Burning issues with PPI

Prof. Angel Lanas

Universidad de Zaragoza. España

Berlin, June 2013

Topics

1. PPI oral vs IV for Peptic Ulcer Bleeding, the new

chalenge

2. PPI and clopidogrel interaction. I

3. PPI and pneumonia

4. PPI and NSAID-induced bleeding in the Lower GI tract

5. Overuse of PPI

Statement C3:

• An intravenous bolus followed by continuous-

infusion proton-pump inhibitor should be used

to decrease re-bleeding and mortality in

patients with high-risk stigmata having

undergone successful endoscopic therapy.

• Agree 94% (Vote: a 65%, b 24%, c 6%, d 3%, e 0%, f 3%; GRADE:

high, 1a Strong recommendation, “do it”) high-quality evidence

Barkun A, et alAnn Intern Med. 2010 Jan 19;152(2):101-13.

Effect of Proton-Pump Inhibition in Peptic-Ulcer Bleeding

Gralnek I et al. N Engl J Med 2008;359:928-937

PPI IV and outcomes in PUB:

Sung JJ y cols. Aliment Pharmacol Ther 2008;27:666–77

PUB Study : Methodology

Recruitment: Endoscopic Treatment

(0 – máx. 24 horas)

Esomeprazole oral, 40 mg once daily

Esomeprazole oral, 40 mg once daily

Esomeprazol i.v.,

80 -30 min followed by

esomeprazole i.v., 8

mg/h for 71,5 h

Placebo i.v. for 30 min followed by placebo i.v. for 71,5 h

A

Treatment oral (27 days)

Treatment i.v. (72 h)

Sung JJ et al. Ann Intern Med 2009; 150:455-64

PUB study: Rebleeding at 72 hours

% o

f patie

nts w

ith re

ble

ed

ing

at 72

ho

urs

n at risk

Esomeprazole 375 347 335 330 327 325 324

Placebo 389 342 326 321 317 316 314 312 311 310 309

30 day re-bleeding rate using effective acid suppression

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Days from randomisation

p=0.0092

esomeprazole

placebo

Cu

mu

lati

ve p

erce

nta

ge (

%)

13.6% (n=53)

7.7% (n=29)

0

2

4

6

8

10

12

14

16

18

Sung et al. Ann Intern Med 2009;150:455–64

Laine et al. Clin Gastroenterol Hepatol 2009; 7: 33-47

PPI IV and outcomes in PUB:

RCT to:

A.- Esomeprazole: 240 mg cont. IV infusion/24 h – 3 d, then 40m/24 h – 60 days

B.- Lansoprazole: 30 mg/ 6h – 3 days, then 30 mg/24 h – 60 days

Main Outcome : Rebleeding at day 15.

Yen et al. BMC Gastro 2012

RCT to

1. Rabeprazole 20 mg/12 hours vs

2. Esomp bolus 80 mg + 8mg/h - 3 days

N = 106 (underpowered)

Rebleeding rates at 3 days:

Rabeprazole: 3.9% vs Esomp : 1.9%

Gastroenterology Research and Practice; 2012, Article ID 317125, 8 pages

A comparison of oral omeprazole 40mg /12 h

and placebo for bleeding peptic ulcer.

No endoscopy therapy

p<0.001

p<0.05

Khuroo et al. N Engl J Med 1997;336:1054-8.

Topics

1. PPI oral vs IV for Peptic Ulcer Bleeding, the new

challenge

2. PPI and clopidogrel interaction.

3. PPI and pneumonia

4. PPI and NSAID-induced bleeding in the Lower GI tract

5. Overuse of PPI

0%

2%

4%

6%

8%

10%

12%

14%

0 100 200 300 400

No PPI

PPI

PPI

No PPI

CV

de

ath

, MI o

r st

roke

Days

CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

Primary endpoint stratified by use of a PPI

O’Donoghue ML, Braunwald E, Antman EM, et al. Lancet. 2009.

