates were similar among groups. Sixteen patients discontinued due to treatment-emergent adverse events. There were no PTFs. There was one PTC, in which the user accidently bumped the pen, which expelled the drug onto the floor.

At baseline, before the first injection, the majority of patients reported that they were not afraid of needles (58%), had past experience with self-injections (55%), and were either “very confident” or “extremely confident” regarding self-injections (55%). After the 12-week assessment phase, when asked about their overall level of satisfaction, 98% of patients reported they were “satisfied” or “very satisfied” with the sarilumab pen.

Treatment emergent adverse events occurred in 66% of patients, with no clinically meaningful differences leading to discontinuation in the pen and syringe groups. The most common adverse events were infections and neutropenia.

Conclusion. Patients successfully completed self-injections with the sarilumab pen and found it easy to use.

Commentary

Rheumatoid arthritis (RA) is a common immune-mediated disease characterized by chronically progressive inflammation and destruction of joints and associated structures, resulting in significant morbidity, mortality, and disability. Improved understanding of RA disease pathogenesis in recent years has led to the development of new biologic treatments designed to target specific elements of the RA inflammatory response.

Sarilumab is an interleukin-6 blocker that was approved in the US in 2017 for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. While a syringe form of this drug is currently available, at the time of this writing the pen has not yet been released.

In this real-world usability study sponsored by Sanofi, there were no technical difficulties with using the pen. Most patients thought the pen was easy or very easy to use, and safety and effeicacy appeared to be generally comparable between the pen and syringe. The pen also offers safety protection features that prevent needlestick injury.

The authors of the current study noted that results from previous studies have shown that patients with RA favor treatment devices that are easy to use, convenient, less painful, and take less time to use, and patients have demonstrated a preference for autoinjector devices over more conventional methods of treatment administration [1–3], such as syringes. Pens have been well accepted for the treatment of other chronic health conditions, including diabetes mellitus, migraine headaches, and growth hormone deficiency, and subcutaneous administration of a tumor necrosis factor (TNF) inhibitor via pen has also been accepted for the treatment of RA [1]. As RA requires lifelong treatment, the use of a pen that is ergonomically designed to take into account the manual dexterity issues relevant to this patient population could potentially enhance compliance.

Applications for Clinical Practice

A prefilled pen was well accepted and associated with favorable patient perceptions, indicating that this delivery system may be a viable option for RA patients who are prescribed sarilumab.

Study Overview

Objective. To assess usability and patient perceptions of the sarilumab auto-injector device  (“sarilumab pen”) among patients with moderate-to-severe rheumatoid arthritis (RA).

Design. 12-week, randomized, parallel-group usability study.

Setting and participants. The study was conducted at 53 centers in 6 countries. Inclusion criteria were a diagnosis of RA (as defined by American College of Rheumatology/ European League Against Rheumatism 2010 Criteria) of ≥ 3-month disease duration, willing and able to self inject, continuous treatment with 1 or a combination of nonbiologic disease modifying antirheumatic drugs (except leflunomide in combination with methotrexate); and moderatly to severely active RA, defined as 4/66 swollen joint, 4/68 tender joints, and high-sensitivity C-reactive protein (hsCRP) measurement ≥ 4 mg/L. Exclusion criteria were age

Patients were randomized 1:1:1:1 to sarilumamb 150 or 200 mg every 2 weeks administered by single-use, disposable, prefilled pen or pre-filled syringe. Randomization method was not reported.

Main outcomes measures. The primary endpoint was number of “product technical failures” (PTFs). Patients randomized to the pen were given a diary that had questions related to their ability to remove the cap, start the injection, and complete the injection. Participants were asked to answer the questions each time they used the pen. If the response was “no” to any of the 3 questions, this was considered a “product technical complaint” (PTC). PTCs that had a validated technical cause based on pen evaluation and analysis were considered PTFs.

In addition, patient perceptions and satisfaction with the pen were assessed via questionnaire. At baseline, patients were asked about injections and prior experience with self-injection, and at 12 weeks they were asked about their experiences in using the pen. Other outcomes assessed included adverse events and pharmokinetic parameters.

Results. 217 participants were enrolled: 108 patients were in the pen group (56 randomized to 150 mg and 52 randomized to 200 mg) and 109 were in the syringe group (53 randomized to 150 mg and 56 randomized to 200 mg). Completion rates were similar among groups. Sixteen patients discontinued due to treatment-emergent adverse events. There were no PTFs. There was one PTC, in which the user accidently bumped the pen, which expelled the drug onto the floor.

At baseline, before the first injection, the majority of patients reported that they were not afraid of needles (58%), had past experience with self-injections (55%), and were either “very confident” or “extremely confident” regarding self-injections (55%). After the 12-week assessment phase, when asked about their overall level of satisfaction, 98% of patients reported they were “satisfied” or “very satisfied” with the sarilumab pen.

