Outpatient Internal Medicine 2014

DCACP Annual Scientific Meeting

November 2014

Two papers appeared in the June 26, 2014 edition of the NEJM studying

the question of how long to monitor heart rhythm after CVAs and TIAs

looking for episodes of Atrial Fibrillation

Why were these studies performed?

Rationale for the studies

• “Current guidelines recommend at least 24 hrs of rhythm monitoring after an ischemic stroke to rule out AFib. However, the most effective duration and type of monitoring have not been established and the cause of ischemic stroke remains uncertain despite a complete diagnostic evaluation in 20-40% of cases.”

Atrial Fibrillation in Patients with Cryptogenic Stroke

NEJM 370;26:2467-2477 (June 26, 2014)

• Study included 572 patients age 55 yrs or older without known Afib with cryptogenic TIA or ischemic CVA within prior 6 months

• Patients were randomly assigned to either i) a conventional 24 hour monitor OR

ii) a 30 day event-triggered recorder

PRIMARY OUTCOME was a newly detected A fib episode of at least 30 seconds in duration within 90 days of randomization

Incremental Yield of Prolonged ECG Monitoring for the Detection of Atrial Fibrillation in Patients with Cryptogenic Stroke or TIA.

Gladstone DJ et al. N Engl J Med 2014;370:2467-2477.

Cryptogenic Stroke and Underlying Atrial Fibrillation NEJM 370;26: 2478-2485

• Randomized controlled study of 441 patients at least 40 yrs old with cryptogenic TIA/CVA with no evidence of Afib during at least 24 hrs monitoring

• Patient randomization within 90 days p TIA/CVA to either

(i) insertable cardiac monitor (ICM) OR

(ii) no ICM

• End Points: First episode of Afib lasting >30 seconds in 6 months and in12 months

Time to First Detection of Atrial Fibrillation.

Sanna T et al. N Engl J Med 2014;370:2478-2486.

Limitations of study

• 1. It was unclear whether newly discovered A Fib was causally related to the index stroke.

• 2. Clinical significance of brief episodes of Atrial Fib detected with an ICM is unknown.

• 3. Not all episodes of A Fib could be accounted for because the devices had limited memory capacity

My father hopes you are enjoying this presentation as much as I enjoyed my pizza

Osteoporosis and its treatment

• Though Prolia is becoming increasingly popular as a treatment for osteoporosis, bisphosphonates (BSPNs )have been the basic pharmacologic treatment for many years now.

• However, there many questions have been raised in recent years about risks of BSPNs, how long to continue treatment, and what is the value of drug holidays (and how long should they last?)

Risk of Atypical Femoral Fracture during and after

Bisphosphonate Use NEJM October 11, 2014 representing an extension of NEJM May 5, 2011 report

• May 2011 study : Case Control Study involving 1234 Swedish women 55 yrs and older with xrays showing subtrochanteric or shaft fractures between 2005 and 2008.

• October 2014 extension: 2 years more data involving 5342 men and women 55 yrs and older with xrays showing femoral shaft fxs

Cohort study

• CASES were patients with atypical fxs who received Bisphosphonates (BSPHs)

• CONTROLs were patients who had similar fractures but who had not received BSPNs.

Risk of Atypical Femoral Fxs on BSPNs vs Not on BSPNs(5 yr data)

• Multivariate Adj Odds Ratio

• Duration of use: – <1.0 yrs 1.7 – 1 - 2 yrs 8.2 – 2 - 3 yrs 28.7 – 3 - 4 yrs 39.7 – 4 – 5 yrs 116.4

However, annual absolute risk of atypical fracture was -- After 2 years of BSPNs: 2/10,000 pt years of tx -- After 4 years of BSPN : 11/10,000 pt years of tx

How Does Risk Diminish off BSPNs?

• Time since last use

– <1 year 42.9 5/10,000 Pt yrs

– 1.0-1.9 years 3.5 <1/10,000 Pt yrs

– 2.0-3.0 years 3.2 <1/10,000 Pt yrs

Your patients have heard about

–THE BIG T--

The Big T (before)

The Big T (after)

The BIG T

• Advertisements promote testosterone replacement for men with decreased energy and low sex drive.

• There is scientific evidence to suggest that in at least some men with low energy testosterone replacement can boost energy, increase libido, improve bone mineral density, and improve lean body mass and strength.

Association of Testosterone Therapy with Mortality, Myocardial Infarction, and Stroke in Men with Low

Testosterone Levels JAMA 310(17):1829-1836 (November 2013)

• Retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the VA system between 2005-1011

• Primary outcome a composite of all-cause mortality and hospitalization for MI or ischemic stroke

Date of download: 11/2/2014 Copyright © 2014 American Medical

Association. All rights reserved.

