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Journal Watch

August 2015

The Cloaking

Remember your ‘white coat ceremony’

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Table of contents

Cardiology 3

EKG challenge 6

Gastroenterology 9

Hepatology 13

General Internal Medicine 18

Hematology/Oncology 20

Infectious Diseases 21

Nephrology 23

Pulmonary/ Critical care 27

Rheumatology 31

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Cardiology Troponin and Cardiac Events in Stable Ischemic Heart Disease and

Diabetes

Dr. Wally Omar reviewing Everett et al, N Engl J Med. 2015 Aug 13;373(7):610-20.

Summary: This retrospective analysis is an ancillary study to a randomized controlled trial known as

BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes). The

original study measured outcomes in patients with both stable ischemic heart disease and

type 2 diabetes after being randomized to receive either intensive medical therapy alone or

both early coronary revascularization in addition intensive medical therapy (statin + strict

glycemic control). The purpose of this study was to assess whether high amounts of

circulating cardiac troponins at baseline conferred a greater risk of the following outcomes:

death from cardiovascular causes; MI; or stroke. It was hypothesized that those with high

troponins would derive a greater benefit from earlier coronary revascularization as well.

Of the 2285 patients enrolled in the original study, 2277 of them had detectable levels of

troponin using the high-sensitivity assay (>3 ng/L) and 897 of those had abnormally

elevated levels of troponins (>14 ng/L). Patients with abnormally high troponins at

baseline demonstrated a 5-year rate of composite end point that was more than double

that of patients with just detectable levels of troponin (27.1% vs. 12.9%). In addition the

study also found that there was no added benefit of coronary revascularization in these

higher risk patients, whether it be CABG or PCI, in the rate of MI, stroke, and death from a

cardiovascular event (hazard ratio 0.96, 95% CI 0.74 to 1.25).

Commentary:

Not all troponins are created equal, and many of us who have had to re-triage an ESRD

patient off of a CCU service know this all too well. This study however, shows us that

regardless of etiology, a high troponin at baseline demands respect. Aside from finding that

the risk of having one of the aforementioned primary outcomes doubled in patients with

high troponins at baseline, the study also found that their troponins were likely to continue

to increase despite aggressive medical and invasive therapies. Above all, the highlight of

this study is that patients with stable ischemic heart disease did not derive any meaningful

benefit from early revascularization techniques. This finding echoes guidelines from

various cardiovascular task forces, which concur that medical therapy is superior to both

CABG and PCI in patients with stable symptoms. As high-sensitivity troponin assays

become more common, so will the frequency with which incidental coronary disease is

found. What sets us apart as physicians, therefore, is how well we listen to our patients and

understand their symptomatology. Should their story be more consistent with stable

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angina, why subject them to invasive testing that evidence suggests would likely do more

harm than good?

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Perioperative Bridging Anticoagulation in Patients with Atrial

Fibrillation

Dr. Wally Omar reviewing Douketis et al, N Engl J Med. 2015 Aug 27;373(9):823-33.

Summary:

This multi-center randomized controlled trial sought to assess whether bridging with low

molecular weight heparin in the perioperative setting is actually necessary for elective

surgeries in patients who are receiving warfarin therapy for atrial fibrillation. Patients

were told to stop warfarin therapy 5 days prior to the procedure. At this point they were

randomized to receive either BID dalteparin or placebo injections until 24 hours prior to

surgery. The study drug was then resumed either 24 hours or 48-72 hours after the

operation depending on the bleeding risk associated with said surgery, and subsequently

discontinued when the patient’s INR became therapeutic. With a total n of 1884, no

significant difference was seen in the incidence of arterial thromboembolism— defined as

stroke, transient ischemic attack, or systemic embolism— between the bridging and non-

bridging groups (0.3% and 0.4% respectively, p = .01 for non-inferiority). In addition to

this, a significant decrease in the rate of major bleeding was found in the non-bridging

group (1.3% vs. 3.2%, p = 0.005). Finally, there was a large decrease in the rate of minor

bleeding in patients who did not receive bridging (12.0% vs. 20.9%, p <0.001).

Commentary:

Despite the increasing availability of newer anticoagulants, warfarin remains the most

widely used form of anticoagulation in patients with A. fib. Physicians are constantly

plagued with the dilemma of whether or not to bridge their patients in the perioperative

setting. As with most dilemmas in medicine, an ethical approach helps to decide which

route to take. When the concept of non-maleficence is employed, it becomes evident that

bridging in the perioperative setting is not right for most patients. The results of the

BRIDGE study only add to a growing body of evidence that interruption of warfarin therapy

is not as bad as once thought. While no study to date has shown an increase in major

thromboembolic events in the perioperative setting, studies like RE-LY and ORBIT-AF have

also demonstrated significant increases in major bleeding associated with bridging. We

should certainly keep in mind, however, that this study is not generalizable to all patients:

the average CHADS2 score for patients enrolled was 2.6, and only a small number of

patients had CHADS2 scores greater than 5. High-risk patients undergoing any type of

surgery, therefore, should be evaluated on a case-by-case basis. As a whole, however, it

finally feels safe to say that bridging for a routine colonoscopy is not necessary.

