Download 65 with no other risk factors

Proton Pump Inhibitors A Curate’s Egg? Dr John O’Malley MA MB ChB MRCGP

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This f***ing egg is off!

This is a fantastic drug

It has an important role in treating x

Why didn’t we realise it has horrendous side effects?

PPIs

£1 billion NHS costs Globally £40 Billion

Pharmacology Unstable at acid ph Parietal cell not stomach activation Act by forming a irreversible bond with cysteine residues in the proton pump Short pharmacological half life

Pharmacology 2

But.... Lasts for 24 hours No tachyphylaxis

The Proton Pump

H2 Antagonists Atropine

Proton Pump Inhibitors

Text Text

Good bits

Dyspepsia Reflux Barretts/? Prevention of cancer Prevention of strictures Diagnostic test Upper GI bleeding Ulcer prophylaxis in NSAIDs and aspirin Ulceration/ HP eradication Zollinger Ellison Syndrome

And the bad bits?

Side effects Slow response Headaches Rashes

Diarrhoea Abdominal pain Flatulence Interactions

Problems Interstitial nephritis Osteoporosis Vitamin B12 absorption C. Diff and other infections Microscopic colitis Inappropriate investigation and referral

And when we should, we don’t

Underuse

•

Gastroprotection

•

Oesophageal strictures

•

? Barrett’s oesophgus

Gastroprotection

NICE 2001 •

Recommendations for patients for whom a regular NSAID is absolutely necessary:

•

Patients at any age with existing cardiovascular disease, including patients on low dose aspirin: Standard NSAID e.g. ibuprofen, diclofenac or naproxen +misoprostol or PPI if misoprostol not tolerated.

•

Patients aged 65+ with no cardiovascular risk factors and not onaspirin:

•

Consider Cox-II selective inhibitor (not sure on that one!)

•

All other patients i.e. patients < 65 with no other risk factors*:

•

• Standard NSAID e.g. ibuprofen or diclofenac

Risk factors for GI complications with NSAIDs • •

Age Previous ulcer, bleed or perforation

•

Concomitant drug treatment (steroids,anticoagulants, SSRIs)

•

Co-morbidity (CVD, renal and hepatic impairment, etc.)

•

Rheumatoid Arthritis

•

NSAID dosage and duration.

HP eradication Maastricht -3 2005 •

Chronic NSAID users

•

Naive NSAID users – test and treat

•

Long term aspirin users – test and treat

•

PPI is superior in preventing ulcers

Risk of NSAID related gastrointestinal bleeding by age for population 100,000 Age Range

Number taking NSAID

Number with GI bleed

Risk in any one year of a GI bleed due to NSAID

Risk in any one year of dying from GI bleed due to NSAID

16-44

2100

1

1 in 2100

45-64

3230

5

1 in 646

1 in 12353 1 in 3800

65-74

2280

4

1 in 570

1 in 3353

75+

1540

14

Anon. Cox-21 roundup. Bandolier 1 in 110 in 647 2000;75

ACUTE Vs CHRONIC NSAID USE Drug exposure

OR (95%CI) for GU

OR (95% CI) for DU

Non use

1

1

Acute use

4.47 (3.19-6.26)

2.39 (1.73 – 3.31)

Chronic use

2.80 (1.97 – 3.99)

1.68 (1.22- 2.33)

SSRIs AND UGIH •

“Our meta-analysis shows that SSRIs

•

more than double the risk of UGIH and

•

concomitant NSAID use increase the risk

•

of UGIH by 500%”

Loke et al. Alim. Pharm. Therapeutics 2007

SSRIs: NUMBER NEEDED TO HARM Patient population

Baseline upper GI Event Rate

NNH per year with SSRI ( 95% CI)

NNH per year with SSRI AND NSAID( 95% CI)

Unselected >50 23 years

318 (152- 979)

82 (41-181)

No previous ulcer drug use or hospitalisation Ulcer drug

18

411 (196- 1266) 106 (52-233)

42

177 (85-545)

46 (24- 101)

Hospitalisation

62

121 (58 – 370)

32 (17-69)

Ulcer drug use and hospitalisation

108

70 (34 -214)

19 (10-41)

SSRIs and NSAIDs

Do PPIs work? Drug

Risk of UGIB

NSAID

5.3

Rofecoxib

2.1

Paracetamol

0.9

NSAID and PPI

0.9

Number needed to treat to avoid a peptic ulcer in elderly NSAID/aspirin users...........