Treatment emergent adverse events occurred in 66% of patients, with no clinically meaningful differences leading to discontinuation in the pen and syringe groups. The most common adverse events were infections and neutropenia.

Conclusion. Patients successfully completed self-injections with the sarilumab pen and found it easy to use.

Commentary

Rheumatoid arthritis (RA) is a common immune-mediated disease characterized by chronically progressive inflammation and destruction of joints and associated structures, resulting in significant morbidity, mortality, and disability. Improved understanding of RA disease pathogenesis in recent years has led to the development of new biologic treatments designed to target specific elements of the RA inflammatory response.

Sarilumab is an interleukin-6 blocker that was approved in the US in 2017 for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. While a syringe form of this drug is currently available, at the time of this writing the pen has not yet been released.

In this real-world usability study sponsored by Sanofi, there were no technical difficulties with using the pen. Most patients thought the pen was easy or very easy to use, and safety and effeicacy appeared to be generally comparable between the pen and syringe. The pen also offers safety protection features that prevent needlestick injury.

The authors of the current study noted that results from previous studies have shown that patients with RA favor treatment devices that are easy to use, convenient, less painful, and take less time to use, and patients have demonstrated a preference for autoinjector devices over more conventional methods of treatment administration [1–3], such as syringes. Pens have been well accepted for the treatment of other chronic health conditions, including diabetes mellitus, migraine headaches, and growth hormone deficiency, and subcutaneous administration of a tumor necrosis factor (TNF) inhibitor via pen has also been accepted for the treatment of RA [1]. As RA requires lifelong treatment, the use of a pen that is ergonomically designed to take into account the manual dexterity issues relevant to this patient population could potentially enhance compliance.

Applications for Clinical Practice

A prefilled pen was well accepted and associated with favorable patient perceptions, indicating that this delivery system may be a viable option for RA patients who are prescribed sarilumab.

Neuroimaging studies have consistently reported reduced activation of the medial prefrontal cortex (mPFC) in patients with posttraumatic stress disorder (PTSD) while they recall and imagine stressful personal events. During script-driven imagery (SDI) sessions, patients with PTSD exhibit increased psychophysiologic (eg, heart rate, skin conductance, and facial electromyographic) responses to trauma-related memories. However, the origin of the responses remained unclear. Are they familial, acquired, or resulting from trauma exposure?

Researchers from Harvard University, University of California Los Angeles, and University of New England conducted a study of 26 male identical twin pairs to help find the answer. The participants were divided into 4 groups: combat-exposed with PTSD (ExP+), their combat-unexposed twins without PTSD, combat-exposed participants without PTSD, and their combat-unexposed twins without PTSD. They engaged in SDI during functional magnetic resonance (fMRI) imaging and concurrent skin conductance measurement.

The results of the fMRI tests showed diminished activation in the medial prefrontal cortex of the patients with PTSD compared with the other groups. The SC response scores did not correlate significantly with PTSD symptom severity.

Contrary to the researchers’ predictions, mPFC activation was not inversely correlated with PTSD symptom severity. However, they say their finding of reduced mPFC activation in the ExP+ group provides evidence that the abnormality is an acquired characteristic. If those findings are replicated, such objectively measured biologic characteristics could potentially aid in diagnosing PTSD or assessing treatment response.

Source:
Dahlgren MK, Laifer LM, VanElzakker MB, et al. Psychol Med. 2018;48(7):1128-1138.
doi: 10.1017/S003329171700263X.

Neuroimaging studies have consistently reported reduced activation of the medial prefrontal cortex (mPFC) in patients with posttraumatic stress disorder (PTSD) while they recall and imagine stressful personal events. During script-driven imagery (SDI) sessions, patients with PTSD exhibit increased psychophysiologic (eg, heart rate, skin conductance, and facial electromyographic) responses to trauma-related memories. However, the origin of the responses remained unclear. Are they familial, acquired, or resulting from trauma exposure?

Researchers from Harvard University, University of California Los Angeles, and University of New England conducted a study of 26 male identical twin pairs to help find the answer. The participants were divided into 4 groups: combat-exposed with PTSD (ExP+), their combat-unexposed twins without PTSD, combat-exposed participants without PTSD, and their combat-unexposed twins without PTSD. They engaged in SDI during functional magnetic resonance (fMRI) imaging and concurrent skin conductance measurement.

The results of the fMRI tests showed diminished activation in the medial prefrontal cortex of the patients with PTSD compared with the other groups. The SC response scores did not correlate significantly with PTSD symptom severity.

Contrary to the researchers’ predictions, mPFC activation was not inversely correlated with PTSD symptom severity. However, they say their finding of reduced mPFC activation in the ExP+ group provides evidence that the abnormality is an acquired characteristic. If those findings are replicated, such objectively measured biologic characteristics could potentially aid in diagnosing PTSD or assessing treatment response.

