Evidence for clinical interventions:

how do probiotics measure up?

Dan Merenstein, MDDirector of Research Family Medicine

Associate Professor of Family MedicineGeorgetown University

Full Disclosure

• Dannon, Sanofi, and Pharmavite have

provided Georgetown funding for separate

clinical trials or consulting

• I have been a scientific expert about

marketing claims for a probiotic product for

Bayer and Procter & Gamble

Goals• Discuss a few probiotic treatments that are

well proven

– These are examples; many others not discussed

• Use traditional treatments as comparisons

• Challenge views of outcomes and

presentation of data

Established Medical Literature

• Reviewed NEJM articles

• There were 3 research articles in weekly

issue

• I will use them as examples of expectations

NEJM-1

• Observational studies for three decades

suggest that subclinical thyroid disease

during pregnancy is associated with adverse

cognitive outcomes for children

– Some medical groups recommend testing and

treatment

• Treatment for subclinical thyroid diseases in

two large RCTs did not result in better

cognitive outcomes in children through 5

years of age compared to no treatment for

subclinical hypothyroidism

NEJM-2

• A humanized antibody against interleukin-

31 receptor A, in the treatment of atopic

dermatitis

• In the per protocol analysis 40% change

from highest dose to placebo

• Most of secondary outcomes very small

effect sizes

NEJM-3

• Blinatumomab (a bispecific monoclonal

antibody) or standard-of-care chemotherapy

for ALL

• Overall survival was significantly longer in

the blinatumomab group than in the

chemotherapy group-this is take home

message

• 7.7 months versus 4 months

Miscarriage and Caffeine

• Pregnant women are discouraged from coffee

during pregnancy

• “Caffeine Miscarriage” to google you get,

“Women who consumed 200 milligrams or

more of caffeine each day (about two cups of

regular coffee or five 12-ounce cans of

caffeinated soda) had twice the miscarriage

risk as those who didn't have any.”

Abstract Direct Quote

An increasing dose of daily caffeine intake during

pregnancy was associated with an increased risk

of miscarriage, compared with no caffeine intake,

with an adjusted hazard ratio (aHR) of 1.42

(95% confidence interval 0.93 to 2.15)

Number Needed to Treat

• Statins for MI for one year=100-427

• Vitamin D for hip fractures=50

• Antibiotics for sinusitis=15

• Aspirin for CV protection=40

• Imitrex for migraine=2.6

• Probiotics to treating colic=4

• Probiotics for preventing AAD in

pediatrics=9

• Probiotics for NEC=41

Influenza Vaccine 16-65 year olds

• 90 reports containing 116 data sets

– 69 clinical trials of over 70,000 people

– 27 comparative cohort studies (about eight million

people)

– 20 case-control studies (nearly 25,000 people)

• Overall effectiveness of influenza-like illness;

NNT = 40 (26, 128)

• Overall efficacy of preventing confirmed

influenza; NNT = 71 (64, 80)

Jefferson T, et al. Vaccines for preventing influenza in healthy adults. Cochrane

Database Syst Rev. 2014 Mar 13;(3).

Influenza Treatment Drugs• Review of 107 studies, 20 of oseltamivir (9623

participants)

• For the treatment of adults, oseltamivir reduced

the time to first alleviation of symptoms by 16.8

hours (8.4, 25.1)

• This represents a reduction in the time to first

alleviation of symptoms from 7 to 6.3 days

• NNT=36

• Oseltamivir increases the risk of adverse effects,

such as nausea (NNH=28), vomiting(NNH=22)

Jefferson T, et al. Neuraminidase inhibitors for preventing and treating influenza

in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr 10;(4).

Probiotics and Acute Infectious

Diarrhea• Review of 63 randomized controlled trials (56/63

in infants and children) of 8,014 subjects with

proven or presumed infectious diarrhea

• Administration of a probiotic agent decreased the

mean duration of diarrhea by 24.7 hours (95% CI

15.9 – 33.6 hours)

Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute

infectious diarrhoea. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD003048.

Review. PMID: 21069673.

Probiotics and URIs• 20 studies included in review

• Average decrease in illness duration was 0.5-1 day

in those who took probiotics vs placebo.

King S, et al. Br J Nutr. 2014 Jul 14;112(1):41-54.

Where Is the Evidence for The Impressive

Statement about Mammogram

“Reduces Their Risk Of Dying From Breast Cancer

By 20%”?

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Nystrom L. et al. Long-term effects of mammography screening: updated overview of

the Swedish randomised trial. Lancet 2002; 359:909-919

But What Is The

Absolute Risk Reduction?

Of 117,260 women who do not undergo mammography

about 584 (0.5%) will die of breast cancer, whereas out

of 129,750 women who do undergo mammography 511

(0.4%) will die of breast cancer.

Relative Risk Reduction = |(0.4 – 0.5)|/0.5) = 0.2 = 20%

Absolute Risk Reduction = |(0.4 – 0.5)| = 0.1 = 0.1%

Number Needed to Treat = 1/0.001 = 1000

Interpretation: 1,000 women must undergo biennial

mammography for 12 years to prevent one breast

cancer death 17

UC Meta-analysis of VSL#3

• 3 low risk of bias studies with 319 patients met the

inclusion criteria

• Remission in 44.6% of the VSL#3 patients versus

25.1% of placebo

• RRR=78%

• ARR=19.5%

• NNT=4, (5,10)

Mardini HE and Grigorian AY. Probiotic mix VSL#3 is effective adjunctive

therapy for mild to moderately active ulcerative colitis: a meta-analysis.

