Paliative Care and Cholestrol

Obesity• July 8, 2011 (Washington DC) — A new report illustrates in stark terms how the obesity epidemic in the US has spiraled in the past two

decades and pinpoints, on a state-by-state basis, where the largest increases have occurred [1]. The authors stress, however, that ranking the states in this way is not a reproof; rather, "we want to raise awareness, drive action, identify solutions, and reverse the epidemic."

• "F as in fat: How obesity threatens American's future 2011," a report from the Trust for America's Health (TFAH) and the Robert Wood Johnson Foundation (RWJF), shows that the problem is greatest in the South, which has nine of the 10 states with the highest adult obesity rates. Mississippi holds the dubious title of state with the highest adult obesity rate, for the seventh year in a row, and obesity has grown fastest in Alabama, Oklahoma, and Tennessee.

• For the first time, the report looks at how obesity levels have altered over the past 20 years; two decades ago, no state had an obesity rate above 15%, whereas now, 12 states have rates above 30% (even just four years ago, only one state had a rate above 30%). Two out of three states have obesity rates over 25%; just one, Colorado, has a rate lower than 20%.

• "Today, the state with the lowest obesity rate would have had the highest rate in 1995," says Dr Jeff Levi (executive director, TFAH) in a statement [2]. "There was a clear tipping point in our national weight gain over the past 20 years, and we can't afford to ignore the impact obesity has on our health."

• In terms of childhood and adolescent obesity, more than one-third of children aged 10 to 17 are obese (16.4%) or overweight (18.2%), and Mississippi again tops the poll, with a rate of 21.9%, with nine other states, plus DC, having childhood obesity rates >20%.

• The report points out the inverse relationship between educational attainment and income and obesity and invites readers to "imagine what it is like to live in a neighborhood where there are no supermarkets, sidewalks, or community playgrounds, where being outside may not be safe, and joining a gym is not an option."

• The aim is to help promote change by advocating a number of policies that are backed by scientific research and likely to make an impact quickly, particularly for those people whose options have been most limited. These include initiatives aimed at improving access to affordable healthy foods and safe places for children to walk, bike, and play in the communities hardest hit by the epidemic and with the fewest resources.

• Late Thursday, the American Heart Association issued a statement highlighting the TFAH report, calling the rise in obesity rates "astonishing" and calling on Americans "to recognize the severity of the obesity crisis" and "the need for collective action among food manufacturers, restaurants, government and consumers to change the direction we are headed."

NSAID’s• July 14, 2011 (Gainesville, Florida) — Older patients with hypertension and coronary artery disease who use nonsteroidal anti-inflammatory drugs (NSAIDs) chronically

for pain are at significantly increased risk of cardiovascular events, a new post hoc analysis from the International Verapamil-Trandolapril Study (INVEST) demonstrates [1]. The research is published in the July 2011 issue of the American Journal of Medicine.

• "We found a significant increase in adverse cardiovascular outcomes, primary driven by an increase in cardiovascular mortality," lead author Dr Anthony A Bavry (University of Florida, Gainesville) told heartwire. "This is not the first study to show there is potential harm with these agents, but I think it further solidifies that concern."

• He says the observational study, conducted within the hypertension trial INVEST, is particularly relevant to everyday practice because the patients included were typical of those seen in internal-medicine, geriatric, and cardiology clinics--they were older, with hypertension and clinically stable CAD.

• Bavry and colleagues were not able to differentiate between NSAIDs in the study--most people were taking ibuprofen, naproxen, or celecoxib--and he says until further work is done, he considers the risks of NSAIDs "a class effect," and their use should be avoided wherever possible.

• I try to get them to switch to an alternative agent, such as acetaminophen.• However, "Patients should not terminate these medicines on their own," he says. "They should have a discussion with their physician. When I see patients like these taking

NSAIDs I will have an informed discussion with them and tell them there is evidence that these agents may be associated with harm. I try to get them to switch to an alternative agent, such as acetaminophen, or if that's not possible I at least try to get them to reduce the dose of NSAID or the frequency of dosing. But ultimately, it's up to them if this potential risk is worth taking depending upon the indication for their use."

• Chronic NSAID Use More Than Doubles CV Mortality • Within the large cohort of more than 22 000 patients in INVEST, Bavry and colleagues identified patients who reported taking NSAIDs at every follow-up visit and termed

them chronic users (n=882). Most often, patients were taking these agents for conditions such as rheumatoid arthritis, osteoarthritis, and lower back pain, Bavry said.• They compared the chronic NSAID users with those who only intermittently (n=7286) or never (n=14 408) used NSAIDs over an average of 2.7 years and adjusted the

findings for potential confounders.• The primary outcome--a composite of all-cause death, nonfatal MI, or nonfatal stroke--occurred at a rate of 4.4 events per 100 patient-years in the chronic-NSAID group vs

3.7 events per 100 patient-years in the nonchronic group (adjusted hazard ratio 1.47; p=0.0003).• As noted by Bavry, the end point was primarily driven by a more than doubling in the risk of death from CV causes in the chronic-NSAID group compared with never or

infrequent users (adjusted HR 2.26; p<0.0001).• The association did not appear to be due to elevated blood pressure, the researchers say, because chronic NSAID users actually had slightly lower on-treatment BP over the

follow-up period.• They note that a recent American Geriatrics Society panel on the treatment of chronic pain in the elderly recommends acetaminophen as a first-line agent and suggests

that nonselective NSAIDs or COX-2 inhibitors be used only with extreme caution. "Our findings support this recommendation," they state.• Bavry added: "We do need more studies to further characterize the risks of these agents, which are widely used and widely available, and perhaps the risks are

underappreciated. We are working on the next level of studies to try to identify which are the most harmful agents."