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EKG Challenge

Dr. Jeomi Maduka

Your biggest fear is about to happen. Its 1:57AM at the VA, you're on call for the CCU

service. “71975”, it’s the ED calling to admit a patient:

67 year old veteran with known history of CAD with prior stents, persistent atrial

fibrillation status-post AVJ ablation with subsequent pacemaker placement, uncontrolled

type 2 diabetes, and hypertension is presenting with chest pain that started 30 minutes

ago. Initial troponin T is 0.02. Initial ECG read by MUSE shows a clearly ventricular-paced

rhythm. You are able to pull up an old ECG and note a V-paced rhythm in the past as well.

How do you interpret this current presentation of chest pain and positive troponin in this

patient with a ventricular paced rhythm?

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Teaching point:

In patients with LBBB or a ventricular-paced rhythm, diagnosis of MI based on ECG can be

challenging.

Sgarbossa criteria were created because of this common dilemma. The Sgarbossa criteria

essentially relies on the presence of “inappropriate concordance” or “excessive

discordance”. In a normal LBBB or V-paced rhythm, we expect the J-point or the ST

segment to be positioned actually in the opposite direction as the QRS complex. For

example, in the leads with a positively deflected QRS complex, we expect the ST segment to

be slightly below the isoelectric line. In leads with a negatively deflected QRS, we expect the

ST segment to be slightly above the isoelectric line. This is what is known as discordance. A

small amount of discordance is appropriate and expected in a normal LBBB or a V-paced

rhythm.

When an ECG shows inappropriate concordance in these leads OR excessive discordance,

there is a 90% likelihood that the patient is having a STEMI.

Sgarbossa Criteria:

There are 3 criteria that are used to diagnose myocardial infarction in patients with V-

paced or LBBB rhythm:

1. Concordant ST elevation >1 mm in leads with a positive QRS complex - gives you 5

points

2. Concordant ST depression >1mm in V1-V3 - gives you 3 points

3. Excessively discordant ST elevation >5 mm in leads with a negative QRS complex - gives

you 2 points

> or equal to 3 points = 90% specificity of STEMI!

**these criteria need not apply to contiguous leads**

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2 points given for excessive discordance + 3 points given for concordant ST segment

depression.

ACTIVATE CATH LAB!

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Gastroenterology

Second-Look Colonoscopies and the Impact on Capacity in FIT-Based

Colorectal Cancer Screening

Colonoscopies undertaken as a result of positive FIT often need repeat colonoscopies in a

short amount of time to evaluate completeness of lesion removal due to the high number of

advanced neoplasms.

Dr. Udayan Shah reviewing Grobbee EJ, et al. Am J Gastroenterol. 2015 Jul;110(7):1072-7.

Summary:

This study evaluated the characteristics of patients undergoing colonoscopy after positive

FIT in terms of the need for second-look colonoscopies, defined as a repeat colonoscopy

within a year. A registry of 1,215 patients aged 50 to 74 living in the southwest Netherlands

undergoing colonoscopy due to positive FIT was used as the study population. Those with

known colorectal cancer, symptoms, or recent colonoscopy were excluded. Of these, 105

(8.6%) underwent second look colonoscopy. Of those undergoing second-look colonoscopy,

28% needed one or more additional colonoscopies, leading to a 12% increase in the total

number of colonoscopies done for positive FIT. In 76% of the cases, the reason for repeat

colonoscopy involved assessing completeness of neoplastic lesion removal or additional

polypectomy, done for reasons ranging from large polyp size to suspected high-grade

dysplasia to complex location. Only 13% of repeat colonoscopies were due to poor bowel

preparation. Additionally, a higher fecal hemoglobin concentration was associated with a

higher risk of repeat colonoscopy.

Commentary:

This was the first study to look at incidence of repeat colonoscopy in colorectal cancer

screening regimens that rely on FIT. While not a direct comparison to screening paradigms

that rely on colonoscopy, the study highlights a number of important features of FIT-based

screening. First, surveillance colonoscopy to evaluate for complete removal or need for

repeat colonoscopy for additional polypectomy drives much of the 1-year repeat rate for

colonoscopies done as a result of positive FIT. This is consistent with the American College

of Gastroenterology’s view of FIT as a colon cancer detection test rather than a colon

cancer prevention test, and is higher than the 4-year repeat rate of 3-4% in colonoscopy-

based screening (Pyenson et al in BMC Health Serv Res, 2014). Trials are currently

underway to assess mortality difference in FIT-based screening compared to colonoscopy-

based screening, eg the CONFIRM trial, but analysis for cost-effectiveness should include

repeat colonoscopy burden. Finally, the fact that a high fecal hemoglobin concentration is

associated with higher risk of repeat colonoscopy is consistent with prior studies

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associating it with a higher risk of advanced neoplasm, and suggests that the actual fecal

hemoglobin concentration, rather than just a positive or negative value, should be reported

since it may help counsel patients regarding the need for colonoscopy.