Days

Su

rviv

al P

rob

ab

ility

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.9

00

.92

0.9

40

.96

0.9

81

.00

Placebo

Treated

Survival Curves for PPI Treated vs Placebo

Composite Cardiovascular Events

Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status

HR = 1.02 95% CI = 0.70; 1.51

Placebo: 67 events, 1821 at risk Treated: 69 events, 1806 at risk

Placebo

Treated

Placebo group = ASA + Clopidogrel + Placebo Treated group = ASA + Clopidogrel + Omeprazole

Bhatt DL, et al NEJM 2010

Concomitant use of clopidogrel and PPI: impact on platelet

function and clinical outcome- a systematic review

Fock et al. Heart 2013;99:520–527

Conclusions Despite indications of reduced antiplatelet activity ex vivo in the case of PPI administration in clopidogrel users, data on the clinical consequences are controversial. This review challenges the validity of conclusions based on quantitative analyses of predominantly non-randomized data.

MACE

Topics

1. PPI oral vs IV for Peptic Ulcer Bleeding, the new

challenge

2. PPI and clopidogrel interaction

3. PPI and pneumonia

4. PPI and NSAID-induced bleeding in the Lower GI tract

5. Overuse of PPI

Are proton pump inhibitors associated with the

development of community acquired pneumonia?

A meta-analysis

Giuliano C et al. Expert Rev. Clin. Pharmacol. 5(3), 337–344 (2012)

Are proton pump inhibitors associated with the

development of community acquired pneumonia?

A meta-analysis

Giuliano C et al. Expert Rev. Clin. Pharmacol. 5(3), 337–344 (2012)

Proton Pump Inhibitors and the Risk of Hospitalization

for Community-Acquired Pneumonia (HCAP):

Replicated Cohort Studies with Meta-Analysis

• 8 restricted cohorts of new users of NSAIDs,

– aged > 40 years using a common protocol I

– 8 databases (Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, U.S. MarketScan, and the

United Kingdom’s General Practice Research Database [GPRD]).

• This specific patient population was studied to minimize bias due to unmeasured

confounders.

• High-dimensional propensity scores were used to estimate site-specific adjusted odds

ratios (aORs) for HCAP at 6 months in PPI patients compared to unexposed patients.

• 4,238,504 new users of NSAIDs, 2.3% also started a PPI.

• PPIs: (adjusted OR = 1.05; 95% CI = 0.89, 1.25).

• Histamine-2RA (adjusted OR = 0.95, 95% CI = 0.75, 1.21).

CONCLUSION: PPI USE WAS NO ASSOCIATED WITH COMMUNITY

ADQUIRED PNEUMONIA

Filion KB, et al. Gut 2013 (in press),

Topics

1. PPI oral vs IV for Peptic Ulcer Bleeding, the new

challenge

2. PPI and clopidogrel interaction.

3. PPI and pneumonia

4. PPI and NSAID-induced bleeding in the Lower GI tract

5. Overuse of PPI

*Modified intent-to-treat population.

Capsule endoscopy: Celecoxib vs traditional NSAID plus PPI in the lower GI tract

Double-blind randomised 2-week prospective studies Healthy subjects with small bowel mucosal breaks*

1. Goldstein J et al. Clin Gastroenterol Hepatol 2005;3:133-141

2. Goldstein J et al. Ali Pharmacol Ther 2007;25:1211-1222

Celecoxib 200mg bid vs naproxen 500mg bid + omeprazole 20mg qd1

p = 0.04

Naproxen + omeprazole

(n = 111)

Celecoxib

(n = 115)

Placebo

(n = 113)

Sub

ject

s w

ith

sm

all b

ow

el

mu

cosa

l bre

aks

(%)

p < 0.001 p < 0.001

16

7

55

0

10

20

30

40

50

60

Celecoxib 200mg bid vs ibuprofen 800mg tid + omeprazole 20mg qd2

Celecoxib

(n = 109)

Ibuprofen + omeprazole

(n = 112)

Placebo

(n = 113)

6.4

25.9

7.1

0

5

10

15

20

25

30

p < 0.001 p < 0.001

p = 0.776

Sub

ject

s w

ith

sm

all b

ow

el

mu

cosa

l bre

aks

(%)