From: Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low

Testosterone Levels

JAMA. 2013;310(17):1829-1836. doi:10.1001/jama.2013.280386

Kaplan-Meier Survival Curves With Testosterone Therapy Evaluated as a Time-Varying Covariate

Figure Legend:

Kaplan-Meier estimated cumulative percentages of men with outcome event

No Testo vs Testo Years since Angiogram One Yr Two Yr Three Yr

No testosterone 10.1% 15.4% 19.9% Testosterone 11.3% 18.5% 25.7%

Association of Testosterone Therapy with Mortality, MI, and CVA (JAMA)

Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men

PLOS One. 2014;9:e85805

• Data based used: The Truven Health MarketScan Commercial Claims and Encounters Database (employees, dependents and retirees with commercial or Medicare insurance whose employers license healthcare data to Truven Health Analytic (Truven).

• The MarketScan data contributors include Fortune 500 employers (60%) and health plans covering other companies and unions (40%)

PLOS ONE

• An open access peer-reviewed scientific journal published by the Public Library of Science since 2006.

• Concept was a free-access biomedical journal “challenging academia’s obsession with journal status and impact factors”

• Financed by charging authors a publication fee

• According to Wikipedia, the journal published 31,500 papers in 2013 (apparently making it the largest journal in the world by volume)

Key comparisons in this study

• Outcome event was a dx of Acute MI (ICD9 Code of 410) occurring within 90 days after men filled a first prescription for testosterone (n=55,593).

• The incidence of these outcome events were compared to the incidence of Acute MI occurring one year prior to the first prescription for testosterone.

• (Data not available on how much of the prescribed medication was consumed).

Table 1. Rates of myocardial infarction per 1,000 persons per year (PY) in men under age 65 years and those age 65 years and older, in pre- and post-prescription intervals for an initial prescription for testosterone therapy rate

ratios (RR) and 95% confidence intervals (CI).

Finkle WD, Greenland S, Ridgeway GK, Adams JL, et al. (2014) Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PLoS ONE 9(1): e85805. doi:10.1371/journal.pone.0085805 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085805

“Testosterone and Mortality” Clin Endocrinol 2014;81(4): 477-487

• “Epidemiologic studies have found that men with low or low normal endogenous testosterone are at an increased risk of mortality than those with higher levels.

• Similarly, multiple epidemiologic studies have shown a link between low testosterone and cardiovascular disease.

• Of the studies linking mortality with low testosterone, increased mortality was mostly attributable to cardiovascular mortality.

And, the other major point of the Clin Endocinology article

• The studies of testosterone replacement are flawed in terms of lacking potentially important data, such as to whether replacement has been done to a normal healthy range or not (e.g., there is a recent French study of 3650 men aged 65 and older where a J-shaped association was found between total testosterone levels and ischemic arterial disease.

• The studies of testosterone replacement have significant methodologic limitations

Some limitations of JAMA study

• Patients were included who were started on testosterone therapy at variable intervals after the initial angiogram (median of 531 days following angiography)

• Patients were included if they filled a first prescription for testosterone following angiography. “Once initiated, a patient was assumed to have continued treatment until an outcome event occurred or the end of follow up”

Limitations in PLOS study

• No data on whether or not hypogonadism had been diagnosed or even if testosterone levels were measured

• No evidence on compliance or monitoring of testosterone levels

• No data on fatal MIs

2014 FDA Testosterone Actions

• On January 31, 2014, FDA issued a Drug Safety Communication informing the public of its investigation of "the risk of stroke, heart attack, and death" in men taking FDA-approved testosterone products

Sept 17th FDA meeting • Panel members at a joint meeting of the Bone

Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSARM) voted 20-1 in favor of changing the labeling of the testosterone replacement therapy.

• A second vote calling on companies to conduct studies related to cardiovascular risks also yielded a tally in favor of such trials.

• The majority of those voting advised narrowing the set of indicators to distinguish classic hypogonadism, such as pituitary or testicular diseases, from hypogonadism due to old age.

And as might be expected

• Lawsuits have been filed against the makers of testosterone therapies, alleging patients were harmed by the use of testosterone and that they were not adequately warned about the risks involved with the therapy.

These presentation are almost as exciting as a MSL soccer game

So what about all those patients who don’t enjoy colonoscopy?

•And what is the role of newer stool tests in screening for colon cancer?

Multitarget Stool DNA Testing for Colorectal-Cancer Screening

NEJM 2014;370:1287-1297 (April 2014)

• From June 2011 to November 2012

• 12,776 asymptomatic persons ages 50-84 at average risk for colorectal cancer who were scheduled to undergo screening colonoscopy were enrolled at 90 sites throughout the US and Canada (enrollment weighted towards persons 65 yrs or older to increase prevalence of cancer).

• 9989 of these participants (78.2%) had results that could be fully evaluated.

Enrollment and Outcomes.

Imperiale TF et al. N Engl J Med 2014;370:1287-1297.

Multitarget Stool DNA (MTSD) Testing for Colorectal-Cancer Screening: Outcomes

• “The primary outcome was the ability of the MTSD test to detect colorectal cancer. “

• “The 2o outcome was the performance of the MTSD test for the detection of advanced precancerous lesions including

– Advanced Adenomas with high-grade dysplasia or with at least 25% villous histologic features or measuring at least 1 cm in greatest dimension

– Sessile serrated polyps of at least 1 cm in diameter

MTSD Testing for Colorectal-Cancer Screening: The Stool Test Itself

• The MTSD test consisted of assays for aberrantly methylated BMP3 and NDRG4 promoter regions, mutant KRAS, and Beta-actin, as well as an immunochemical assay for human hemoglobin

• “Gold Standard” were results from follow up colonoscopy.