Algorithm for Treatment of Hypertension in the ElderlyACEI indicates angiotensin-converting enzyme inhibitor; ALDO ANT, aldosterone antagonist; ARB, aldosterone receptor

blocker; BB, beta blocker; CA, calcium antagonist; CAD, coronary artery disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; RAS, renin-angiotensin system; SBP, systolic blood pressure; and THIAZ, thiazide diuretic.

Breast Cancer and OCs: Still Worried After All These Years?

• Two studies confirm that oral contraceptives are not associated with breast cancer–specific or all-cause mortality.

• Epidemiologic studies have yielded reassuring findings that oral contraceptives (OCs) do not raise risk for developing breast cancer (JW Womens Health Aug 20 2002). To evaluate risk for all-cause or breast cancer–related death in women with invasive breast cancer who used OCs, investigators assessed mortality of 4565 participants in the Women's Contraceptive and Reproductive Experiences (CARE) Study (a population-based case-control study) and 3929 participants in the California Teachers Study (CTS; a cohort study).

• No associations were observed between OC use and breast cancer–specific mortality in the CARE study (828 breast cancer deaths; median follow-up, 8.6 years) or the CTS (261 breast cancer deaths; median follow-up, 6.1 years). In addition, no association was observed between OC use and all-cause mortality (CARE relative risk, 1.01; CTS RR, 0.84). Lower risk for all-cause death (but not breast cancer–related death) was observed in those CTS participants who used OCs for 10 years (RR, 0.67); however, no trend for decreasing risk with increasing OC duration was observed (P for trend, 0.22).

Don't Miss the New AHA Recommendations on Triglycerides

• A new scientific statement raises the threshold for pharmacologic treatment of hypertriglyceridemia.• The following was published as a "Voices" blog on CardioExchange, an online forum for cardiology news

and discussion. The blog prompted a lively conversation, which you can access and join by registering for CardioExchange.

• I've been surprised at the lack of fanfare surrounding the American Heart Association's recently published scientific statement on triglycerides and cardiovascular disease (CVD). The attention it did receive focused on the lower fasting triglyceride level that is now considered optimal: <100 mg/dL. In my opinion, the real headline was the committee's important statements in support of less drug treatment — in particular, the recommendation for a substantial increase in the triglyceride level that should trigger consideration of pharmacologic therapy.

• After a careful review of the recent literature, the committee concluded that pharmacologic therapy should not be started until a patient's fasting triglyceride level is 500 mg/dL (in contrast to the Adult Treatment Panel's recommendation of 200 mg/dL). See the figure, which also appears on page 2308 of the AHA statement.

• The AHA committee also explicitly acknowledges (on page 2297) that "the independence of triglyceride level as a causal factor in promoting CVD remains debatable. Rather, triglyceride levels appear to provide unique information as a biomarker of risk, especially when combined with low HDL-C and elevated LDL-C." This clear statement — together with the new, higher threshold for initiating drug treatment — represents a remarkable change.

• Meanwhile, on April 20, Abbott announced that sales of its flagship fenofibrate drugs increased by 28% in the first quarter.

Cumulative Antibiotic Exposure Is Associated with Risk for C. difficile Infection

• In a retrospective study among hospitalized patients, higher cumulative dose, number, and duration of antibiotics were independently associated with greater risk.

• Antibiotic therapy is a major risk factor for Clostridium difficile infection (CDI), but little is known about the effect of cumulative exposure. To explore this issue, researchers performed a retrospective cohort study involving adults who were hospitalized at a Rochester, New York, medical center in 2005 and received antibiotics for 2 consecutive days during their stay.

• For each day of antibiotic exposure, the total dose of each agent was calculated. Daily doses were standardized according to the WHO Defined Daily Dose system. The number of different antibiotics and the duration of exposure were also calculated.

• A total of 10,154 hospitalizations involving 7792 unique patients met study criteria. The incidence of CDI in this group was 4.3 per 10,000 patient-days. Factors significantly associated with increased CDI risk included older age, gastrointestinal procedures, HIV infection, history of CDI, higher chronic disease score, longer length of stay, and receipt of antacid therapy, including proton-pump or histamine-2 inhibitors. In addition, CDI risk rose, in a dose-dependent manner, with increases in cumulative dose, number, and days of antibiotics. Risk was 7.8-fold higher in patients with >18 antibiotic days than in those with <4 days and 9.6-fold higher in patients who received five or more antibiotics than in those who received only one. Intravenous cephalosporins, β-lactamase inhibitor combinations, sulfa drugs, fluoroquinolones, and vancomycin were all associated with an increased risk for CDI.

