3. Indications for use of NSAIDs
Analgesic - Anti-inflammatory - Antipyretic - Antithrombotic
• Rheumatic diseases (8% of people at any time)
• Prophylaxis of stroke & myocardial infarction
• Reduction of colorectal cancer
• Reduction of colorectal adenomatous polyps
• Treatment of Alzheimer’s disease
4. NSAID prescribing in Europe (1997)
Country Percentage
Belgium 5.3%
England 5.0%
Irish Republic 8.4%
Italy 11.0%
Northern Ireland 7.8%
Portugal 8.5%
Scotland 5.7%
Spain 7.0%
Overall 7.7%
Adapted from P Jepson, unpublished data, 1999.
Jones R. Am J Med 2001 ; 110 : 4S – 7S.
5. Use & cost of NSAIDs in USA in 1997
• 13 million people use NSAID regularly for various arthritides
• Hospitalizations for serious GI complications: 100 000/year
• Costs of complications > $ 2 billions/year ($ 20 000/ hosp)
• NSAID-related death: 16 500/year (15th most common cause)
• Total cost of NSAIDs use > $ 6 billions/year
Public greatly underestimate risks associated with NSAIDs use
J Rheumatol 1999 ; 26 : suppl 26 : 18 – 24.
6. US mortality from 7 selected disorders in 1997
NSAID complications represents 15th most common cause of death
Statistics don’t include deaths due to OTC NSAIDs
J Rheumatol 1999 ; 26 : suppl 26 : 18 – 24.
“Silent epidemic”
7. Sales of Bayer Aspirin
• the 1940s 100 million DM
• the mid-1990s 800 million DM annually
• 21th century Projected sales 2 billion DM per year
Jones R. Am J Med. 2001; 110: 4S – 7S.
“Aspirin” registered in 1899
Felix Hoffmann (chemist with Bayer in Germany)
8. Side effects of NSAIDs
Cardiovascular Serious CV events: MI – Stroke
Gastrointestinal GI symptoms – endoscopic lesions – GI ulcers
Renal Retention of sodium & fluid – Acute renal failure
Interstitial nephritis – nephrotic syndrome – papillary necrosis
Hepatic Modest elevation of aminotransferases (< 2-3 fold)
Acute liver injury
CNS Aseptic meningitis – Headaches – Dysphoria
Tinnitus & hearing loss Frequent in high doses of aspirin – Occurs in other NSAIDs
Neutropenia
Hypersensitivity reactions
Imboden JB et al Current diagnosis & treatment in rheumatology.
McGrawHill, Boston, MA, USA, 2nd edition, 2007.
9. Choice between various NSAIDs dominated by
“least harm principle”
balancing various potential adverse events
Key consideration when selecting NSAIDs
Cardiovascular risk
followed by risk of GI adverse events
10. NSAID-related cardiovascular morbidity
• Increased blood pressure Average of 5 mm Hg
• Congestive heart failure
• Serious CV events Myocardial infarction
Stroke
Risser A et al. Am Fam Physician 2009 ; 80 : 1371 – 1378.
11. VIGOR study
VIGOR: Vioxx Gastrointestinal Outcomes Research
Nissen SE et al. JAMA 2001; 286 : 954 – 959.
8,076 RA patients – Rofecoxib 50 mg qd vs naproxen 500 mg bid
Exclusion: Stroke, MI, CABG, aspirin, or gastroprotective agent
MI higher in rofecoxib than in naproxen group
13. Myocardial infarction of Coxibs versus NSAIDs
Kearney PM et al. BMJ 2006 ; 332 : 1302 – 8.
Naproxen may have some cardioprotective properties
14. GI side effects of NSAIDs
Organ Side Effects
Esophagus Esophagitis – Ulcer – Stricture
Ano-rectum Inflammation – Ulcer – Stricture
Stomach & duodenum Subepithelial hemorrhage – Erosion – Ulcer
Small Intestine Ulcers – Strictures – NSAID enteropathy
Colon No pre-existing colonic disease:
Ulcerations – Stricture – Diaphragm – Colitis
Pre-existing colonic disease:
↑ Complications of diverticular disease
Activate IBD
15. Complicated ulcers
1 – 1.5% in first year
Clinical ulcers
4 – 5%
Endoscopic ulcers
30%
Relative Severity
GI symptoms
40%
Relative Frequency
NSAID-related gastro-duodenal side effects
16. NSAIDs gastropathy
Arthritis Rheum 1995 ; 38 : 5 – 18.