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Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A

Multicenter, Randomized Controlled Study

Amitriptyline, not escitalopram, improves symptoms in the subset of functional dyspepsia

patients with pain as the predominant symptom. Neither relieves symptoms in the subset

with early satiety and postprandial fullness as the predominant symptoms.

Dr. Udayan Shah reviewing Talley NJ, et al. Gastroenterology. 2015 Aug;149(2):340-349.e2.

Summary: In this multi-site double-blind randomized controlled trial conducted by the Mayo Clinic,

investigators sought to evaluate response to antidepressants commonly used in the

treatment of functional dyspepsia. Over a 6-year period, 292 patients who met Rome II

criteria for functional dyspepsia with a negative EGD in the past 5 years were randomized

to placebo, amitriptyline, or escitalopram. Exclusion criteria included those with symptom

resolution with PPI, active NSAID or anti-depressant use, history of organic UGI disease,

drug abuse, and those with significant depressive symptoms. The primary endpoint

involved self-reported improvement in symptoms for at least 50% of a 10-week period

following enrollment. In an intention to treat analysis, relief rates for placebo,

amitriptyline, and escitalopram were 40%, 53%, and 38%, respectively, with an overall p-

value of 0.05 and no significant difference between either treatment arm and placebo.

Results were stratified based on the type of functional dyspepsia, ulcer-like (pain-

predominant) or dysmotility-like (satiety- and postprandial fullness-predominant). In

ulcer-like functional dyspepsia, which accounted for approximately 30% of enrolled

patients, amitriptyline was associated with a 3-fold increase in response (95% CI 1.1 – 9).

No benefit was found for escitalopram. The dysmotility-like subgroup showed no benefit

with either escitalopram or amitriptyline. Results were also stratified by normal or

abnormal gastric emptying study, with those with normal gastric emptying study showing

a higher response to amitriptyline but not escitalopram, and those with abnormal gastric

emptying showing no response to either drug.

Commentary:

Functional dyspepsia has long been a challenging disease to treat. This study sought to

provide evidence for use of SSRIs and TCAs, which have been proven efficacious in the

treatment of IBS, in this different but seemingly related disease. Regarding escitalopram,

the study results are unequivocally negative, with no benefit compared to placebo overall

or in subgroup analysis. Amitriptyline results were positive only in the ulcer-like and

normal gastric emptying subgroups (Figure). While the most significant functional

dyspepsia study to date, the relatively small sample size limits subgroup analysis and helps

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explain the wide confidence intervals. Overall, the results suggest that SSRIs are not helpful

in functional dyspepsia and that TCAs are only helpful in ulcer-like (renamed epigastric

pain syndrome in Rome III) as opposed to dysmotility-like (renamed postprandial distress

syndrome in Rome III) functional dyspepsia. This is consistent with the demonstrated

efficacy of TCAs in chronic pain syndromes. The results also suggest that the

pathophysiology for functional dyspepsia (upper GI complaints) may be different from that

for IBS (primarily lower GI complaints), though there is a portion of the population that

meet criteria for both. The search is still on for drugs that improve functional dyspepsia,

and one in particular, acotiamide, has shown promise in postprandial distress syndrome.

Figure

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Hepatology

Toward a More Complete Understanding of the Association Between a

Hepatitis C Sustained Viral Response and Cause-Specific Outcomes.

Sustained viral response (SVR) of hepatitis C virus (HCV) is associated with reduced liver

and non-liver mortality as well as positive changes in patients’ behaviors. These benefits

are greater in HCV patients who have moderate to severe liver disease and attain SVR.

Dr. Brian Davis reviewing Innes et al., Hepatology 2015;62:355-364.

Summary:

In this study, Innes and colleagues evaluated a large cohort of patients with HCV in

Scotland in order to determine the association of sustained viral response (SVR) with

various clinical outcomes. The cohort consisted of 3,385 patients in Scotland who

underwent treatment for HCV from January 1996 to December 2013. SVR was defined as

negative PCR testing for viral RNA for at least 6 months after stopping therapy. The

primary outcome events were liver mortality and hospitalization for severe liver

morbidity, defined as decompensated liver cirrhosis or hepatocellular carcinoma (HCC).

The authors controlled for basic demographics, medical comorbidities, behavior factors,

and liver function tests. The cohort was mostly male (70%) with an average age of 42

years. Cirrhosis was present in 8.4% and most had acquired HCV through IV drug use

(58%). SVR was initially obtained in 54% of patients, and 7% of non-SVRs later attained

SVR. The fully adjusted hazard ratio (FAHR) for liver mortality was 0.24 (95% CI 0.14-0.42)

and 0.21 (95% CI: 0.49-0.95) for severe liver morbidity. SVR was also associated with

reduced non-hepatic mortality and coronary vascular diseases (FAHR 0.68, 95% CI 0.49-

0.95 and 0.70, 95% CI 0.57-0.87, respectively.) SVR was associated with an absolute risk

reduction (ARR) in liver mortality (3% at 7.5 years), all-cause mortality (3.9% at 7.5 years),

severe liver morbidity (4.7% at 7.5 years), and CVD (3.4% at 7.5 years). The ARR increased

over time, and was higher in patients with non-mild liver disease. Patients who achieved

SVR were also less likely to have hospitalizations for alcohol intoxication and violence-

related injuries.