Does the HbA1c Criterion for Prediabetes Predict Incident Diabetes?• Measuring both fasting glucose and glycosylated hemoglobin levels might be the best method.• The American Diabetes Association recently added a new criterion for diagnosis of prediabetes —

glycosylated hemoglobin (HbA1c) level of 5.7% to 6.4%. To evaluate this new criterion, Japanese investigators studied 6241 people who had five or six consecutive annual health examinations that included measurements of fasting glucose and HbA1c levels.

• At their baseline examinations, 2092 patients were identified as prediabetic: 60% by impaired fasting glucose (IFG; 100–125 mg/dL) alone, 20% by HbA1c alone, and 20% by both tests. During a mean 4.7-year follow-up, 338 patients progressed to diabetes, of whom 292 (86%) had been identified as prediabetic at baseline: 32% by IFG alone, 9% by HbA1c alone, and 46% by both tests. Both IFG alone and HbA1c alone predicted incident diabetes equally strongly, with multivariate-adjusted hazard ratios of about 6, compared with that for baseline normoglycemia. Patients who were prediabetic by both criteria at baseline were 32 times more likely to progress to diabetes than those who were normoglycemic.

• Comment: These results are similar to those from a U.S. data set (Diabetes Care 2010; 33:2190). Impaired fasting glucose and HbA1c measure different aspects of dysglycemia and, together, provide more sensitive and specific prediction of excess risk for diabetes than does either one alone. However, whether this accuracy improves clinically meaningful long-term outcomes remains unclear.

The Latest Word on Pot and Susceptibility to Psychosis

• A meta-analysis indicates a specific association between cannabis use and earlier onset of psychosis.• Marijuana evokes psychotic-like symptoms in susceptible individuals (see JW Psychiatry Mar 14 2011), and

cannabis use may be associated with an earlier age of onset of psychotic illness. But does marijuana cause psychosis, or are the people who are destined to become psychotic more likely to use the drug? With more than 16 million regular pot smokers in the U.S., the question is important. This meta-analysis of 83 studies of the age at onset of psychosis involved 8167 psychosis patients who used psychoactive substances and 14,352 nonusing psychosis patients.

• The results confirmed that the age at onset of psychosis was almost 3 years earlier in cannabis users than in nonusers. Alcohol use was not significantly associated with earlier onset of psychosis. Studies with a higher percentage of cannabis users reported an earlier mean age at psychosis onset. The association was not explained by sex, schizophrenia versus affective psychosis, study methodology, or, to a lesser extent, patient age at the time of the study.

• Comment: Because alcohol use was not associated with a younger age at onset of psychosis, the results do not suggest that people who are going to develop psychosis just start using drugs earlier than people who are less vulnerable to psychosis. Still, it is not known whether people who would not otherwise become psychotic might develop a chronic psychosis after prolonged cannabis use, as has been noted with amphetamine use. Also unknown is whether the risk results from a primary toxic effect, from an interaction of cannabis with dopamine metabolism or with an intracellular signal, or from an effect of the drug on brain maturation in adolescents. Regardless of pathogenesis, even if a psychotic illness is to develop anyway, avoiding marijuana may delay its onset or reduce its severity.

Parenteral Nutrition in ICU Patients: What's the Rush?

• Delaying intravenous nutrition for 1 week led to fewer infectious complications, shorter length of stay, and lower hospital costs than did early initiation.

• Guidelines differ substantially in their recommendations about when to start parenteral nutrition in critically ill patients; these guidelines are based primarily on expert opinion. To evaluate prospectively the optimal timing of nutritional support, investigators in Belgium randomized 4640 nutritionally at-risk patients in the intensive care unit (ICU; ~85% surgical patients, including 60% who underwent cardiac surgery) to receive early initiation (ICU day 3) or late initiation (ICU day 8) of parenteral nutrition. The study was not blinded, but allocation was concealed.

• Although no differences were noted in mortality (ICU, in-hospital, or 90-day) between the groups, the late-initiation group had significantly shorter lengths of stay (LOS) in the ICU (3 vs. 4 days) and in the hospital (14 vs. 16 days); fewer infections, including fewer lung, bloodstream, and wound infections (22.8% vs. 26.2%, number needed to treat [NNT], 29); shorter mean duration of mechanical ventilation; and lower costs (~US$1600 less per patient). Surprisingly, surgical patients in the late-initiation group for whom early enteral nutrition was contraindicated benefited substantially in lower infection rate (30% vs. 40% for similar early-initiation patients; NNT, 10) and shorter ICU LOS.