Confined to mucosa
Erosion
Extend into submucosa
> 3 or 5 mm
Ulceration
No break in mucosa
Hemorrhage
Endoscopic definition more practical
Erosion: Small & superficial
Ulceration: Larger ( > 5 mm) & deeper
17. Stage Characteristics Rebleeding
I a Jet arterial bleeding 90 %
Ib Oozing 50 %
IIa Visible Vessel 25 – 30 %
IIb Adherent clot 10 – 20 %
IIc Black spot in ulcer crater 7 – 10 %
III Clean base ulcer 3 – 5 %
Forrest’s classification for PU bleeding
18. Forrest’s classification for PU bleeding
III (clean base)II-b (adherent clot)
II-a (visible vessel)I-b (oozing)
II-c (black spot)
I-a (arterial jet )
21. Pathogenesis of NSAID-induced GI Injury
Three main components
Best Pract Res Clin Gastroenterol 2001 ; 15 : 691 – 703.
22. GI safety of non-selective NSAIDs
RR of different NSAIDs could differ 10-fold
* Risk at higher doses (> 1.5 –2.4 g/d) comparable to others NSAIDs
Br Med J 1996 ; 312 : 1563 – 1566.
Lowest risk Ibuprofen *
Diclofenac
Moderate risk Indomethacin
Naproxen
Sulindac
Aspirin
Highest risk Azapropazone
Tolmetin
Ketoprofen
Piroxicam
Longer half-time
23. Differences between Cox-1 & Cox-2
COX-1
Housekeeping
COX-2
Inflammation
Regulation Constitutive Inducible
Range of expression 2 – 4 fold 10 – 80 fold
Tissue Expression Most tissues notably
Platelets
Endothelial cells
Kidneys
Stomach
Inflammatory sites
Synoviocytes
Fibroblasts
Monocytes
24. Clinical ulcer complications with COX-2s vs NSAIDs
Rostom A et al. Clin Gastroenterol Hepatol 2007 ; 5 : 818 – 828.
Cochrane Collaboration Systematic Review
8 studies – 73 449 patients – POB
25. RR of UGI bleeding/perforation from NSAIDs
Systematic review of observational studies since 1990
n values: number of studies
Asterix: reported in studies published after 2000
Massó González EL et al. Arthritis Rheum 2010 ; 62 : 159 2 – 1601.
26. Major GI bleeding in low dose aspirin
14 RCTs – over 57 000 patients
McQuaid KR et all. Am J Med 2006 ; 119 : 624 – 638.
Major GI bleeding: fatal – hospitalization – transfusion
Low dose asipirin: 75 – 325 mg/day
NNH during 1 year period: 833
27. Risk of UGI bleeding with aspirin
Daily aspirin dose Odds ratio (95% CI)
Any 3.2 (2.3 – 4.4)
75 mg 2.3 (1.2 – 4.4)
150 mg 3.2 (1.7 – 6.5)
300 mg 3.9 (2.5 – 6.3)
Weil J et al. BMJ 1995 ; 310 : 827 – 30.
Risk of bleeding with aspirin is dose related
28. Major GI bleeding & type of aspirin
550 incident cases & 1202 controls, 28 MA hospitals
Aspirin RR of UGI bleeding
≤ 325 mg > 325 mg/day
Plain 2.6 5.8
Enteric-coated 2.7 insufficient data
Buffered 3.1 7.0
Kelly JP et al. Lancet 1996 ; 348 : 1413 – 16.
Same risk for plain, buffered & enteric-coated aspirin
29. Risk factors for NSAID-related ulcer complications
Scheiman JM. Drugs 2006 ; 66 : 15S – 21S.
30. Helicobacter pylori eradication in prevention
of peptic ulcer in NSAID users
Vergara M et al. Aliment Pharmacol Ther 2005 ; 21 : 1411 – 1418.