Commentary:

The main take-away of this article is the linking of sustained viral response (SVR) to

improved clinical outcomes in patients with HCV. While SVR is often cited as the goal for

patients undergoing treatment for HCV, it is a surrogate endpoint. It is important to

remember that randomized, double blind and placebo controlled trials with the myriad of

new HCV medications have never evaluated hard clinical outcomes such as morbidity and

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mortality as the primary endpoint. Observational studies have explored the link between

SVR and clinical outcomes, but none to this degree in terms of number of patients (>3,000)

and measured clinical outcomes. Importantly, they documented that the absolute risk

reduction (ARR) for all cause mortality, liver related mortality, and liver related morbidity

increased over time, which suggests the earlier the treatment, the longer the benefit of

obtaining SVR. Interestingly, they also found that obtaining SVR reduced future

cardiovascular events (suggestive of non-hepatic pathophysiology with HCV), and modified

patient behavior, as evidenced by reduced admissions for alcohol intoxication and

violence-related injuries. Furthermore, the benefits of SVR were more pronounced in

patients with moderate to severe fibrosis compared to those with mild fibrosis. Given that

the ARRs are somewhat low coupled with the exorbitant costs of new HCV drugs, one care

argue to limit the new drugs to patients with moderate to advanced liver disease.

Conversely, these data also suggest the earlier the treatment of HCV, the greater the

likelihood of preventing morbidity and mortality associated with HCV.

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The Cholangiopathies

Dr. Brian Davis reviewing Lazaridis at al, Mayo Clin Proc. 2015 Jun;90(6):791-800.

Summary:

Cholangiopathies are a group of chronic liver diseases affecting the epithelial cells lining

the bile ducts, often resulting in high rates of morbidity and mortality with substantial

diagnostic and clinical challenges.

Commentary:

The review article summarizes the physiologic role of the cholangiocyte and discusses the

pathophysiology, diagnosis, and management of 6 diseases:

1. Primary biliary cirrhosis (PBC): defined as nonsuppurative inflammation and

destruction of the interlobular bile ducts that may progress to biliary cirrhosis. 90% of

cases occur in women (mean age of diagnosis 55 years.) Diagnostic criteria include >6

months of serum alkaline phosphatase levels twice the upper limit of normal, positive

serum antimitochondrial antibodies, and diagnostic liver biopsy. Ursodeoxycholic acid

(UDCA) (13-15 mg/kg/day) is FDA approved for the treatment of PBC, but does not

prolong survival or time to transplant. About 30% of patients do not respond and

progress to cirrhosis.

2. Primary sclerosing cholangitis (PSC): chronic inflammation of the intrahepatic and

extrahepatic bile ducts, often leading to strictures (obliterative cholangitis) and

progression to cirrhosis. The disease is seen in males (median age of diagnosis between

30-40 years.) About 70% of patients also have inflammatory bowel disease (typically

ulcerative colitis). Diagnostic criteria include >6 months of serum alkaline phosphatase

twice the upper limit of normal, cholangiographic evidence of strictures (often using

MRCP), and exclusion of secondary sclerosing cholangitis. No effective medical therapy

exists for PSC (UDCA is controversial) and treatment focuses on liver transplantation

for advanced cases.

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3. Cystic fibrosis (CF): systemic disease defined

as mutation in the CFTR gene. Cholangiocytes are

the only cells in the liver that express the CFTR

gene. Around 30% of patients with CF have clinically

significant liver disease, ranging from asymptomatic

elevation of liver enzymes, focal biliary cirrhosis, or

cirrhosis with portal hypertension. Ursodeoxycholic

acid therapy is recommended for these patients (20

mg/kg/day divided in 2-3 doses), but there is no

evidence that it slows disease progression.

4. Biliary atresia: defined as obstructive

cholangiopathy of unknown etiology and occurs in

infants. It has an incidence of 1 per 12,000 births in

the U.S. and accounts for 50% of pediatric liver

transplantation.

5. Polycystic liver disease: inherited disorders

that occur either alone (autosomal dominant

polycystic liver disease, AD-PLD) or in conjunction

with polycystic kidney disease. AD-PLD has a

prevalence of 1 in 100,000 people and is caused by

mutations in the PRKCSH or Sec63 genes, which are

both expressed in cholangiocytes. Treatment

options included surgical resection of liver cysts and

octreotide in patients who are symptomatic or have

progressive cystic liver disease.