• Comment: This well-designed study reveals that the early routine administration of parenteral nutrition in critically ill, nutritionally at-risk patients leads to worse outcomes. Delaying parenteral nutrition for at least 1 week should be standard practice for surgical ICU patients. Although this study included relatively few medical ICU patients (~500), this conclusion also can be reasonably applied to such patients, unless new evidence becomes available.

First-Trimester SSRI Exposure and Congenital Anomalies

• Specific antidepressants are associated with risk for cardiovascular or neural-tube defects in a population-based study.

• Studies have only inconsistently linked cardiovascular anomalies with first-trimester exposure to selective serotonin reuptake inhibitors (SSRIs). The very low base rates of these anomalies require researchers to use large samples to detect statistically significant differences. The current researchers examined the issue in a retrospective study using Finnish national registries.

• Data included pregnancies ending in live birth, stillbirth, or termination due to severe fetal anomaly between 1996 and 2006. SSRI exposure was defined as at least one purchase of an SSRI in the month before pregnancy or in the first trimester. SSRI-exposed women were less likely to be married than nonexposed women, twice as likely to smoke or to have a chronic medical condition, and 20 times more likely to have purchased other psychiatric medications.

• Overall, after adjustment for confounders such as maternal age, diabetes, and purchase of other psychiatric drugs, major anomalies were not more common among the 6976 offspring exposed to SSRIs than among the 628,607 nonexposed offspring. In adjusted analyses, significant associations existed between fluoxetine and both overall cardiovascular anomalies (2.04% vs. 1.29% without SSRI exposure) and ventricular septal defects (1.43% vs. 0.87%); between paroxetine and right ventricular outflow defects (0.31% vs. 0.07%); and between citalopram and neural tube defects (0.29% vs. 0.09%). Prevalence of fetal alcohol spectrum disorders was higher with SSRI exposure than with no exposure (0.12% vs. 0.012%).

• Comment: Even in this large, population-based study, anomalies were rare, making it difficult to reach definite conclusions. Still, the study gives further evidence of associations between SSRIs and at least cardiovascular anomalies, and clinicians must inform patients of these potential risks. Within the informed consent process, weighing these risks against those of untreated depression is essential. Clinicians should also address their patients' smoking and alcohol use and should avoid multiple psychiatric prescriptions during pregnancy.

A 2008 study in JAMA found that cancer patients who had end-of-life discussion with a health care professional were less likely to

be:A) Resuscitated

B) On a ventilatorC) In the intensive care unit

D) All the above

Answer

• D) All the above

Which of the following is the more effective interview

structure for eliciting patients' end-of-life concerns?

A) Tell-ask-tellB) Ask-tell-ask

Answer

• B) Ask-tell-ask

When interviewing a patient during an end-of-life

conversation, it is recommended that the physician not allow more than 5 to 7 sec of silence between

questions and responses.A) TrueB) False

Answer

• B) False

Which of the following is not one of the criteria for a major

depressive episode?A) Feeling of helplessness

B) Weight loss or gainC) Anger

D) Decreased energy

Answer

• C) Anger

Which of the following statements about depressive symptoms is true?

A) Not considered the norm for terminally ill patients

B) Occur in the majority of patients receiving palliative care

C) Occur in >75% of patients with advanced cancer

D) None of the above

Answer

• A) Not considered the norm for terminally ill patients

Depression is often _______ at the end of life.

A) Overdiagnosed and overtreated

B) Underrecognized and under- or untreated

Answer

• B) Underrecognized and under- or untreated

Which of the following is not considered a risk factor for

depression at the end of life?A) Poorly controlled pain

B) Treatment with corticosteroidsC) Older age

D) History of substance abuse

Answer

• C) Older age

All the following are characteristics of grief and not of

depression, except:A) Focus on loss

B) Having specific guilt or regretC) Emotions that come in waves

D) Preference for isolation

Answer

• D) Preference for isolation

Choose the incorrect statement about dignity therapy for treatment of depression in patients

receiving palliative care.A) Targets psychosocial and existential

distressB) In a recent study, achieved high patient

satisfaction ratingC) Shown to be effective in improving sense of dignity, but had no effect on depressive

symptomsD) Shown to improve sense of purpose and

meaning

Answer

• C) Shown to be effective in improving sense of dignity, but had no effect on depressive symptoms

Which of the following statements about psychostimulant therapy for the

treatment of depression in hospice patients is incorrect?