• Results were also compared to those from an immunochemical assay for human hemoglobin (FIT test)

Sensitivity and Specificity of the Multitarget Stool DNA Test and the Fecal Immunochemical Test (FIT) for the Most Advanced Findings on Colonoscopy.

Imperiale TF et al. N Engl J Med 2014;370:1287-1297.

Numbers of Persons Who Would Need to Be Screened with Colonoscopy, Multitarget DNA Test, and FIT to Detect One Colorectal Cancer and One Advanced Precancerous Lesion.

Imperiale TF et al. N Engl J Med 2014;370:1287-1297.

False Positive results for the MTSD test and FIT test

• False positive rate of MTSD test 13.4% for non advanced adenomas and no adenomas (16.3% for those 65 and older) and 10.2% for no adenomas at all

• False positive rate of the FIT test was 5.1% for advanced adenomas and no adenomas and 3.6% for no adenomas at all

A Pooled Analysis of Advanced Colorectal Neoplasia Diagnoses After Colonoscopic Polypectomy Gastroenterology 2009;136:832-841

• Individual data from 8 prospective studies comprising 9167 men and women aged 22-80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer, as well as identify factors associated with the development of advanced adenoma or cancer

A Pooled Analysis of Advanced Colorectal Neoplasia Diagnoses After Colonoscopic Polypectomy: Results

• During a median follow up period of 47.2 months, advanced adenoma or neoplasia was diagnosed in 11.8% of the patients.

• 58 of the patients (o.6%) had invasive colon cancer

• Risk of advanced adenomas or neoplasm was highest in certain subgroups

Figure 1

Gastroenterology 2009 136, 832-841DOI: (10.1053/j.gastro.2008.12.007)

Copyright © 2009 AGA Institute Terms and Conditions

Polypectomy May Reduce Risk of Death from Colon Cancer

NEJM 2012;366: 687-696 Feb 23, 2012

• Data from the National Polyp Study (NPS) was analyzed. Subjects in this trial were patients referred for colonoscopy between 11/80 and 2/90. Patients were referred for colonoscopy because of positive findings on BaEnema (27%), sigmoidoscopy (15%), Positive occult test (11%), other tests (10%), Symptoms (32%), or family history of colon cancer (5%).

Outcomes sought

• Death rates from colon cancer of the 2602 patients who had adenomas removed during participation in the study after a median of 15.8 years were compared to the estimated number of expected deaths from colorectal cancer in the general population

• Study participants had colonoscopies offered at 1, 3, and 6 years or at 1 and 6 years.

Deaths from Colorectal Cancer in the Adenoma Cohort, as Compared with Incidence-Based Mortality from Colorectal Cancer in the General Population.

Zauber AG et al. N Engl J Med 2012;366:687-696.

Cumulative Mortality from Colorectal Cancer in the General Population, as Compared with the Adenoma and Nonadenoma Cohorts.

Zauber AG et al. N Engl J Med 2012;366:687-696.

Tabular data analysis

And, finally, what about the “practical” aspects of Cologuard Testing

Decision Memo for Screening for Colorectal Cancer-Stool DNA Testing (CAG-00440N)

“the Centers for Medicare and Medicaid Services (CMS) has determined that the evidence is sufficient to cover Cologuard as a colorectal cancer screeing test for asymptomatic, average risk beneficiaries, aged 50-85 years.”

CMS Memo: The details

• CMS will cover the Cologuard test once every three years if: – 1. Age 50-85 yrs old

– 2. Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower GI pain, blood in stool, positive guiac fecal occult or fecal immunochemical test, AND

– 3. At average risk (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease and no family history of colorectal cancers or adenomatous polyps, familial adenomatous polyposis, or hereditary non polyposis colorectal cancer.)

And what about private insurance coverage

• 1. $50 deposit required for specimen to be processed

• 2. The Cologuard company will then work to collect payment from the patient’s private insurance company

• 3. Patient is responsible for amount not covered by the insurance company (maximum of $599)

Thank you for your attention to my father’s presentation

Characteristics of the Five Patients with Colorectal Cancer (Malignant Polyp) Detected at Follow-up Colonoscopy.

Winawer SJ et al. N Engl J Med 1993;329:1977-1981.

Prevention of Colorectal Cancer by Colonoscopic Polypectomy NEJM 1993;329:197701981

• Data from the National Polyp Study (NPS) was analyzed. Subjects in this trial were patients referred for colonoscopy between 11/80 and 2/90. Patients were referred for colonoscopy because of positive findings on BaEnema (27%), sigmoidoscopy (15%), Positive occult test (11%), other tests (10%), Symptoms (32%), or family history of colon cancer (5%).