Testing for HP infection & eradicating infection if positive
in patients requiring long-term NSAID therapy
31. Prevention strategies of GI risk due to NSAIDs
• Avoid use of NSAID & substitute with acetaminophen
• Use “safer” NSAID: Diclofenac, ibuprofen, coxibs
• Avoid NSAID with higher toxicity: Ketorolac, piroxicam
• Use lowest effective dose for shortest period of time
• Avoid concomitant therapy with:
Anticoagulants, corticosteroids, low-dose aspirin, APT
• Eradicate HP infection in patients with prior ulcer history
Sostres C et al. Best Pract Res Clin Gastroenterology 2010 ; 24 : 121 – 132.
34. Primary prevention of MIs by aspirin
Current situation of evidence
Men Women
Low risk No trial No benefit
Intermediate risk No benefit No benefit
High risk Reduced MI No trial
Kappagoda T et al. J Cardiopulmo Rehabil Prev 2011 ; 31 : 1 – 8.
Dose of aspirin: 500 mg/d (British Male Doctors’ Study)
100 mg on alternate days (Women’s Health Study)
35. Primary prevention of CV events & aspirin
97,387 adults aged > 40 years
CV risk % of patient taking low-dose aspirin
(ATP III)* Male Female
High risk (14%%) 59% 46%
Intermediate risk (48%) 31% 27%
Low risk (38%) 25% 18%
* According to Adult Treatment Panel III definitions (ATP III)
Kim C, et al. Am J Prev Med 2004 ; 27 : 1 – 7.
38. Strategies used during the 20th century for
counteracting action of gastric acid
Inflexion occurs during the 1980s
with introduction of drugs inhibiting gastric acid secretion
Dı az-Rubio M. Drugs 2005 ; 65 (Suppl. 1) : 1 – 6.
39. “Potent acid inhibition”
• pH > 4 1000-fold ↓ H concentration in stomach
Reduced the pepsin activity
• At least 16 h No clear evidence to 16 h as cut-off
Used in many studies
Described arbitrarily as maintaining an intragastric
pH > 4 for at least 16 h out of every 24 h
42. Patients at increased risk for NSAIDs CV toxicity
High risk Patients with risk factors for CV disease often
receive prophylactic aspirin
Arbitrarily defined as requirement for low-dose
aspirin for prevention of serious CV events
Low risk No risk factors
43. Patients at increased risk for NSAIDs GI toxicity
High risk 1. History of complicated ulcer especially recent
2. Multiple (> 2 risk factors)
HP is independent & additive risk factor & addressed separately
ACG guidelines for prevention of NSAID-related ulcer complications .
Am J Gastroenterol 2009 ; 104: 728 – 738.
Moderate risk
(1 – 2 risk factors)
1. Age > 65 years
2. High dose NSAID therapy
3. Previous history of uncomplicated ulcer
4. Concurrent use of aspirin
5. Concurrent use of corticosteroids
6. Concurrent use of anticoagulants
Low risk No risk factors
44. Prevention of NSAID-related ulcer complications
Naproxen may have some cardioprotective properties
Patients with ulcer history: search for HP & if present eradicated
ACG guidelines for prevention of NSAID-related ulcer complications.
Am J Gastroenterol 2009 ; 104: 728 – 738.