A) Often poorly tolerated in this population

B) Has rapid effectC) Can counteract opioid-induced

sedationD) May provide adjuvant analgesia

Answer

• A) Often poorly tolerated in this population

The measurement of which of the following cardiac biomarkers is

recommended as part of the early risk stratification of a patient with suspected

acute coronary syndrome (ACS)?A) Creatine kinase-myocardial band

B) Brain natriuretic peptideC) Troponin I or T

D) Myoglobin

Answer

• C) Troponin I or T

The 2007 American College of Cardiology/American Heart Association

(ACC/AHA) Class I recommendations for initial management and anti-ischemic therapy

for ACS include all the following, except:A) Bed rest

B) Continuous electrocardiography (ECG) monitoring

C) Intravenous (IV) nitroglycerineD) Supplemental oxygen (O2) in all patients

Answer

• D) Supplemental oxygen (O2) in all patients

Which glycoprotein (GP) IIb/IIIa inhibitor is generally

contraindicated as upstream therapy for ACS and indicated

only if there is no delay in taking the patient to the cardiac

catheterization laboratory?A) AbciximabB) EptifibatideC) Tirofiban

Answer

• A) Abciximab

The antithrombotic agent _______is associated with a lower rate of bleeding but requires that patients be

pretreated with clopidogrel.A) Enoxaparin

B) FondaparinuxC) Bivalrudin

D) Unfractionated heparin

Answer

• C) Bivalrudin

A conservative treatment strategy for ACS is recommended for:

A) All men with low-risk features

B) All women with low-risk features

C) Almost all women, whether low or high risk

Answer

• B) All women with low-risk features

There is a huge overlap of cholesterol levels in people with

and without coronary heart disease (CHD).

A) TrueB) False

Answer

• A) True

The National Cholesterol Education Program (NCEP) Adult Treatment Panel

(ATP) III 2004 update recommends a therapeutic goal of LDL<70 mg/dL for

"very high risk patients," defined as those with:

A) Established coronary artery disease plus multiple risk factors

B) Severe and poorly controlled risk factorsC) ACS

D) All the above

Answer

• D) All the above

In a recent cost analysis of lipid-lowering therapy, which statin

regimen was found to achieve the greatest reduction in LDL?A) Atorvastatin 80 mg/dayB) Simvastatin 80 mg/dayC) Rosuvastatin 40 mg/dayD) Simvastatin 40 mg/day

Answer

• C) Rosuvastatin 40 mg/day

Choose the incorrect statement about statin intolerance.

A) Patient complaints about statins in clinical practice higher than reported in

clinical trialsB) Muscle aches usually due to statin

toxicityC) Rhabdomyolysis extremely rare

D) True toxicity greater at higher doses

Answer

• B) Muscle aches usually due to statin toxicity

After the starting dose, each time a patient's statin dose is doubled, it provides an additional _______

reduction in LDL.A) 3% to 4%

B) 6%C) 10% to 12%

D) 18%

Answer

• B) 6%

Introductory remarks:• physicians generally make sense of situations through biomedical or scientific approach• however, most people make sense of situations and handle major decision making through narrative• having patients relate their “stories” and express desired outcomes represents different approach to medicine• physician’s role often involves giving patients information• particularly in area of severe end-stage illness (where medical options limited), information relayed often

includes facts patients would rather not hear (least effective way to share information)• more effective to engage in dialogue that helps patient and family understand where treatment of disease ends

and natural fate of all human beings (ie, death) begins; having ongoing relationship with patient provides trust and intimacy necessary for this conversation

• end-of-life conversations known to have tremendous effect on patient choices (2008 study in JAMA found cancer patients who had end-of-life discussion with health care professional 8 times less likely to be resuscitated

• 7 times less likely to be on ventilator• 3 times less likely to be in intensive care unit [ICU], and in hospice longer and• Earlier• bereavement of surviving caregivers much less severe)• taking on responsibility of having discussion takes considerable courage and involves sharing both positive and• negative emotions with patients and their families

Determining when to have discussion

• see patient and read his or her chart

• perform physical examination

• if, in your opinion, it would not be surprising for patient to die within 1 yr, professional responsibility requires that you discuss type of care patient would want if he or she became diminished

Essential Conversation Skills• Set up “safe space” for discussion• studies of physician-patient communication have shown patients commonly do

not take lead in discussing preferences• Talking within concept of paradox• paradox—facts that appear contradictory although actually compatible• Paradoxes in medicine—life and death (ie, cells start deteriorating at 35 yr of age• after that, “living and dying at same time”)• certainty and uncertainty (physicians try to limit uncertainty through accumulation

of information• however, when dealing with severely ill people, more information not necessarily

more helpful)• explain state of uncertainty and palliative care physician’s role in determining

family’s important concerns, needs for information, and preferences

Setting up structure of interview• most common interview structure for physicians is “tell-ask-tell”• in biomedically decision-based discussion, patient typically asks questions

about biomedicine and decisions only• instead of telling patient, ask how patient sees his or her situation• patient’s reply provides clues to questions that will elicit “deeper” issues• speaker generally finds that he has information necessary to best serve

patient as physician by third question and response• silence—average physician can tolerate silence from patient for more than

7 sec before “rescuing” him or her;• however, speaker suggests that longer interval (eg, up to 60 sec)• appropriate when asking patient facing mortality about his or her greatest

fears• in this type of interviewing, silence is powerful tool

Patient cues• shown to be elicited in interviews lasting >15 min• represent powerful emotional statements (either

verbal or nonverbal)• can be followed by “continuer” or “terminator” (eg,

terminator attempts to move crying patient toward decision)

• speaker advocates being continuer (show patience and ask patient to share his or her thoughts and feelings)