Source:
Dahlgren MK, Laifer LM, VanElzakker MB, et al. Psychol Med. 2018;48(7):1128-1138.
doi: 10.1017/S003329171700263X.

Neuroimaging studies have consistently reported reduced activation of the medial prefrontal cortex (mPFC) in patients with posttraumatic stress disorder (PTSD) while they recall and imagine stressful personal events. During script-driven imagery (SDI) sessions, patients with PTSD exhibit increased psychophysiologic (eg, heart rate, skin conductance, and facial electromyographic) responses to trauma-related memories. However, the origin of the responses remained unclear. Are they familial, acquired, or resulting from trauma exposure?

Researchers from Harvard University, University of California Los Angeles, and University of New England conducted a study of 26 male identical twin pairs to help find the answer. The participants were divided into 4 groups: combat-exposed with PTSD (ExP+), their combat-unexposed twins without PTSD, combat-exposed participants without PTSD, and their combat-unexposed twins without PTSD. They engaged in SDI during functional magnetic resonance (fMRI) imaging and concurrent skin conductance measurement.

The results of the fMRI tests showed diminished activation in the medial prefrontal cortex of the patients with PTSD compared with the other groups. The SC response scores did not correlate significantly with PTSD symptom severity.

Contrary to the researchers’ predictions, mPFC activation was not inversely correlated with PTSD symptom severity. However, they say their finding of reduced mPFC activation in the ExP+ group provides evidence that the abnormality is an acquired characteristic. If those findings are replicated, such objectively measured biologic characteristics could potentially aid in diagnosing PTSD or assessing treatment response.

Source:
Dahlgren MK, Laifer LM, VanElzakker MB, et al. Psychol Med. 2018;48(7):1128-1138.
doi: 10.1017/S003329171700263X.

According to the VA, 8,744,000 veterans served in the Armed Forces in the time between the Gulf of Tonkin incident and the signing of the Paris Peace Accords.1 Of those, 3,403,000 were deployed to Southeast Asia. Those who served during this period often were exposed to unique environmental hazards, such as commonly used pesticides and herbicides, as well as diseases attributed to the tropical environment, such as fungal infections, and there were more than 40,000 reported cases of malaria. Upon returning home, these veterans faced a tough readjustment that often magnified the stress associated with combat.

Today, the VA recognizes 8 conditions related to service in Vietnam for the purposes of establishing service-connection: soft tissue sarcoma, non-Hodgkin lymphoma, Hodgkin disease, chloracne, porphyria cutanea tarda, respiratory cancers, multiple myeloma, prostate cancer, acute peripheral neuropathy, and spina bifida in offspring. As the veterans of this conflict age into their retirement years, the VA now also faces the challenge of providing care to this growing senior population.

According to the VA, 8,744,000 veterans served in the Armed Forces in the time between the Gulf of Tonkin incident and the signing of the Paris Peace Accords.1 Of those, 3,403,000 were deployed to Southeast Asia. Those who served during this period often were exposed to unique environmental hazards, such as commonly used pesticides and herbicides, as well as diseases attributed to the tropical environment, such as fungal infections, and there were more than 40,000 reported cases of malaria. Upon returning home, these veterans faced a tough readjustment that often magnified the stress associated with combat.

Today, the VA recognizes 8 conditions related to service in Vietnam for the purposes of establishing service-connection: soft tissue sarcoma, non-Hodgkin lymphoma, Hodgkin disease, chloracne, porphyria cutanea tarda, respiratory cancers, multiple myeloma, prostate cancer, acute peripheral neuropathy, and spina bifida in offspring. As the veterans of this conflict age into their retirement years, the VA now also faces the challenge of providing care to this growing senior population.

According to the VA, 8,744,000 veterans served in the Armed Forces in the time between the Gulf of Tonkin incident and the signing of the Paris Peace Accords.1 Of those, 3,403,000 were deployed to Southeast Asia. Those who served during this period often were exposed to unique environmental hazards, such as commonly used pesticides and herbicides, as well as diseases attributed to the tropical environment, such as fungal infections, and there were more than 40,000 reported cases of malaria. Upon returning home, these veterans faced a tough readjustment that often magnified the stress associated with combat.

Today, the VA recognizes 8 conditions related to service in Vietnam for the purposes of establishing service-connection: soft tissue sarcoma, non-Hodgkin lymphoma, Hodgkin disease, chloracne, porphyria cutanea tarda, respiratory cancers, multiple myeloma, prostate cancer, acute peripheral neuropathy, and spina bifida in offspring. As the veterans of this conflict age into their retirement years, the VA now also faces the challenge of providing care to this growing senior population.

Obinutuzumab (Gazyva)

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

Health Canada previously approved obinutuzumab for the following indications:

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

Obinutuzumab (Gazyva)

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

Health Canada previously approved obinutuzumab for the following indications:

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

Obinutuzumab (Gazyva)

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

Health Canada previously approved obinutuzumab for the following indications:

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”