Venous Thromboembolism: A Good Question for Pediatric Collaboration

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Two recent clinical review articles (see below) indicate that most adults with inflammatory bowel disease (IBD) admitted to the hospital would benefit from venous thromboembolism (VTE) prophylaxis.  Since children with IBD have a lower risk of VTE, it is unclear whether more efforts at VTE prophylaxis are needed in the pediatric population.  Previous studies have shown that in those IBD patients less than 20 years, the incidence rate was 8.9 per 10,000 person years.  In contrast, in those IBD patients older than 60, the incidence rate was 54.6 per 10,000 person years (VTE with IBD | gutsandgrowth).

  • Inflammatory Bowel Dis 2015; 21: 1195-1203.
  • Inflammatory Bowel Dis 2015; 21: 1204-1213.

In the first article, the authors review common risk factors and disease-specific risk factors.  They state the following:

Because hospitalization puts the patient at greater risk for TE compared with an outpatient setting, all hospitalized patients should receive anticoagulant therapy in the absence of severe bleeding, even if the patients are in remission.

The second review describes epidemiological data, pathophysiology, and VTE prevention. They also state the following:

Currently, the most effective strategy for preventing VTE in hospitalized patients with IBD with active disease is prophylactic anticoagulation.  In fact, all of the current guidelines for the management of patients with IBD suggest the use of anticoagulants to prevent VTE.

The authors note that the rates of thromboprophylaxis are “still unacceptably low.”

Bottomline: In adults with active IBD, VTE prophylaxis is recommended. In the pediatric population due to the lower incidence of VTE, more study is needed –perhaps another project for ImproveCareNow.

Briefly noted:

Cochrane Review of Vedolizumab for Ulcerative Colitis.  Inflammatory Bowel Dis 2015; 21: 1151-59.  Based on four studies (n=606 patients) with low risk of bias, pooled analysis showed that vedolizumab was superior to placebo for induction of remission (RR=0.86), clinical response (RR=0.82), endoscopic remission (RR=0.82) and for achieving remission at 52 weeks in week 6 responders (RR=2.73).  No statistically significant difference was observed in the incidence of adverse events between vedolizumab and placebo.

Zoo Atlanta

Zoo Atlanta

Lumacaftor-Ivacaftor for Cystic Fibrosis

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“Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR”  DOI: 10.1056/NEJMoa1409547

Abstract (from NEJM twitter feed):

BACKGROUND

Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTRmutation.

Full Text of Background…

METHODS

We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508delCFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.

Full Text of Methods…

RESULTS

A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute 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). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor–ivacaftor and placebo groups. 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.

Full Text of Results…

CONCLUSIONS

These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers,NCT01807923 and NCT01807949.)

Take-home point: The combination of a CFTR corrector and potentiator may “benefit patients who are homozygous for the Phe508del CFTR mutation and represents a treatment milestone for the 45% of patients with cystic fibrosis who are homozygous for this mutation.”

Related blog post: Ivacaftor for Cystic Fibrosis | gutsandgrowth

Using NSAIDs After Tonsillectomy & More on Coffee

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Many times all of the treatment choices are flawed and choosing the least worst option is required.  A recent study (Kelly LE et al. Pediatrics 2015; 135: 307-13) helps provide some useful data regarding pain management in the setting of tonsillectomy.  I chose to highlight this study because the findings seem at odds with what I would have predicted; that is, I was surprised that, in this small study, use of ibuprofen was not associated with increased bleeding risk.

Background: More than 500,000 tonsillectomies are performed on pediatric patients each year in the U.S.  Pain control afterwards has been problematic.  Codeine-containing products now have a black-box warning for post-tonsillectomy analgesia due to risk of life-threatening respiratory failure.  So choosing between a different narcotic agent like morphine or using a nonsteroidal anti-inflammatory drug (NSAID) which could contribute to bleeding is not clear cut.  While morphine’s metabolism is more predictable than codeine, all narcotics have the potential to suppress breathing.  In addition, patients undergoing tonsillectomy have a higher risk of breathing abnormalities than the general population.

Design: Randomized control trial with 91 children aged 1 to 10 years.