Case example• 68-yr-old man with advanced lung cancer• had just been transferred from intensive care unit (ICU)• family informed of patient’s dire prognosis• patient and family initially in denial• through conversation interview techniques previously described,

speaker able to engage in narrative with family and allow them to express hidden concerns and fears

• this enabled family to move from denial• to understanding, which allowed resolution of fears and gave

direction to patient’s end-of-life care, based on his stated desires (using evidence-based best practice approach)

Cultural variations in physician-patient communication

• ask patients whether they would prefer that information be given to them or to their families

• have family members share important values and cultural beliefs about disease and/or death before starting discussion and interview process

Depression end of life• symptom, episode, or disorder; Diagnostic and Statistical Manual of

Mental Disorders, 4th Edition (DSMIV)

• criteria for major depressive episode (MDE)—

• depressed mood or diminished interest or pleasure, plus 4 of following (feeling helpless, hopeless, worthless, or

• Guilty

• indecision or poor concentration

• suicidal ideation

• weight loss or gain

• insomnia or hypersomnia

• Decreased energy

• psychomotor retardation or agitation) during significant portion of day over 2-wk period

Case example• 89-yr-old white man

• prostate cancer diagnosed 14 yr previously

• had metastasis to spine and lost ability to walk, with debulking surgery performed 6 mo before visit

• Symptoms at presentation—depressed mood

• feeling hopeless and helpless

• decreased appetite and energy (symptoms confounded by patient’s physical issues)

• suicidal ideation

Depression in palliative care• somatic symptoms often not helpful when assessing for depression in this setting• Focus on cognitive and emotional symptoms (dysphoria, despair, and/or sadness• Anhedonia• worthlessness, helplessness, and/or hopelessness• excessive guilt• loss of self-esteem• desire for hastened death)• paranoia does not necessarily indicate depression (possibly delirium)• depression represents treatable form of suffering• anger not criterion for MDE, but can be psychologic symptom requiring intervention• prevalence—depressive symptoms occur in 42% of patients receiving palliative care

and 58% of patients with advanced cancer (ie, not “normal” for these patients• 15% meet criteria for MDE)

Recognition• depression often misdiagnosed or

underrecognized (in study of 2700 hospice patients, depression recognized in only 10% of home-care patients and 14% of inpatients)

• often mis-, under-, or untreated at end of life

Consequences• untreated, depression associated with

poor prognosis and causes suffering

• can undermine self-esteem, worsen medical illness and quality of life, lengthen inpatient stays, and interfere with preparations for death (ability to make decisions, understand situation, interact with caregivers and loved ones, or reach final goals)

Assessment for depression• typical medical assessment• Requires good interview, family observations, review of risk factors, and

thorough medical examination• if assessment difficult, consult with mental health professional• Initial assessment• determine desired outcomes for patient and context of symptoms (eg, medical

illness, sudden loss, anniversary of spouse’s death)• Screening for depression• 2 questions to ask—over past 2 wk, has patient 1) ever felt “down,” depressed, or

hopeless, or 2) felt little pleasure or interest in doing things• positive answer to either or both questions has 96% to 100% sensitivity and 57%

to 100% specificity• Study showed depression screening not burdensome for either staff administering

questions or for patients

Risk Factors• Risk factors for depression at end of life or in palliative care• poorly controlled pain or other symptoms• progressive physical impairment• advanced disease• medications (steroids; chemotherapeutics;• benzodiazepines)• particular diseases (eg, pancreatic, breast, or lung cancer, metastases to

nervous system)• younger age• spiritual pain• risk factors in general population (previous or family history of

depression; social stressors; suicide attempts; substance use)

Differentiate depression from delirium and dementia

• delirium (particularly hypoactive)• dementia (characterized by changes in cognitive function• depression not typically associated with cognitive impairment)• adjustment disorders (occur within 3 mo of stressor and resolve within 6 mo if stressor removed)• Grief, Grief vs depression• grief—identifiable loss• focus on loss; emotions come in waves• fluctuating ability to feel pleasure• closeness of others reassuring• relatively stable self-esteem• specific guilt or regret• thoughts of wanting to be with deceased• “nonbizarre” hallucinations• depression—loss may or may not be identifiable• focus on self• emotions chronic• inability to feel pleasure• isolation preferred• loss of self-esteem or feelings of worthlessness• guilt out of proportion• Active thoughts of suicide• both—hallucinations and/or delusions• sadness and emptiness

Treatment• review desired outcomes• provide nonpharmacologic and pharmacologic relief• consult mental heath professional for assistance• Psychotherapy• all physicians provide supportive psychotherapy• group therapy shown to reduce stress and mood• symptoms at end of life• existential group therapy focuses• on value and meaning as well• Dignity therapy: targets psychosocial and existential distress;• protocol of semistructured questions; transcript made of patient’s• responses (document edited, title and summary added,• and given to patient and family); in study of 100 patients,• achieved 91% satisfaction rate; patients experienced heightened• sense of dignity (76%), purpose (68%), and meaning• (67%), and increased will to live (47%), and had significantly• reduced depressive symptoms and sense of suffering• Complementary therapies• guided imagery• muscle relaxation• Hypnosis• Meditation• Massage• aromatherapy• avoidance of caffeine and alcohol• treatment of insomnia• exercise (if possible)• exposure to bright light

