Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation. Hot Off the Press and into Your Practice: The Last Year in Medical News

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1 Hot Off the Press and into Your Practice: The Last Year in Medical News Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Moyer VA, et al. Ann Internal Med. 2014;160(5): USPSTF Lung Cancer Screening Guideline Development Methods USPSTF Lung Cancer Screening: Systematic review Modeling Studies to estimate benefits and harms by age groups and screening frequencies Leading cause of cancer death in US men and women Older studies of CXR and sputum cytology for lung cancer screening found no benefit Benefits = Harms = Poorly characterized Prevention of lung cancer related deaths 95% of positive tests are false positives 10 12% of diagnosed cancers are cancers that would not have impacted the patient s health Radiation harms high in patients undergoing multiple screens Moyer VA, et al. Ann Internal Med. 2014;160(5): USPSTF Lung Cancer Screening: NLST Randomized Trial 53,000 smokers, 30 pack-years aged years Annual Low- Dose CT Annual CXR Lung Cancer Mortality Median 6.5 years 1.3% 1.6% Number-needed to screen: 333 to prevent 1 lung cancer death 2004 USPSTF stated that the evidence was insufficient to recommend for or against screening. Moyer VA, et al. Ann Internal Med. 2014;160(5): Aberle DR, et al. New Engl J Med. 2011;365(5): USPSTF Lung Cancer Screening: Major Recommendation (B Level) Annual screening in people age 55 to 80 who: Have at least a 30 pack-year smoking history Have actively smoked within the past 15 years Do not have limited life expectancy Would undergo curative lung surgery Note the recommendation to screen patients older than the oldest patients in the NLST, based on modeling studies. Moyer VA, et al. Ann Internal Med. 2014;160(5):

2 USPSTF Lung Cancer Screening: Screening is already happening Recommendation will continue what has already begun screening of heavy smokers Harms likely to outweigh benefits in other populations: Patients who quit smoking >15 years ago Patients with < 30 pack-year smoking history Patients < 55 years 25-Year Follow-up for Breast Cancer Incidence and Mortality of the Canadian National Breast Screening Study Moyer VA, et al. Ann Internal Med. 2014;160(5): Year Follow-up of Breast Cancer Screening The benefits and harms of breast cancer screening remain controversial. What are the long-term benefits and harms of breast cancer screening in women aged 40 to 59 years? 25-Year Follow-up of Breast Cancer Screening: Methods 89,835 women aged years Canadian National Breast Screening Study Randomized Trial of Mammography in 89,835 Women Age years Age years 5 years Yearly Mammogram + Breast Exam Initial Breast Exam, No Yearly Screening Yearly Mammogram + Breast Exam Yearly Breast Exam Alone Follow-Up: Mean 21.9 years *All breast exams performed by trained nurses and took approximately 10 min. 25-Year Follow-up of Breast Cancer Screening: Results 25-Year Follow-up of Breast Cancer Screening: Results (cont.) Screening Period Follow Up Impact of screening on death from cancer diagnosed in screening period: Intervention (n=44,925) Cancers diagnosed Node + cancers Palpable cancers Cancers diagnosed 666 (1.5%) 204 (0.45%) 454 (1.0%) 2584 (5.8%) Hazard Ratio Confidence Interval Overall to 1.30 Age years to 1.49 Age years to 1.36 All-Cause Mortality 10.6% in both groups Control (n=44,910) 524 (1.2%) 170 (0.38%) 524 (1.2%) 2609 (5.8%) At 15 years, 106 excess cancers in the screened group, implying that 22% of screen-detected cancers represented over-diagnosis