Key findings:

  • No significant difference in reported pain control
  • Similar frequency of tonsillar bleeing –3 in children with ibuprofen and 2 who received morphine.
  • Children in the ibuprofen group were much more likely to see an improvement in oxygen desaturations on the first postoperative night: 68% compared to 14%.
  • One child in the morphine group had a severe drug reaction requiring admittance to the intensive care unit.

Take-home point: The researchers concluded that ibuprofen is as effective as and safer than morphine for post tonsillectomy analgesia in children, without a higher risk of bleeding.

Related blog posts:

More on coffee:

I often have discussed with families how coffee can improve bowel frequency.  Here is a link on that topic from Huffington Post:  “Why Does Coffee Make You Poop?”

Previous blogs on coffee:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

PPIs and Associated Heart Risk

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A NY Times review PPIs and Heart Attacks of PLos One study showing an association between PPI usage (eg. prilosec, prevacid, and nexium) and heart attacks -this study does not prove any causality, but is likely to spark some questions. Excerpt:

The widely used drugs known as proton pump inhibitors, or P.P.I.’s — gastric reflux preventives like Prilosec and Prevacid — may increase the risk for heart attack, according to analysis of data involving almost three million people.

A significant limitation of the study, in PLOS One, is that P.P.I. usage may be a marker of a sicker patient population, more subject to heart disease in any case.

Here’s NPR’s take on the same study: Data Dive -Possible Link Between PPIs and Heart Attacks

“The increase in risk is about 16 to 20 percent, depending on the particular drug involved”…

Someone with a low risk of heart attack doesn’t have much to worry about. “If your risk of a cardiovascular event or a heart attack is one in a million, now it is 1.2 in a million,” [Nigham] Shah [one of the authors] says.

“The problem is, it’s very easy to do studies of this sort that lead to conclusions that can be misleading,” says Dr. David Juurlink, a drug-safety researcher at the University of Toronto…

“Having a bad diet, drinking too much alcohol, smoking and all sorts of other things … might lead people to be on a PPI,” Juurlink says. One would expect those people to be at higher risk of heart attack, which leads Juurlink to think the medicine is likely not to blame.”

 

Also noted:

Working on Transition Readiness

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A recent study (Gray WN, et al. Inflamm Bowel Dis 2015; 21: 1125-31) examines preparedness of patients with inflammatory bowel disease (IBD) on the verge of transitioning to adult gastroenterologists from pediatric gastroenterologists.

Using a population of 195 patients (16-25 years), the authors used the Transition Readiness Assessment Questionnaire (TRAQ).  Scoring system:

  • 5= Yes, I always do this when I need to
  • 4= Yes, I have started doing this
  • 3= No, but I am learning to do this
  • 2= No, but I want to learn
  • 1= No, I do not know how

Specific Readiness Skills & Mean Scores (more complete data listed in Table 3):

  • Taking medicines correctly and on own 4.66
  • Arranging for ride to medical appointment 4.39
  • Managing money and budgeting 3.69
  • Calling doctor about unusual change in health 3.64
  • Reordering and getting refills on time 3.60
  • Calling doctor’s office to schedule an appointment 3.09
  • Getting financial help with school or work 2.92
  • Knowing what health insurance covers 2.60
  • Applying for health insurance if coverage lost 2.44

Key finding: “Only 5.6% older adolescents/young adults …met our institutional benchmark.”

To help with transition readiness the authors recommend the CDHNF/NASPGHAN Transition Checklist for parents and starting on transition issues between 12-15 years of age.  Transition checklist available here: Transitioning a Patient With IBD From Pediatric to Adult Care –this is a simple 2-page handout!

Conclusion: Most patients need more work on transition readiness.  If patients are not prepared, it is more likely that this will lead to medical setbacks.

Briefly noted:

“Exercise Decreases Risk of Future Active Disease in Patients with Inflammatory Bowel Disease in Remission” Inflammatory Bowel Dis 2015; 21: 1063-71. This prospective study used the CCFA’s Partners’ internet-based cohort. 227 of 1308 (17.4%) Crohn’s disease (CD) patients and 135 of 549 (24.6%) Ulcerative colitis/indeterminate colitis (UC/IC) patients developed active disease after 6 months.  Key finding: Higher exercise level was associated with decreased risk of active disease for CD (adjusted relative risk 0.72) and UC/IC (adjusted relative risk 0.78).  Take-home point: While there are several limitations to this study, it does seem likely that regular physical exercise is a good idea (not just in patients with IBD).  In this population, subjective markers of disease activity (sCDAI and SCCAI) improved in those who exercised more.