Celecoxib 2238 2101 2000 1911 1858 1769 1117 57 17

Diclofenac +

omeprazole

2246 2095 1921 1792 1734 1653 1060 53 10

Cu

mu

lati

ve I

nci

de

nce

of

Ad

jud

icat

ed

C

linic

ally

Sig

nif

ican

t Ev

en

ts T

hro

ugh

th

e G

I tra

ct

Days From First Dose

Log rank P < 0.0001

Celecoxib 200 mg bid (N = 2238)

Diclofenac SR 75 mg bid +

omeprazole 20 mg qd (N = 2246)

1 0

9

8

7

6

5

4

3

2

1

0

0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0 2 1 0 2 4 0

Condor: Primary End Point

1 Chan et al. Lancet 2010 (

ORs of Lower GI bleeding by drug use

Adjusted OR (CI 95%) adjusted. LGIB/Controls

*Adjusted for age, gender, calendar semester, ulcer history, protom pump inhibitors, antiplatelets, coxibs, NSAIDs and aspirin use Lanas et al . DDW 2012

PPI may contribute to increase the Small Bowel damage induced by NSAIDs

Wallace et al. Gastroenterology 2011

PPI – NSAID Small Bowel damage and bacteria

Wallace et al. Gastroenterology 2011

Effect of Probiotics in patients taking aspirin with unexplained anemia

35 patients on low-dose enteric-coated aspirin 100mg daily (for more than 3 months) plus omeprazole 20 mg daily and diagnosed as having unexplained iron deficiency anemia

Patients received probiotic with Lactobacillus casei for 3 months (L. casei group) or not receive the probiotic (Control group).

Endo H, et al Gastroenterology. 2012;142 Suppl 1:S1066

Significant decreases in the number of lesions in the L. casei group as compared with the results in the Control group.

Increase in the hemoglobin concentration from the baseline to the post-treatment was greater in the L. casei group than that in the Control group, however, the difference did not reach statistical significance (P = 0.183).

Endo H, et al Gastroenterology. 2012;142 Suppl 1:S1066

Topics

1. PPI oral vs IV for Peptic Ulcer Bleeding, the new challenge

2. PPI and clopidogrel interaction.

3. PPI and pneumonia

4. PPI and NSAID-induced bleeding in the Lower GI tract

5. Overuse of PPI

Ulcer bleeding complications are decreasing with time at least in some countries

Lanas A et al. Am J Gastroenterol 2009

Hospitalisations due to GI events in Spain in 10 years time

Estimated rates per 100,000 people per year 100

90

70

60,

50

40

30

20

10

0

80

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Upper GI

Lower GI

Undefined GI

PPI Prescriptions by Country

Source: IMS Health, IMS MIDAS (MAT to December 2009, Prescriptions)

Notes: These data cover PPIs prescribed to patients with osteoarthritis or rheumatoid arthritis. The data source does not show whether they were

co-prescribed with NSAIDs

Trends in Pain Management in Europe

0

2.000

4.000

6.000

8.000

10.000

12.000

14.000

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

Years

Sta

ndar

d U

nits

(m

illio

ns)

PPIstNSAIDsCOX-2 inhibitors

Source: IMS Health, IMS MIDAS (MAT to November 2010, Standard Units)

Notes: “Standard Units” = tablets, capsules, etc; These data cover all indications.

Eid SK, et al. Intern Med 2010; 49: 2561-2568)

PPI Use Innapropriate Use of PPI

Addmision Addmision

Hospital. Hospital. Discharge Discharge

Inapropiate use of PPI during Hospitalization

Most common reasons

– GI prevention of Antiplatelet agents

– Stress Ulcer prevention

76% of patients on PPI at addmission are mantained on PPI till discharge

Rate of adverse effects due to interaction:

2,6/1000 patients

Ramirez E, et al. Curr Pharm Ther 2010

C. Difficile infection Risk

Risk of Clostridium difficile recurrence with proton-pump inhibitor (PPI) use.

Kowck et al. Am J Gastroenterol 2012; 107:1011–1019

¡ Thanks so much !

Hospital Clínico Universitario. Zaragoza. España