3 25-Year Follow-up of Breast Cancer Screening Mammography does not impact long-term mortality Women in their 50s in control group received annual 10-min breast exams, study used older technology, intervention was only 5 years 1/5 of breast cancers found during screening represent over-diagnosis Estimate of overdiagnosis helpful for patient counseling Not likely to fundamentally change screening practice in US 2013 ACC/AHA Guideline on the Treatment of to Reduce Atherosclerotic Cardiovascular Risk in Adults Stone NJ, et al. J Am Coll Cardiol (Nov 7); Epub ahead of print ACC/AHA Guideline: Treatment of and Methods Resulted from the NHLBI s decision to no longer issue guidelines Evidence reviews completed by NHLBI-appointed panels Rated for quality of evidence and strength of recommendation Focused around key questions ACC/AHA Guideline: Treatment of Assess risk for atherosclerotic cardiovascular disease in all patients Major Recommendations Use a tool to assess riskrecommended using a calculator based on the pooled cohort equations Statin therapy and intensity of statin therapy based on risk for atherosclerotic cardiovascular disease (no more concept of goal LDL ) ACC/AHA Guideline: Treatment of Blood Cholesterol Gender Male Age 59 Race African American Total Cholesterol 185 HDL Cholesterol 55 Systolic Blood Pressure Hypertension Treatment Diabetes Smoker 130 No Yes No Based on the data entered (assuming no clinical CVD and LDL C mg/dl) Consider high intensity statin Moderate intensity statin therapy should be initiated or continued in adults aged years with DM (1A) High intensity statin therapy is reasonable for adults aged years with DM and 7.5% estimated 10 year ASCVD risk unless contraindicated (IIaB) ACC/AHA Guideline: Treatment of Statin Intensity High Moderate Low Patients to Receive Age <75 with: CVD, estimated 10 year CVD risk 7.5%, LDL >190 mg/dl Age 75 with: CVD, DM with 10 year CVD risk <7.5% Patients who do not tolerate higher intensity therapy Drugs Atorvastatin mg Rosuvastatin mg Atorvastatin mg Rosuvastatin 5 10 mg Simvastatin mg Pravastatin mg Lovastatin 40 mg Simvastatin 10 mg Pravastatin mg Lovastatin 20 mg

4 ACC/AHA Guideline: Treatment of Areas of Controversy Risk assessment calculator is new and seems to overestimate risk compared to other validated tools (like Framingham calculator) Is 7.5% risk the right threshold at which to recommend highintensity statin therapy? Adherence to new guideline will likely result in statin therapy for more patients but checking lipids less frequently since no need to worry about reaching lipid goals ACC/AHA Guideline: Treatment of Clinical Bottom Line Perform risk assessment using tool of your choice (Framingham is a good option) Target statin intensity to risk Major paradigm shift away from goal LDL and toward treating high-risk patients with more intensive statin therapy Details may change but paradigm likely to be retained Combined strategy may emerge, with risk-based care and target- LDL-based care for patients with very high cholesterols New U.S. Hypertension Guidelines: Finding Order in the Chaos Go AS, et al. Hypertension (Nov 15); Epub ahead of print. James PA, et al. JAMA. 2014;311(5): U.S. Hypertension Guidelines: The Back Story 2008 Jun 2013 Nov 2013 JNC-8 panel convened by NHLBI Formalized guideline development process and conducted a detailed systematic review, rating the quality of all evidence NHLBI announced withdrawal from guideline generation ACC/AHA would take over hypertension and lipid guidelines; JNC-8 guideline was complete and under review 2 separate guidelines published because JNC-8 panelists opted not to collaborate with ACC/AHA U.S. Hypertension Guidelines: 2 Separate Guidelines AHA/ACC/CDC Science Advisory: An Effective Approach to High Blood Pressure Control Essentially a simple algorithm Plan to follow-up with a full guideline in Evidence-Based Guideline for the Management of High Blood Pressure in Adults (from the panel members appointed to JNC8 ) A full guideline, but not endorsed by any formal organization Adheres to current standards for evidence assessment and transparency Go AS, et al. Hypertension (Nov 15); Epub ahead of print. James PA, et al. JAMA. 2014;311(5): U.S. Hypertension Guidelines: Similarities and Differences Goal blood pressure First line agents (general population) Special populations Treatment thresholds JNC 8 Panelists <150/90 in patients aged 60 without DM or CKD; 140/90 in everyone else Non black: thiazide, CCB, ACE I, or ARB Black: thiazide or CCB DM: same as general population CKD: include an ACE I or ARB Not specified Go AS, et al. Hypertension (Nov 15); Epub ahead of print. James PA, et al. JAMA. 2014;311(5): AHA/ACC/CDC <140/90 ( may be lower for some patients ) Thiazide first line Additional agents: ACE I, ARB, CCB DM: ACE I or ARB, thiazide, CCB, β blocker CKD: ACE I or ARB (others mentioned as well) BP <160/100: trial of lifestyle ±thiazide SBP 160 or DBP 100: lifestyle plus 2 drugs (thiazide + ACE I, ARB, or CCB)