NSAID alone
(least ulcerogenic
at lowest dose)
NSAID
+
PPI/misoprostol
Alternative therapy
or
Coxibs + PPI/misoprostol
Naproxen
+
PPI/misoprostol
Naproxen
+
PPI/misoprostol
Avoid NSAIDs & coxibs
Use alternative therapy
High GI riskModerate GI riskLow GI risk
Low CV risk
High CV risk
45. SENSAR software
Appropriate use of NSAIDs in chronic rheumatic disease
• 18 experts from 10 European countries
• English-language literature from 1998 to 2008
• Three panel meeting: January, June, & November 2008
• 144 different patient profiles & 10 treatment options
• Research & Development at UCLA(RAND/UCLA)
• Statement: Appropriate – Uncertain – Inappropriate
• Coordinated by Center for Decision Analysis & Support
• Supported by Pfizer Inc
http://www.e-hims.com/Sensar/
46. European expert panel on appropriate use of NSAID
Name Speciality Country
1- Gerd R Burmester Rheumatology Germany
2-Francis Berenbaum Rheumatology France
3- Ferdinand Breedveld Rheumatology The Netherlands
4- Maxime Dougados Rheumatology France
5- Emilio Martín Mola Rheumatology Spain
6- Ignazio Olivieri Rheumatology Italy
7- Josef Smolen Rheumatology Austria
8- Stefan Lohmander Orthopaedics Sweden
9- Luigi M Biasucci Cardiology Italy
10- Matthias Hermann Cardiology Switzerland
11- Tom MacDonald Cardiology and Clinical Pharmacology UK
12- Chris Hawkey Gastroenterology UK
13- Angel Lanas Gastroenterology Spain
14- Carmelo Scarpignato Gastroenterology and Clinical Pharmacology Italy
15- Adam Bajkowski Family Medicine UK
16- Peter Dieleman Family Medicine Belgium
17- Tony Mets Geriatrics Belgium
18- Nele Van Den Noortgate Geriatrics Belgium
48. SENSAR software
Appropriate use of NSAIDs in chronic rheumatic disease
• Electronic tool may offer best opportunities as quick
reference guide to panel results
• In the complex and dynamic area of NSAID use:
Such approach offer best chances of benefiting from
perspective of both science & practice
http://www.e-hims.com/Sensar/
Burmester G et al. Ann Rheum Dis 2011 ; 70 : 818 – 822.
49. Fries JF et al. Arthritis Rheum 2004; 50: 2433 – 4.
Declining risk of NSAID-induced GI complications
RA patients with serious GI events (hospitalization)
5598 patients followed over 20-year period
Dotted line: second-degree spline-fitted curve
Reduction of 67% in serious GI complications since 1992
50. Six available PPIs
Generic name Trade name Daily dose Route
Delayed release PPIs
Omeprazole Losec® 20 mg Oral
Lanzoprazole Lanzor® 30 mg Oral – IV
Pantoprazole Protonix® 40 mg Oral – IV
Rabeprazole Pariet® 20 mg Oral
Esomeprazole Nexium® 40 mg Oral – IV
Are all PPIs the same?
Immediate release PPIs
OMP Na bicarbonate Zegerid® 20 mg Oral
51. Major metabolic pathways for various PPIs
De Argila CM. Drugs 2005; 65 (Suppl. 1) : 97 – 104.
Contribution of each isoenzyme represented by thickness of arrow
Rabeprazole: Important non-enzymatic metabolism
Pantoprazole: sulfotransferase not saturable
52. Helpful facts on the use of PPIs
• Take twice daily for first 2 – 3 days of therapy
Steady state is not reached for a couple of days
• First dose should be ½ hour before breakfast
• Second dose, if used, should be ½ hour before dinner
• Not likely to be effective when used as required
Wolfe MM, Sachs G. Gastroenterology 2000; 118: S9 – S31.
53. PPI dose adjustment
• Renal failure No repercussion on PPI elimination
No need to adjust dosage
• Liver failure Half-life increases to 4 – 8 h (nl: 1 h)
Reduction of dosage
• Aged patients No dosage adjustment usually
Adjustment if hepatic or renal failure
is added to advanced age
de Argila CM. Drugs 2005; 65 (Suppl 1) : 97 – 104.
54. Which PPIs?
Efficacy
Esomeprazole Slightly more effective
Refractory ulcer & difficult GERD
IR-omeprazole Quick onset of action – NAB*
Interactions with other drugs
Less interaction in rabeprazole & especially pantoprazole
Dose adjustment in AVK, benzodiazepines, phenytoin
PPI & Clopidogrel: COGENT trial
Cost considerations
* NAB: Noctural Acid Breakthrough
55. COGENT trial – Cardiovascular outcomes
4.9%
5.7%
P= 0.98
Log rang test
* DAT: Dual Antiplatelet Therapy (clpidogrel & aspirin)
Bhatt DL et al. N Engl J Med 2010 ; 363 : 1909 – 1917.
RCT – 3761 patients – Omeprazole vs placebo in DAT*
Death, nonfatal MI, revascularization, or stroke
56. COGENT trial – Gastrointestinal outcomes
1.1%
2.9%
P<0.001
Log rang test
* DAT: Dual Antiplatelet Therapy (clpidogrel & aspirin)
Bhatt DL et al. N Engl J Med 2010 ; 363 : 1909 – 1917.