6. Cholangiocarcinoma: biliary malignancy originating from oncogenic transformation of

cholangiocytes and divided into intrahepatic (10%), perihilar (50%), or distal (40%).

Intrahepatic cholangiocarcinoma presents as a liver mass and perihilar and distal

disease often present with jaundice. The 5-year survival rate for patients with

microscopically negative surgical margins are 63% for intrahepatic, 30% for perihilar,

and 27% for distal disease. ERCP, MRCP, and EUS can be used to define the extent and

surgical resectability of the tumors. Diagnosis in PSC can be challenging due to

uncertainty of benign versus malignant strictures. Cytology may be useful in biliary

sampling obtained via ERCP. IgG4-associated cholangitis should be ruled out (benign

biliary strictures and elevated serum IgG4 levels). Surgery is mainstay of therapy, but

curative resection is achieved in 30% of cases. Liver transplantation may be an option

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in selected patients with perihilar disease. For unresectable disease, chemotherapy

with gemcitabine and cisplatin is used.

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General Internal Medicine

Systemic Inflammatory Response Syndrome Criteria in Defining Severe

Sepsis Dr. Arjun Gupta reviewing Kaukonen et al, N Engl J Med. 2015 Apr 23;372(17):1629-38.

Summary: The criteria requiring the presence of ≥ 2 SIRS criteria to define severe sepsis may warrant

reconsideration since it results in the exclusion of one in eight patients with infection and

organ failure, and fails to identify a clear transition point in the risk of death.

Commentary: This retrospective study of 109,663 patients with organ dysfunction and infection included

90% of all ICU admissions in Australia/ New Zealand from 2000-2013. Of the included

patients, 88% were labeled as SIRS-positive severe sepsis (SPSS), and 12% did not fulfill 2

SIRS criteria and were labeled as SIRS-negative severe sepsis (SNSS). Within the SNSS

group, 20% met 0/4 SIRS criteria while 80% met 1/ 4 SIRS criteria.

The 12% (1 in 8) patients with SNSS had lower mortality compared to patients with SPSS;

HR for death in SPSS patients vs SPSS patients was 1.26 (95%CI 1.18- 1.34, p value <0.001),

but mortality decreased similarly in both groups individually over the study period. In

statistical modeling correlating mortality with the number of SIRS criteria present (0 to 4),

a 13% linear increase in mortality was seen with the presence of each additional SIRS

criteria, but there was no specific threshold in mortality when 2 criteria were met.

SIRS criteria are universally utilized to identify patients with severe sepsis and septic

shock. The traditional criticism of the SIRS criteria is low specificity for infection, with both

pathological (pancreatitis, burns) and physiological (pregnancy, exercise) non-infectious

conditions potentially meeting 2 or more SIRS criteria. This study shows that the SIRS

criteria may have a lower sensitivity for severe sepsis than previously thought, and the lack

of 2 or more SIRS criteria does not exclude patients with clinically significant infections at

risk for poor outcomes. Patients with organ dysfunction and infection may present with 0

SIRS criteria, and clinical judgment must be exercised while treating these patients. Also,

the presence of additional SIRS criteria portends a worse mortality although no threshold

effect of <2 or ≥ 2 SIRS criteria was seen. The presence of SIRS criteria may help screen for

sicker, infected patients with subsequent higher mortality, but they should not supersede

clinical judgment in determining whether patients have clinically significant infections.

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Screening for Occult Cancer in Unprovoked Venous Thromboembolism

Dr. Arjun Gupta reviewing Carrier et al, N Engl J Med. 2015 Aug 20;373(8):697-704.

Summary:

Enhanced CT abdomen and pelvis after an episode of unprovoked VTE did not provide

additional benefit for detecting occult malignancy compared to limited malignancy

screening in the SOME (Screening for Occult Malignancy in idiopathic venous

thromboEmbolism) trial.

Commentary:

VTE, described as DVT/PE, can be provoked when associated with a predisposing factor

(post-op, puerperal, line-associated or malignancy) or unprovoked. Up to 10% of

unprovoked VTE may precede a diagnosis of cancer within 1 year. A multi-center RCT was

conducted in Canada to compare contrast enhanced CT abdomen and pelvis in addition to

limited occult malignancy screening (CBC, BMP, LFT plus USPSTF screening for breast,

cervical and prostate cancer) versus limited occult malignancy testing alone. The primary

outcome was newly diagnosed cancer in a 1- year follow up period in patients who had a

NEGATIVE malignancy screening.

854 patients (431 limited screen and 423 limited screen + CT) were included in the

intention-to-treat analysis after excluding patients with ‘provoked VTE’. A total of 33 new

diagnosis of cancer were made in the two groups- 14/431 in the limited screening arm and

19/423 in the screening + CT arm (p=0.28). In the primary analysis, 4/14 and 5/19 cancers

were missed during screening in the limited screening and CT arms, respectively, and

detected during 1 year follow-up (p=1.0). There was also no difference in mean time to

cancer detection or cancer-related mortality between the two groups. A broad range of

cancer types were represented among the 33 cases.