5 U.S. Hypertension Guidelines Areas of Consensus Goal BP: 140/90 for most patients, regardless of comorbidities Tolerate higher BP in patients with DM and probably CKD (especially if there are side effects) First line agents: Thiazide ACE-I ARB CCB Take β-blockers off the list of first-line agents Do NOT use β-blocker as firstline agent (for hypertension) Wait for the next round in 2015! Chlorthalidone vs. Hydrochlorothiazide for the Treatment of Hypertension in Older Adults: A Population-based Cohort Study Dhalla IA, et al. Ann Intern Med. 2013;158(6): Go AS, et al. Hypertension (Nov 15); Epub ahead of print. James PA, et al. JAMA. 2014;311(5): Chlorthalidone vs. Hydrochlorothiazide For Treatment of Hypertension in Older Adults Some evidence suggests chlorthalidone is superior to hydrochlorothiazide (HCTZ) for preventing complications of hypertension, but the evidence is inconclusive. Dhalla IA et al. Annals Int Med. 2013; 158(6): What are the relative safety and effectiveness of chlorthalidone and HCTZ for treating hypertension in older adults? Chlorthalidone vs. Hydrochlorothiazide: Methods Retrospective Population-Based Cohort Study in Ontario Patients aged 66+ newly prescribed either drug 1993 to 2010 Identified through multiple province-wide databases Dhalla IA, et al. Ann Intern Med. 2013;158(6): Matched patients receiving each drug for baseline characteristics Excluded patients with major comorbidities (MI, CVA, etc) to find those with primary hypertension Primary outcome: death, or hospitalization for MI, heart failure or stroke Chlorthalidone vs. Hydrochlorothiazide: Results Chlorthalidone vs. Hydrochlorothiazide Chlorthalidone N = 10,384 vs HCTZ N = 19,489 Some baseline differences adjusted for in the analysis Both drugs have similar efficacy for preventing complications of hypertension. Chlorthalidone may lead to more hypokalemia and possibly hyponatremia. Patients receiving chlorthalidone (vs. HCTZ) had: Adjusted HR (CI) Similar rates of primary outcome 0.93 (0.81 to 1.06) Higher rates of hypokalemia 3.06 (2.04 to 4.58) Higher rates of hyponatremia 1.68 (1.24 to 2.28) Dhalla IA, et al. Ann Intern Med. 2013;158(6): Implications for practice Either drug can be used for blood pressure control. Monitor for hypokalemia with either drug, but note this may be worse with chlorthalidone. Dhalla IA, et al. Ann Intern Med. 2013;158(6): Since other studies have shown chlorthalidone more effective, a randomized trial may be needed.

6 Use of Azithromycin and Death from Cardiovascular Causes Use of Azithromycin and Death from Cardiovascular (CV) Causes Observational study in Medicaid beneficiaries Azithromycin associated with 2-3 times higher risk for CV death compared to other antibiotics (small absolute risk) Called into question the safety of this commonlyprescribed antibiotic Is azithromycin associated with increased risk for death from cardiovascular causes, compared with penicillin or no antibiotic, in a population-based sample. Use of Azithromycin and Death from Cardiovascular Causes: Methods Demographic and clinical information from Danish Civil Registration System All people aged living in Denmark Population-Based Cohort Study National prescription registry National register of causes of death Defined population who used azithromycin, penicillin V, or no antibiotics (control), incl. timing of treatment Propensity scores to stratify patients by overall risk, but unable to adjust for some cardiac risk factors Use of Azithromycin and Death from Cardiovascular Causes: Results Episodes of Use Azithromycin: 1.1 million Penicillin: 7.4 million No antibiotics: 7.1 million Baseline Differences Many differences across treatment groups Adjusted for in analysis Risk of CV Death Low overall, much lower than in study that found increased risk with azithromycin Matched Propensity Score Analysis Current use of azithromycin increased risk of CV death compared to no antibiotics RR: 2.85 (CI, 1.13 to 7.24) Likely reflects risk associated with infection Use of Azithromycin and Death from Cardiovascular Causes In a generally healthy population, azithromycin did not increase the risk for CV death compared to penicillin. SSRI Use During Pregnancy and Risk of Stillbirth and Neonatal Mortality Azithromycin probably safe in patients otherwise at low risk for CV events. To minimize risk and optimize care, avoid unnecessary antibiotic use. Consider avoiding azithromycin in patients at increased risk for CV events and when alternative antibiotics are effective.