RCT – 3761 patients – Omeprazole vs placebo in DAT*
Symptomatic ulcers or erosions, complicated ulcer
57. PPI & clopidogrel co-therapy
Administer PPI in patients at high risk
Administer PPI in all patients with dyspepsia
Prefer pantoprazole or rabeprazole
Weak inhibitors of CYP2C19
Pantoprazole considered the first choice PPI
Separate administration by 12 – 15 hours
Half-life of PPI 1 – 2 h & clopidogrel 4 – 6 h
PPI before breakfast & clopidogrel after dinner
Lettino M. Eur J Intern Med 2010 (in press).
58. Side effects of PPI
No therapy is completely without risk
• Osteoporosis & fractures Conflicting results
• Clostridum difficile OR 2.05 (95% CI: 1.4 – 2.8)
• Pneumonia OR 1.3 (95% CI: 1.1 – 1.4)
• Acute interstitial nephritis Very rare
• Iron & vit B12 deficiencies Little evidence
Madanick RD. Clevland Clin J Med 2011 ; 78 : 39 – 49.
59. The lowest effective dose
of the cheapest drug
for the shortest possible time
Which PPIs?
Nonetheless, the US Food and Drug Administration Advisory Committee concluded in 2005 that the COX-2-associated cardiovascularrisk was a class effect, although there is a variation in risk among doses and drugs within the class.
The sad history of Vioxx1999: Food and Drug Administration (FDA) approved Vioxx for relief of arthritis symptoms. Approval based on data from trials lasting 3 to 6 months & involving patients at low risk for cardiovascular illness.2000: Vioxx Gastrointestinal Outcomes Research (VIGOR) study published.2001: Increases risk of MI from VIGOR) study published.2004, sep 30: Merck & Co. withdrew its blockbuster arthritis medication rofecoxib (Vioxx) from the market after the drug was found to increase the risk of myocardial infarction (MI) and stroke.
Use of NSAIDs (except for aspirin) is associated with increased cardiovascular morbidity including:Worsened congestive heart failureIncreased blood pressureAdverse CV events: MI & ischemia
Cox-1 Inhibition:Decreased mucosal PGs synthesisDecreased of mucosal blood flow (+++).Cox-2 Inhibition:Increased neutrophils adherent to vascular epithelium Important factor of ulcer developmentTopical Irritation:Acidic NSAIDs exerts topical irritant effects leading to epithelial injury.Suppression of COX-1 causes a profound reduction of mucosal prostaglandin synthesis which probably impairs many components of mucosal defence. Among these, the reduction of mucosal blood flow may be most important. Suppression of COX-2 leads to an increase in the number of neutrophils adhering to the vascular endothelium in the gastrointestinal microcirculation, which has been shown to be an important factor in ulcer development. Many NSAIDs, particularly acidic ones, also exert topical irritant effects on the mucosa, leading to epithelial injury.
Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymesare associated with a greater risk of upper GI bleeding/perforation.Rofecoxibwas withdrawn from the market in September 2004 after an increased relative risk of cardiovascular events emerged from a number of trials.Valdecoxib has similar pharmacological properties to rofecoxib, and was associated with increased thromboembolic events when usedfor pain relief after coronary-artery bypass grafting. With an increased risk of life-threatening allergic skin reactions and without a clear arthritis therapy benefit compared with traditional NSAID, valdecoxib was withdrawn in April 2005 at the request of the US FDA.
number-needed-to-harm (NNH) is a clinically useful result:the number of patients who would need to be treated with low-dose aspirin instead of no therapy (placebo) to cause one additionalepisode of GI bleeding.No difference between 75-162.5 mg/d & 162.5-325 mg/d.
Aspirin tablet coated with a combination of cellulose, silicon, or other inactive ingredients has resistance to disintegration in the stomach; this property allows dissolution of the drug in the more neutral to alkaline environment of the duodenum.safety of this type of product has been confirmed by several endoscopic studies that compared enteric-coated with plain aspirinpreparations in healthy volunteers with less gastric erosion and microbleeding in those who used the enteric-coated preparation.Buffering agents (calcium carbonate, magnesium oxide, and magnesium carbonate) lower hydrogen ion concentration in themicroenvironment of aspirin particles; this results in increased gastrointestinal solubility of aspirin, and reduced contact time between aspirin particles and the gastric mucosa. The expectation that buffering would reduce gastric damage has been largely unsupported by endoscopic studies. Although buffered preparations are better tolerated by some patients.Use of low doses of enteric-coated or buffered aspirin carries a three-fold increase in the risk of major UGIB. The assumption that these formulations are less harmful than plain aspirin may be mistaken.