Zoo Atlanta

Zoo Atlanta

Financial Relief For Patients with Hepatitis C

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From AASLD:  AASLD Financial Help for patients with HCV

Are your patients struggling to afford the costs of Hepatitis C treatments?

A new program through the HealthWell Foundation may be able to help. The HealthWell Foundation has launched a new Hepatitis C Fund. The fund provides copayment assistance to eligible patients to ease the burden of out-of-pocket costs associated with the treatment of Hepatitis C. Since 2004, HealthWell has assisted more than 200,000 adults and children faced with medical emergencies in paying for life-changing treatments they otherwise would not be able to afford. These patients have insurance, and yet cannot afford their part. To determine eligibility and apply for assistance through the HealthWell Foundation’s Hepatitis C Fund, visit HealthWell’s website. Please lend a hand by spreading the word about the fund.

Related blog posts:

Hepatitis C -Can We Really Accomplish Widespread Screening?

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A pessimist sees the difficulty in every opportunity; an optimist sees the opportunity in every difficulty.  -Winston Churchill

The aforementioned quote leads a recent editorial (Lutchman G, Kim WR, Hepatology 2015; 1455-8) which discusses the challenges of widespread Hepatitis C virus (HCV) screening and avoiding late diagnosis/missed opportunity for timely treatment.  The associated article (Moorman AC et al. Hepatology 2015; 1479-84) reviewed a large cohort of 14,717 patients with HCV and noted that 17% (n=1056) had a ‘late diagnosis’ which resulted in high rates of hospitalization and mortality.  Late diagnosis was defined as having cirrhosis at time of diagnosis or hepatic decompensation within 12 months of initial diagnosis.

The editorialists note that the related article presents data from 2006-11 which models ‘real-life’ practice settings.  Late diagnosis was more common in African-Americans and in patients with Medicare insurance.

With regard to widespread screening, pessimists argue that “we do not have coherent strategies and resources” to implement.

  • there are too few health care providers who are qualified and interested
  • the ‘treat-all” strategy is too expensive.  “For example, in the first 3 months after the release of sofosbuvir, a large commercial health insurance carrier announced that it had spent over $100 million on hepatitis C prescriptions…cause[d] a substantial drop in its stock price”
  • “while prioritizing treatment to patients who are at risk of future problems seems the optimal solution to deliver the most benefits at the lowest costs, the problems lies in the identification of those patients.”

Optimists see the opportunity for early intervention and improved outcomes.

Bottomline: While more effective treatment is available, there are still many questions, especially who should receive treatment and how to identify those most in need.  If/when costs of therapy are reduced, some of the difficult questions will resolve.

Related blog posts:

Briefly noted:

  • “Adding Pegylated Interferon to Entecavir for Hepatitis e Antigen-Positive Chronic Hepatitis B: A Multicenter Randomized Trial (ARES Study)” Brouwer WP et al. Hepatology 2015; 1512-22). “Peg-IFN add-on therapy may facilitate the discontinuation of nucleus(t)ice analogs.”
  • “The Impact of Phlebotomy in Nonalcoholic Fatty Liver Disease: A prospective, randomized, controlled trial.” Adams LA et al. Hepatology 2015; 1555-64).  “Reduction in ferritin by phlebotomy does not improve liver enzymes, hepatic fat, or IR in subjects with NAFLD”
  • “Nonalcoholic Steatohepatitis is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United States.” Wong RJ et al. Gastroenterol 2015; 148: 547-55.
Chattahoochee River

Chattahoochee River

Increasing Inflammatory Bowel Disease Among U.S. Patients From India

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An interesting epidemiology study (Malhotra R, et al. Clin Gastroenterol Hepatol 2015; 13: 683-89) shows a high prevalence of inflammatory bowel disease among U.S. residents with Indian Ancestry.