Pharmacologic options• consist of usual armamentarium of >24 antidepressants

with 7 different mechanisms of action• tricyclic antidepressants [TCAs]• monoamine oxidase inhibitors (MAOIs)• selective serotonin reuptake inhibitors [SSRIs]• serotonin–norepinephrine reuptake inhibitors [SNRIs]• bupropion [Wellbutrin; Zyban; Aplenzin]• mirtazapine• trazodone

Current depression treatment guidelines (American Psychiatric Association)

• moderate to severe depression— psychotherapy plus antidepressants• titrate dose over weeks• if no moderate improvement by 6 to 8 wk, adjust treatment and monitor

another 6 to 8 wk• continue after remission for 16 to 20 wk, followed by maintenance for 1 yr• partial response associated with poor outcomes• Poor outcomes in hospice patients• Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial

demonstrated 14 wk of SSRI monotherapy produces only 50% response and 30 remission rates

• average time on hospice in United States <9 wk (median <3 wk)• 33% of patients at speaker’s hospice die within 1 wk (insufficient time to

achieve response)

Psychostimulants• much anecdotal and small amount of controlled data on

use in medically ill and geriatric populations and in palliative care

• benefits—rapid effect in hours to days• minimal adverse effects• can be continued indefinitely• can titrate to effect or until side effect• Tolerance seems not to be factor• diminish opioid-induced sedation• may provide adjuvant analgesia

Methylphenidate (Ritalin; Concerta; Metadate)

• starts with 5 mg in morning and if no adverse effects within 1 hr, repeats dose at noon

• next day, increases dose to 10 mg

• in rare instances, dose increased to 15 mg, to 20 mg in extremely rare cases (if no effect seen at this dose, response unlikely)

• response to methylphenidate—in recent study patients diagnosed with MDE randomized to receive methylphenidate, SSRI, “other” medication (eg, bupropion,

• mirtazapine, SNRI), or usual care

• 95% of patients who received methylphenidate responded (vs 44% of those who received SSRI and 0% who received usual care)

• time to response—methylphenidate proved significantly faster than SSRIs or other therapies

Selective serotonin reuptake inhibitors• if patient already on SSRI, maximize or possibly augment it• prescribes SSRI if patient (or family member) has had good

response to drug in past• can take 3 to 6 wk to produce response• only 30% effective• well tolerated• requires once-daily dosing• lower doses may be effective, but should still titrate to effect• check for drug-drug interactions

Other antidepressants might be helpful for

• sedation (mirtazapine or trazodone)

• energy (SNRIs, bupropion)

• Appetite stimulation (mirtazapine)

• pain (several have data supporting use for treatment of pain and as analgesic adjuvant)

• effects still being studied in this population

Comments• all SSRIs approximately equally effective

• Must try 3 before finding drug that works for patient

• Choose based on drug-drug interactions or other side effects

Management of patient in case example

• treated with psychotherapy and 5 mg methylphenidate in morning and at noon

• within 24 hr, no longer met criteria for MDE (patient engaging with family, taking phone calls from friends, and sitting outside)

• did not change goals for end-of-life care• (ie, no antibiotic treatment for aspiration pneumonias)• 7 day later, patient developed pneumonia and died• conclusion—treatment worthwhile despite short period during which

patient enjoyed benefits• returning patient to more typical mental state before death has lasting

beneficial effect on surviving family members and caregivers

“Normal” cholesterol• average total cholesterol for Americans 208 mg/dL

• average low-density lipoprotein (LDL) 130 mg/dL

• modern humans only adult mammals with mean LDL >80 mg/dL (and total cholesterol level double that of many species)

• population studies have shown life expectancy 4 to 9 yr longer if total cholesterol <200 mg/dL

• huge overlap of cholesterol levels in people with and without coronary heart disease (CHD), received aspirin within range of 150 to 300 mg/dL (>300 mg/dL synonymous with CHD, but seen in 10% of that patient population)

Can LDL be too low?• no cholesterol treatment trials have demonstrated levels can

get too low• Results of trials on lowering LDL with statin therapy• Data from primary prevention trials show rate of CHD events

drops to 0% when LDL lowered to 57 mg/dL, while data extrapolated from secondary prevention trials show rate drops to 0% when LDL lowered to 30 mg/dL (suggesting secondary prevention requires even lower LDL)

• in primary and secondary prevention trials, subgroup of patients with DM had higher risk for CHD events if untreated, but greater reduction in risk with statin intervention than patients without DM

Study of the Effectiveness of Additional Reductions in Cholesterol

and Homocysteine (SEARCH) trial

• 12,000 patients with history of MI randomized to 80 or 20 mg/day simvastatin; during