Limitations of this study included a younger, predominantly male population than previous

similar studies (mean age 54); low rates of colorectal cancer screening in both arms; and a

lower event rate than the study’s power calculation predicted. However, with these

caveats, this well-designed study shows that a screening strategy for occult cancer

including CT of the abdomen and pelvis did not lead to fewer missed cancers than a limited

screening strategy. Furthermore, the screening strategy that included CT did not appear to

shorten the time to cancer diagnosis, or reduce cancer-related mortality. Based on this

study, routine CT scan of the abdomen and pelvis after diagnosis of unprovoked VTE is

unlikely to add significant clinical benefit beyond age-appropriate cancer screening.

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Hematology / Oncology

Chemotherapy Use, Performance Status, and Quality of Life at the End of

Life Dr. Tri Le reviewing Prigerson et al. JAMA Oncol 2015 Jul 23. [Epub ahead of print]

Summary:

This month’s Hematology/Oncology Journal Watch article is co-authored by our own Dr.

Elizabeth Paulk! It was published in JAMA Oncology on July 23, 2015 and is titled

Chemotherapy Use, Performance Status, and Qualify of Life at the End of Life. It explored the

use of systemic chemotherapy in patients with end-stage metastatic solid tumor cancer

who previously failed at least 1 line of chemotherapy and who had a life expectancy of less

than 6 months. It was a prospective, multi-institutional (including Parkland and Simmons

Cancer Center) cohort analysis of 312 patients that examined the relationship of baseline

ECOG performance status, use of palliative chemotherapy and quality of life near death. The

results were troubling. It was found that palliative chemotherapy in this population failed

to improve quality of life near death and in patients with high baseline performance status,

significantly worsened performance status. While the study was not powered nor designed

to examine patient survival in relation to chemotherapy use, it is notable that there was no

survival benefit in the studied patients.

Commentary:

The goal of oncologic treatment is to make patients live better and/or longer. The results of

this study address a troubling reality of current practice in which palliative chemotherapy

is. at times, being administered to patients with futile and, worse, harmful outcomes. While

the patient population chosen was notably heterogeneous in cancer type and subtype,

chemotherapy, and responsiveness to different regimens, this study highlights the need for

further research into which patients are most likely to benefit from additional

chemotherapy at the end of life.

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Infectious Diseases

Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection Dr. Natalia Rocha reviewing The INSIGHT START Study Group, N Engl J Med. 2015 Aug

27;373(9):795-807

Summary:

According to the 2015 DHHS guidelines, initiation of antiretroviral therapy (ART) in

asymptomatic patients with HIV should be considered, regardless of CD4 count, but the

strength of evidence and recommendation varied based on CD4 count (CD4 < 350, class AI

recommendation; CD4 350-500, class AII recommendation; CD4 > 500, class BIII

recommendation). The lower strength of evidence for initiation of therapy in asymptomatic

patients with a high CD4 count (>500) was due to an absence of randomized trials

demonstrating clinical benefit and potential short- and long-term drug-related

complications. The INSIGHT START study, published in July in NEJM, was designed in

response to this gap in evidence, with the purpose to determine the risks and benefits of

the immediate initiation of antiretroviral therapy as compared with deferred initiation

until the CD4+ count is 350 cells per cubic millimeter. The study was conducted in 35

countries and enrolled 4685 HIV positive patients ages 18 and older. At time of

recruitment, all participants had CD4 count > 500 cells/mm3 and were ART naive. They

were randomized to either start treatment immediately or wait until CD4 count declined to

350 cells/mm3. Participants were followed for an average of 3 years from randomization.

The study end point had two main outcome components: 1) serious AIDS-related events or

death from AIDS; 2) serious non-AIDS-related events or death from non-AIDS related

events (cardiovascular disease, end-stage renal disease, liver disease, non-AIDS defining

cancer or causes of death not attributable to AIDS). The results showed an impressive 72%

relative risk reduction in serious AIDS related events and 39% relative risk reduction in

serious non-AIDS related event in the group receiving immediate ART. The beneficial

effects were seen across different ages, sex, races, regions of the world, viral load and CD4

count, and no increased rate of adverse outcomes was observed comparing the two groups.

Commentary:

Previous studies have concluded that antiretroviral therapy reduces the risk of sexual

transmission of HIV. However, it was unclear if a policy to treat all HIV infected individuals

would be appropriate given the lack of evidence of individual health benefit. The INSIGHT

START study was the first multi-continental randomized study able to prove that the

advantages of early antiretroviral therapy prevails over any adverse outcomes, and

strengthens the proposition to offer immediate therapy to all patients. For the first time,

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early treatment is unequivocally justified for individual health benefits in addition to

population benefits in reducing transmission.