7 SSRI Use During Pregnancy and Risk of Stillbirth and Neonatal Mortality The use of SSRIs during pregnancy remains controversial, though SSRI continuation in women who become pregnant is increasingly common. Does the use of SSRIs during pregnancy increase the risk for stillbirth or neonatal mortality? SSRI Use During Pregnancy and Risk of Stillbirth and Neonatal Mortality: Study Design Retrospective Population-Based Cohort Study in Denmark Fertility database ( ) Data on pregnancies and births Prescription database Identified exposure to citalopram, escitalopram, fluoxetine, paroxetine, or sertraline during each trimester of pregnancy* Outcomes: Stillbirth Neonatal mortality (death within 28 days of birth) Adjusted for other prognostic factors in multivariate analysis *other SSRIs were very rare SSRI Use During Pregnancy and Risk of Stillbirth and Neonatal Mortality: Results Cohort: 920,620 pregnancies SSRI Exposure: 1.3% of pregnancies Neonatal Mortality: 0.34% Stillbirth 0.43% Trimester of exposure otherwise did not impact risk Not associated with SSRIs overall OR 1.14 (CI, ) Associated with citalopram in 3 rd trimester OR 2.13 (CI, ) Not associated with SSRIs overall OR 1.19 (CI, ) or with individual drugs SSRI Use During Pregnancy and Risk of Stillbirth and Neonatal Mortality SSRI use overall does not appear to increase rates of stillbirth or neonatal mortality. Prudent to avoid citalopram, escitalopram (closely related to citalopram), and paroxetine* during pregnancy. *associated with congenital malformations in other studies Citalopram may be specifically associated with neonatal mortality, though only with exposure throughout pregnancy. Sertraline and fluoxetine likely safe in pregnant women in whom medication for depression is needed. Combined Angiotensin Inhibition for Treatment of Diabetic Nephropathy Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy Combination therapy with ACE-inhibitors and angiotensin receptor blockers (ARBs) can decrease proteinuria, but may increase complications, such as renal failure and hyperkalemia. Does combination therapy with an ARB and ACE-inhibitor slow the progression of diabetic nephropathy compared with an ARB alone?

8 Combined Angiotensin Inhibition for Treatment of Diabetic Nephropathy: Methods Randomized Trial at VA Hospitals 1448 veterans Type 2 diabetes + GFR 30 to 90 ml/min/1.73 m 2 + Micro- or macroalbuminuria Losartan 100 mg/day plus placebo Losartan 100 mg/day plus lisinopril mg/d Primary endpoint: First occurrence of GFR decline, ESRD, or death Note: Study had industry funding and involvement. Combined Angiotensin Inhibition for Treatment of Diabetic Nephropathy: Results Study stopped early (after median 2.2 years) due to increased adverse events in the combination therapy group Endpoint Combination Group ARB Alone group P value Number needed to harm Primary outcome 18.2% 21.0% 0.30 NA (efficacy) Serious adverse 57.5% 52.5% 0.06 NA events Acute kidney injury 18.0% 11.0% < Hyperkalemia 9.9% 4.4% < Combined Angiotensin Inhibition for Treatment of Diabetic Nephropathy Combination therapy with ACE-inhibitor and ARB Did not improve outcomes compared to an ARB alone in patients with diabetic nephropathy Led to higher rates of hyperkalemia and acute kidney injury Effect of Vitamin E and Memantine on Functional Decline in Alzheimer s Disease: The TEAM-AD VA Cooperative Randomized Trial Do not use combination of ACE-inhibitors and ARBs to prevent progression in patients with diabetic nephropathy. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease Vitamin E and memantine may slow disease progression in moderate-severe Alzheimer s dementia, but effects in mild-moderate dementia are unclear What are the effects of vitamin E, memantine, or both on functional decline in patients with mild-moderate Alzheimer s disease who are already on an acetylcholinesterase inhibitor? Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: Methods Randomized, Blinded Trial of Veterans with Alzheimer Disease Veterans with MMSE* while on an acetylcholinesterase inhibitor Vitamin E 2000 IU/d plus memantine placebo Memantine 20 mg/d plus vitamin E placebo Vitamin E plus memantine Placebo vitamin E and placebo memantine Primary Outcome Score on ADCS-ADL Inventory** Validated score : 0 to 78 Lower score worse 2-point difference is clinically meaningful *Mini Mental State Exam **Alzheimer Disease Cooperative Study-Activities of Daily Living

9 Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: Results 613 patients randomized (97% men) Mean follow-up: 2.7 years Dropout rate: 42% Similar across groups; 50% due to death Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease Memantine did not slow progression of mildmoderate disease but did have adverse effects. Vitamin E slowed progression of disease slightly. Slower rate of decline in ADCS-ADL scores for vitamin E than placebo (difference 3.15 points) Rates of decline for memantine and combination did not differ from placebo. Memantine groups had higher rates of infection or infestation than placebo Do not use memantine with an acetylcholinesterase inhibitor to slow disease progression in mildmoderate Alzheimer s disease. If patients or families request additional therapy, use vitamin E. Regardless of therapy, Alzheimer s disease is progressive and effect of treatment is small.