Using a national pathology database on 1,027,977 subjects who had ileocolonic biopsies from 2008-2013, the authors identified 30,812 patients who were diagnosed with inflammatory bowel disease (IBD): 20,308 with ulcerative colitis (UC), 7706 with Crohn’s disease (CD), and 2798 with indeterminate colitis (IC).

Key findings:

  • Among patients with Indian ancestry, the overall prevalence of IBD was 9.1% (n=197 compared with 1960 controls) compared with 4.3% for those of Jewish ethnicity, 2.4% for hispanic ethnicity, and 1.4% for East Asian ethnicity.  The adjusted odds ratio for patients with Indian ancestry was 2.5.
  • In addition, UC was predominant, accounting for 153 of the 197 cases; 26 were diagnosed with CD and 18 were IC.  IBD and UC were highest in subjects with roots in Gujarat.

Take-home point (from authors): “Considering the reported relatively low prevalence of IBD in India, these findings suggest that genetic factors may interact with new environmental conditions to trigger the expression of disease.”

Related blog post: Emigration -One Way to Acquire IBD

Briefly Noted:

Rungoe C, et al. “Inflammatory Bowel Disease and Cervical Neoplasia: A Population-Based Nationwide Cohort Study” Clin Gastroenterol Hepatol 2015; 13: 693-700. Using a Dutch national cohort with more than 27,000 patients, the authors showed a “2-way association between IBD, notably CD, and neoplastic lesions of the uterine cervix.” Overall the risk was mildly increased; for CD, the incidence rate ratio of cervical cancer was 1.53 (CI 1.04-2.27).

Reinisch W, et al. “Factors Associated with Poor Outcomes in Adults with Newly Diagnosed Ulcerative Colitis” Clin Gastroenterol Hepatol 2015; 13: 635-42. The tables in this article summarize clinical characteristics, biologic markers, and treatment factors associated with poor outcomes.  For clinical factors, younger age at diagnosis and age >65 years increase the risk for more severe disease. For biomarkers, increased CRP, ESR, and cal protection were associated with higher risk of progressing to colectomy. For treatment factors, not surprisingly, failing to respond to therapy and absence of mucosal healing were associated with higher risk of progressing to colectomy.

Chattahoochee River National Recreation Area

Chattahoochee River National Recreation Area

Vaccination Can Lower the Risk of a Childhood Cancer

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From NY Times: How a Childhood Vaccine Reduces the Risk of a Cancer

An excerpt:

Young children are routinely vaccinated against Haemophilus influenza type B, or HiB, a bacterium that can cause meningitis and other serious problems. But the HiB vaccine has an added benefit: It reduces the risk for acute lymphoblastic leukemia, or ALL, the most common childhood cancer, and now scientists know why.

Dr. Markus Müschen, the senior author of a new study published in Nature Immunology,… using a mouse model … found that in some cases, the HiB virus triggers a vigorous immune reaction that activates two enzymes. These enzymes can cause mutations in certain types of blood cells, driving them into malignancy. When this happens, children are more likely to develop leukemia when they are 5 to 7 years old.

Dr. Müschen, a professor of medicine at the University of California, San Francisco, said that the effect of the vaccine was a 20 percent reduction in risk for leukemia. “This seems small,” he said. “But it’s highly significant in large populations. Whatever activates the immune system early in life reduces the risk for ALL.”

Turner Field, June 6th

Turner Field, June 6th

How Does Exercise Improve Your Heart?

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Probably like a lot of people, I presumed that the main way that exercise improved cardiovascular outcomes was due to beneficial effects on weight, serum lipid levels, and adiposity. However, recent research (Liu X et al. Cell Metab 2015; 21: 584-95) has shown a critical role for microRNA miR-222.  This research is summarized by Hill JA (“Braking Bad Hypertrophy” NEJM 2015; 372: 2160-62).

Key points:

  • “Liu et al provide compelling evidence that miR-222 is up-regulated by exercise and serves to brake pathologic cardiac remodeling and release the heart (“braking the brake”) to grow in a beneficial way”
  • Thus, “exercise triggers a robust and adaptive growth response in the myocardium.”
  • “Current evidence suggests that the heart, in response to stress (eg. exercise) can help it retrace its steps and move toward “good” heart growth.”

Bottomline: “Exercise is a powerful medicine with few noorthopedic side effects.”

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.