• 6.5-yr follow up, 80-mg therapy achieved• mean LDL of 83 mg/dL vs 97 mg/dL with 20-

mg therapy• rate of major vascular events 24.5% vs 25.7%

(6% reduction in relative risk and 1.2% reduction in absolute risk)

2010 meta-analysis of cholesterol treatment trial participants

170,000 participants from statin trials that included 1000 patients and had 2 yr follow up; focused on more vs less intensive statin treatment

conclusions—every 38 to 39 mg/dL lowering of LDL associated with 14% to 15% reduction in vascular mortality (with no difference in nonvascular death or risk for cancers)

LDL reduction achieved through more intensive statin regimen produces significant further reduction in risk for major vascular events

LDL goal recommendations• National Cholesterol Education Program (NCEP) Adult Treatment Panel

(ATP) III 2004 update—

• LDL <100 mg/dL overall therapeutic goal

• for very high-risk patients (defined as having established CAD plus multiple risk factors [RFs], or severe and poorly controlled RFs, or multiple RFs of metabolic syndrome, or ACS), therapeutic goal LDL<70 mg/dL

• Intensity of drug therapy should be sufficient to achieve 30% to 40% reduction in LDL

• 2006 AHA/ACC update—similar recommendations for high-risk patients, but states intensity of therapy should be sufficient to achieve 50% reduction in LDL

• 2011 AHA recommendations for CAD prevention in women—LDL<100 mg/dL overall goal

• LDL <70 mg/dL for very high-risk women

Economics of statin therapy

• recent cost-effectiveness analysis suggests atorvastatin 80 mg/day will become most cost-effective therapy once drug becomes generic

• percentage of LDL reduction—atorvastatin 80 mg/day achieves 50% reduction

• rosuvastatin 40 mg/day, 56% reduction

• simvastatin 80 mg/day, 45% reduction

• simvastatin 40 mg/day, 37% reduction

Statin intolerance and/or nonadherence

• many complaints from patients (incidence 5%-10% in clinical practice; higher than

• reported in clinical trials)

• however, studies show muscle aches usually not due to statin toxicity

• rhabdomyolysis extremely rare

• true toxicity greater at higher doses

• Management strategies

• clarify whether symptom truly began and sustained on new drug

• identify barriers to adherence (eg, cost; lack of education about necessity of continuous intervention)

• If patient complains of muscle soreness—measure creatine kinase (CK)

• if not elevated, myopathy not statin-related

• if <5 times ULN, continue therapy and monitor patient

• modify other RFs (eg, physical activity; hypothyroidism, alcohol consumption)

• change to less lipophilic drug

• try lower dose, alternate-day or weekly dosing

• can combine lower-dose statin with another lipid-lowering agent (eg, bile acid binding agents, niacin, fibrates)

• insist on lifestyle management

• can consider vitamin D or coenzyme Q10 to help manage complaints (no strong supporting data)

• stop statin if patient refuses to continue, symptoms intolerable, or CK >10 times ULN

Can LDL of 70 mg/dL be achieved

• with 1 exception, no clinical trial on lowering LDL has achieved 70 mg/dL (in early 2000s, very few patients on treatment lowered LDL to <100 mg/dL)

• first-dose effect (bulk of lowering with initial dose of whatever statin used)• need higher-efficacy statins• may need higher doses (but be careful of toxicity)• might want to shift goal to 30% to 50% reduction in LDL rather than actual

target number• “rule of 6”—after starting dose, each time statin doubled, only additional

6% reduction in LDL• even with 22% reduction in relative risk for cardiovascular (CV) events

seen in Treating to New Targets (TNT) study with atorvastatin, much greater residual risk remained

Steps for lowering residual risk

• ongoing emphasis on lifestyle Modification• improve all lipid targets (pay particular

attention to high-density lipoproteins [HDL] and triglycerides)

• combination therapy useful with good monitoring

• Improve other RFs (eg, glycemic and blood pressure control)

Who needs LDL of 70 mg/dL?

• 55-yr-old who has just experienced STEMI (yes)• 60-yr-old with hypertension and DM (not• Necessarily would need overt CHD and uncontrolled

RFs)• 25-yr-old with familial hypercholesterolemia

(patient at extremely high risk, multiple drug treatment indicated to lower LDL as much as possible, but will not be able to achieve 70 mg/dL)

• 80-yr-old with stroke (yes)

Questions and Answers• Should LDL be lowered to 70 mg/dL regardless of patient’s HDL level? Yes• this is about targeting LDL• HDL should also be evaluated• any patient being considered for statin intervention must have baseline lipid profile, so

will know HDL level as well• Role for ezetimibe (Zetia)? Unclear• in combination with statins, does achieve additional lowering of LDL• however, current clinical trials have not demonstrated additional benefit• Advantage to testing for apolipoprotein E (ApoE)4 genotype (less responsive to

statins)?• not yet ready for use in clinical practice• Is there role for measuring small particles? advocates claim additional benefit• however, speaker usually does not do submolecular assessments (expensive and do not

alter treatment in most cases)