Inflamm Bowel Dis. 2014 Sep;20(9):1562-7.

FMT, where is the evidence?

• 7562 original articles, not studies, about FMT

• AEs 28.5% of the time

• 3, yes THREE, CDI RCTs– One fresh vs. frozen stools-enema

– One via-nasoduodenal tube

– One in C. Diff-colonoscopy, 91% vs 63% of placebo

showed improvement, 46 total patients

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Cochrane Pediatric AAD

• The incidence of AAD in the probiotic group was

8% (163/1992)

• Control group 19% (364/1906)

Relative Risk Reduction = |(0.08 – 0.19)|/0.19) = 0.58 =

58%

Absolute Risk Reduction = |(0.08 – 0.19)| = 0.11 = 11%

Number Needed to Treat = 1/0.11 = 9 (8,12)

Goldenberg JZ, PMID: 26695080

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Cochrane C. Diff

• A total of 31 trials (4492 participants), 11 studies

were rated as a high risk of bias due mostly to missing

outcome data.

Relative Risk Reduction = |(5.5 – 2.0)|/5.5) = 0.64 = 64%

Absolute Risk Reduction = 3.5%

Number Needed to Treat = 28

Conclusion: Based on this systematic review and meta-analysis of 23

randomized controlled trials including 4213 patients, moderate quality

evidence suggests that probiotics are both safe and effective for preventing

Clostridium difficile-associated diarrhea

Goldenberg JZ, et al. PMID: 2372865821

Colic

• L. reuteri DSM 17938

• Four double-blind RCTs involving 345 infants with colic

(174 probiotic, 171 placebo)

• Decreased crying -25.4 minutes [95% CI: -47.3, -3.5]

• In breastfed 28% success vs. 9%, NNT 4

• No AEs reported in any trials

Sung et al. Lactobacillus reuteri DSM 17938 is effective in breastfed infants with colic: an

individual participant data meta-analysis, Under Review

Cochrane NEC Review

• 20 studies, 5,529 infants

• Reduce incidence of severe NEC; RR=0.43, (0.33,

0.56); NNT=30

• Death; RR=0.65, (0.52, 0.81); NNT=41

• Our updated review of available evidence strongly

supports a change in practice. Head to head

comparative studies are required to assess the

most effective preparations, timing, and length of

therapy to be utilized.

AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm

infants. Cochrane Database Syst Rev. 2014 Apr 10;(4)

Cochrane Mammogram

To help ensure that the women are fully informed

before they decide whether or not to attend

screening, we have written an evidence-based leaflet

for lay people that is available in several languages

on www.cochrane.dk. Because of substantial

advances in treatment and greater breast cancer

awareness since the trials were carried out, it is

likely that the absolute effect of screening today is

smaller than in the trials. Recent observational

studies show more overdiagnosis than in the trials

and very little or no reduction in the incidence of

advanced cancers with screening.

A Tipping Point?

• 156% increase in probiotic usage in the U.S. in last 10

years, p value trend=0.03

• “Not all supplements, of course, lack evidence of efficacy.

Many supplements, including vitamins, minerals, and

probiotics, are important components of modern health

care.”

• “BOTTOM LINE Moderate-quality evidence suggests that

probiotics are associated with lower rates of antibiotic-

associated diarrhea in children (aged 1 month to 18 years)

without an increase in adverse events.”

JAMA October 11, 2016 Volume 316, Number 14

Board Review Question

• Cramping abdominal pain is the most

common symptom along with diarrhea,

constipation, or alternating diarrhea and

constipation. The goals of treatment are

symptom relief and improved quality of life.

Probiotics appear to improve symptoms.

Use Recommendation ReferencePediatric

mild UC

European Society for Paediatric Gastroenterology,

Hepatology and Nutrition (ESPGHAN) -

probiotics for children with mild ulcerative colitis

when standard therapy isn’t working

Turner et al.

2012. JPGN

AAD ESPGHAN - probiotics in prevention of pediatric AAD.

L. rhamnosus GG or S. boulardiiCanani et al.

2016

Acute

pediatric

gastro-

enteritis

ESPGHAN - probiotics in the management of

acute gastroenteritis in children

Piescik-Lech

et al. 2013.

Allergy

prevention

World Allergy Organization recommends

probiotics for allergy prevention in pregnant and

breast-feeding mothers at high risk of having an

allergic child and in infants at high risk of

developing allergic disease

Fiocchi et al.

2015. World

Allergy

Organ J

Recommendations of probiotics from global

medical organizations or authorities

World Gastroenterology

Organisation

www.worldgastroenterology.org/guidelines/global-guidelines/probiotics-and-

prebiotics

Take Home Points

• The data are there for probiotics

• Have realistic expectations; conduct and review

studies as such– NEJM study 4 vs 7 months

• Small changes are often important, especially if

costs are low and AEs not very significant

• Probiotics aren’t the flu shot, but neither is the flu

shot

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