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Nephrology

Systolic BP and Mortality in Older Adults with CKD

Dr. Jeanney Lew reviewing Weiss et al, Clin J Am Soc Nephrol. 2015 Aug 14

Summary:

In patients with pre-dialysis CKD, the relationship between systolic blood pressure (BP)

and mortality varies by age. While higher SBP (>140 mmHg) is associated with increased

mortality in the age group 65-70, this is not seen seen in those over the age of 70. There is

an increased mortality seen among CKD patients over the age of 65 with lower BP ranges

(SBP130).

BACKGROUND:

BP control has been an essential part of the management of patients with CKD. While exact

blood pressure targets have been a source of debate, more stringent goals have been

applied to patients with CKD compared to the general population. This practice is largely

motivated by higher incidence of cardiovascular events in CKD patients and observational

data suggesting decreased risk of progression of CKD with tighter BP control. The current

gap in knowledge is whether strict BP control in older CKD patients offers more benefit

versus harm.

STUDY DESIGN & POPULATION:

This retrospective cohort study found that the relationship between SBP and all-cause

mortality varies by age in older patients with CKD. The final study population included

21,015 adults age 65 or higher with stage 3-5 pre-dialysis CKD and diagnosis of

hypertension or use of anti-hypertensive medications. Patients were divided into 3 age

groups (age 65-70, 71-80, and >80 years). Each age group was further stratified into 5

categories based on baseline SBP (SBP120, 121-130, 131-140, 141-150, and >150 mmHg),

with SBP 131-140 serving as the reference group. Patients were followed for up to 11 years

from time of cohort entry. The primary outcome of all-cause mortality was evaluated as a

function of both age group and baseline SBP.

RESULTS / FINDINGS:

There was a differential relationship between SBP and mortality depending on age group.

The younger age group (65-70) demonstrated a U-shaped relationship with lowest

mortality seen in those with SBP between 131-140 (reference group) and increased

mortality with SBP lower or higher than this range. In contrast, patients older than age 70

did not demonstrate increased mortality with higher blood pressure (SBP>140). In all age

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groups studied, those with the lowest blood pressures (SBP<130 mmHg) had the highest

mortality.

Commentary:

These findings suggest that blood pressure targets in patients with CKD should be geared

towards age, with more lenient goals in older individuals. More ambitious attempts at

decreasing blood pressure may cause more harm than benefit, especially in patients over

age 70.

UTSW Link

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Implantable Cardioverter-Defibrillators in Patients with CKD: A

Propensity-Matched Mortality Analysis

Dr. Jeanney Lew reviewing Nakhoul et al, Clin J Am Soc Nephrol. 2015 Jul 7;10(7):1119-27

Summary:

In patients with pre-dialysis CKD (defined as eGFR<60 ml/min per 1.73 min2), implantable

cardioverter-defibrillators (ICDs) placed for primary prevention of sudden cardiac death

offer survival benefit in those with stage 3 disease, but not in those with stage 4 or higher.

BACKGROUND:

CKD is associated with increased cardiovascular mortality and sudden cardiac death.

Devices such as implantable cardioverter-defibrillators (ICDs) have lead to significant

improvement in mortality in select populations of patients and have become the standard

of care in these situations. However, data supporting use in those with advanced CKD is

lacking (as clinical trials on ICDs have previously either excluded or failed to mention such

subjects).

STUDY DESIGN & POPULATION:

This prospective propensity-matched case-control study included patients from an

electronic health record-based CKD registry with pre-dialysis CKD. Subjects with ICD

placed for primary prevention were matched to control patients without ICD based on a

propensity score of likelihood of receiving an ICD. The primary end point of all-cause

mortality was compared between the two cohorts. Additional mortality analysis involved

categorizing subjects within three eGFR groups (45-59, 30-44, and <30 ml/min per 1.73

min2).

RESULTS

ICDs were associated with overall mortality benefit in patients with CKD (hazard ratio

[HR], 0.69; 95% confidence interval [95% CI], 0.59 to 0.82). Further stratification based on

eGFR showed similar findings in those with eGFR 45-59 (hazard ratio [HR], 0.58; 95%CI,

0.44 to 0.77) and eGFR 30-44 (HR, 0.65; 95%CI, 0.50 to 0.85). However, those with eGFR

<30 did not experience improved mortality (HR, 0.98; 95% CI, 0.71 to 1.35).

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Commentary:

While ICDs have demonstrated overall mortality benefit in eligible patients, the question of

whether those with advanced CKD also reap similar benefits has not yet been elaborated.

This study shows that even after accounting for demographics, comorbid conditions, and

other variables related to cardiac and renal function, ICD therapy provides overall

mortality benefit in patients with CKD. However, this study suggests that this benefit

extends to those with CKD stage 3, but not to those with higher levels of renal dysfunction.

These findings should be taken into account when weighing the possible benefits vs risks of

implanting such a device in patients with advanced CKD.

UTSW Link

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Pulmonary/ Critical care

Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for

Phe508del CFTR

Dr. Fernando Woll Plenge reviewing Wainwright et al. N Engl J Med. 2015 Jul 16;373(3):220-31.