3

Compliance - GPs “In individual studies in primary care adherence to prescribing guidelines varied from 9% to 27%.”

Compliance - patients “...adherence to NSAID plus PPI or H2RA declined rapidly, so that after 6 months the majority of patients were not taking gastroprotection prescribed.” Moore et al. BMC Musculoskeletal Disorders 2006; 7:79

Cost Resource

Mean cost £

Minimum

Maximum

Diagnostic endoscopy Therapeutic endoscopy GI opd Surgical procedure Rebleed costs

435.38

282.68

650.67

1158.61

682.1

1532.73

72 3181.80

50 1731

84 3804.13

17025

14619

19964

Omeprazole cost

• 28

days of 20mg/day =£1.62

Conclusion

•

Right person with the right drug gives the right outcome

Problems Interstitial nephritis Osteoporosis Vitamin B12 absorption C. Diff and other infections Microscopic colitis Inappropriate investigation and referral

Interstitial nephritis

Interstitial nephritis 15% of all acute admission with acute kidney damage Immune mediated? Can lead to severe kidney damage Who checks kidney function?

Osteoporosis UK study (GPRD) 13,556 patients with hip fracture Risk 1.4 after using PPI for >1 year Risk 2.65 if long term high dose

Causal? Reduces absorption of dietary calcium Inhibits magnesium absorption

Also inhibit osteoclasts ? Prevent osteoporosis Coincidental?

Iron deficiency

Iron absorption

? Long term, high dose PPI link Theoretical but not proven

Vitamin B12 Deficiency

B12 bound to protein

Pepsin needed B12 levels reduced but significant deficiency?

Infections

PPI use and Salmonella/ campylobacter

Clostridium Difficile infection Gram positive bacteria Anaerobic spore forming Severe diarrhoea Can lead to pseudomembranous colitis Toxic megacolon Absent gut flora

PPI problems

Often taken as antacids

Not all reflux is acid Misdiagnosis

50-60% of PPI scripts there is no or an inappropriate reason for prescribing £100 million in the NHS wrongly prescribed £2 billion worldwide Decrease in price but increase use has increased costs PPIs make up 90% of the drug budget for dyspepsia

63%

33%

67%

NICE NICE Guidance 2000 Treat with healing doses then step down Shortest length of treatment with smallest dose No long term use without definitive diagnosis

NICE Dyspepsia Guidelines 2004 Check if PPI needed Lifestyle advice

Avoid precipitants Educate Review need

So who do we need to treat more?

Who should we treat more?

NSAID Aspirin

And who less?

Rebound hyperacidity

Prolonged treatment

Increased parietal cell mass Peaks at 2 weeks.

Problems caused

Increased use of PPIs

Unwillingness to try step down Gastroscopies

Overuse/ wrong use 40% ‘unknown reason’ Mean duration of use 450 days 50% taking drugs that cause or worsen GORD 18% smokers

GORD and effect of medication

H2 blockers 30-60 minutes PPI 24 hours

Step down

42% couldn’t be stepped down 43% reduced need for PPI or changed to antacid/alginate or H2RA 15% stopped completely

Lifestyle

Lifestyle changes •

Obesity

•

Smoking

•

Raising the head of the bed

•

Decrease fat intake ( chocolate, peppermint, garlic and onions)

•

Large volume meals

•

Rich energy dense meals

•

Low dietary fibre

•

Alcohol decrease

Lifestyle

•

Only reduce severity and frequency

•

Very few patients do it well

•

And some don’t want to........

PPIs

•

Used too much

•

Used not enough

•

‘Lifestyle drug’

Thank you