Summary:

Cystic fibrosis is a genetic disease caused by a defective CFTR protein. Delta 508

homozygous is the most common mutation (45% of the patients) found in these patients.

Lumacaftor is a CFTR co-receptor that has showed in vitro to correct CFTR misprocessing

in patients with delta 508 homozygous. Ivacaftor is an approved CFTR potentiator that

increases the open probability of CFTR channels. Neither, ivacaftor or lumacaftor

monotherapy was found to have meaningful clinical efficacy. A previous phase 2 trial

suggested that the combination might improve clinical outcomes.

The TRAFFIC and TRANSPORT trials were two phase 3, multinational, randomized, double-

blind, placebo-controlled, parallel-group studies in which lumacaftor was orally

administered in combination with ivacaftor for 24 weeks. Patients were randomly assigned

(in a 1:1:1 ratio) to one of three study groups: 600 mg of lumacaftor once daily in

combination with 250 mg of ivacaftor every 12 hours (LUM [600 mg/day]–IVA), 400 mg of

lumacaftor every 12 hours in combination with 250 mg of ivacaftor every 12 hours (LUM

[400 mg every 12 hr]–IVA), or lumacaftor-matched placebo every 12 hours in combination

with ivacaftor-matched placebo every 12 hours.

1122 patients underwent randomization. 371 where assigned to Placebo, 368 to LUM600-

IVA and 369 to LUM400-IVA. There was no difference in the demographics between the

groups. FEV1 improvements are shown in Figure 1 Improvement in the percentage of

predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded

to a mean relative treatment difference of 4.3 to 6.7% (P<0.001).. Also sub-analysis was

performed and no differences where found between the 2 treatment groups but both of

them were better than the placebo group (figure 2). Finally the treatment groups had fewer

pulmonary exacerbations as shown in figure 3. Of note the rate of discontinuation due to an

adverse event was 4.2% among patients who received lumacaftor–ivacaftor versus 1.6%

among those who received placebo.

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Comment:

Lumacaftor in combination with ivacaftor improved FEV1 and reduced the rate of

pulmonary exacerbations that makes this combination a novel therapy that should be

considered in all patients with CF and delta 508 homozygous. This medication will be

beneficial for up to 8500 patients in the United States and hopefully it can continue to

increase the life expectancy of CF patients to that of an average American.

UTSW Link

Figure 1

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Figure 2

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Figure 3

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Rheumatology

Risk of major cardiovascular events in patients with psoriatic arthritis,

psoriasis and rheumatoid arthritis: a population-based cohort study

Dr. John Matt Hancock reviewing Ogdie, et al Ann Rheum Dis. 2015 Feb;74(2):326-32.

Summary:

In this population based longitudinal cohort study from 1994 -2010 Ogdie et al show an

increase in major adverse cardiovascular events (or MACE) among patient with psoriatic

arthritis not prescribed a DMARD, RA, patients with psoriasis not prescribed a DMARD and

in patients with severe psoriasis compared to the general population after adjusting for

traditional cardiac risk factors. The major conclusion of this study is that cardiovascular

risk should be addressed with all patients affected by psoriasis or rheumatoid arthritis.

Commentary:

While it is generally well known that there is an increase in cardiovascular risk in patients

with RA and severe psoriasis, this led to the question if psoriatic arthritis is associated with

an increase in cardiovascular disease. End points used in this study included MI, CVA and

cardiac death. The study was performed using the Health Improvement Network or THIN

in the UK between 1994 and 2010, a large database in which General Practitioners record

routine data about patients.

This study included 8706 patients with psoriatic arthritis (PsA), 41,752 patients with RA

and 138,424 patients with psoriasis and 82,258 randomly selected unexposed patients

meeting inclusion criteria. Compared to the unexposed population, the prevalence of

cardiovascular risk factors, MI were elevated in patients with psoriatic arthritis RA and

psoriasis. Patients with PsA (N=8,706), RA (N=41,752), psoriasis (N=138,424) and

unexposed controls (N=81,573) were identified. After adjustment for traditional risk

factors, the risk of MACE was higher in PsA patients not prescribed a DMARD (HR 1.24,

95%CI: 1.03 to 1.49), patients with RA (No DMARD: HR 1.39, 95%CI: 1.28 to 1.50, DMARD:

HR 1.58, 95%CI: 1.46 to 1.70), patients with psoriasis not prescribed a DMARD (HR 1.08,

95%CI: 1.02 to 1.15) and patients with severe psoriasis (DMARD users: HR 1.42, 95%CI:

1.17 to 1.73). This is the first population based study dedicated to examining MACE in PsA

which may be an independent risk factor for major cardiac events including MI and stroke

although this was only statistically significant for patients who were not prescribed a

DMARD. Al three diseases had statistically similar risks for the development of incident

cardiovascular events after adjustment for age, sex, calendar year of cohort entry and

traditional cardiac risk factors.

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UTSW Link

Figure 1