Cardiovascular risk based on Framingham Heart Study data is readily estimated using an online risk assessment tool, available on websites such as the US National Heart, Lung, and Blood Institute.Total cholesterol: should be average of at least 2 measurements obtained from lipoprotein analysis. HDL cholesterol: - should be average of at least two measurements obtained from lipoprotein analysis. Smoker: the designation “smoker” means any cigarette smoking in the past month. Systolic blood pressure: blood pressure value used is that obtained at the time of assessment, regardless of whether the person is on antihypertensive therapy (treated hypertension carries residual risk). More Information - Determining 10-year (short term) risk for developing CHD is carried out using Framingham risk scoring. The risk factors included in the Framingham calculation are age, total cholesterol, HDL cholesterol, systolic blood pressure, treatment for hypertension, and cigarette smoking. Because of a larger database, Framingham estimates are more robust for total cholesterol than for LDL cholesterol. Note, however, that LDL cholesterol remains the primary target of therapy. The Framingham risk score gives estimates for “hard CHD” which includes myocardial infarction and coronary death.
Self reported questionnaire as initial sourceSilent MIs cannot be diagnosed without ECG or imaging studiesSome studies lost up to 5% of dataDose of aspirin: 500 mg/d (British Male Doctors’ Study) -100 mg on alternate days in Women’s Health Study
Half of patients most likely to benefit from low-dose aspirin are not receiving it.Whereas many low-risk patients are being placed at risk of GI complications through unnecessary use of aspirin
Non-selective NSAIDs: Ibuprofen/Diclofenac/NaproxenC2SI: Celecoxib, EtoricoxibThe later introduced cyclooxygenase-2selective inhibitors (C2SI) exhibit a more favorable gastrointestinal safety profile, albeit with individual differences. However, serious concerns about their cardiovascular toxicity have led to the market withdrawal of rofecoxib and regulatory warnings (European Medicines Agency) for the others. Following new reports that the increased cardiovascular risk may also apply to non-selective NSAID, the US Food and Drug Administration issued ‘black box’ safety warnings for the entire NSAID drug class (July 2010).
Following the RAND/UCLA definition, a treatment had to be considered appropriate if the expected benefits exceeded the potential negative consequences by a sufficient margin.
Cardiovascular risk (low; high)10-Year risk of fatal CV disease (heart attack, stroke), based on the (country-specific) HeartScore of European Society of CardiologyLow: <10%High: ≥10%
Although multiple factors were identified, including1- safer NSAID2- lower doses of some NSAID3- introduction of COX-2 inhibitors4- increasing co-therapy with PPI made a considerable contribution to the observed decline in NSAID complications.
The success of these drugs, with sales totalling $13.6 billion worldwide in 2009.
The effects of drugs of the same pharmacological group are mostly ‘class’ or ‘group’ effectsThus all statins would have similar clinical usefulness, & all ACE inhibitors would be equally useful in management of HTN.It is not scientifically valid to assume that this is always the case.For instance, it was necessary to withdraw cerivastatin from the market because of a greater frequency of rhabdomyolysis,which was detected only during postmarketing surveillance, & it has recently been suggested that the effect of ramipril on mortality inheart failure might be greater than that of other ACE inhibitors. Scientifically valid conclusions should be based on head-to-head comparative trials between the various drugs. However, as thedemonstration of differences may be quite expensive (long-term trials with large study populations), smaller studies are usually carried out, the clinical relevance of which is quite debatable. Even more to the point: all too often, equivalence studies are accepted as valid while being methodologically clearly inadequate.The concept of bioequivalence is important because these drugs are highly labile in an acid environment and are rapidly degraded ifreleased in the stomach. the effect of a given preparation depends, not only on the amount of the active molecule contained in the capsule or tablet, but at least as much on the quality and stability of the enteric coating protecting the active molecule.The potency of these bioequivalence studies is all too often debatable.
Patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dosecombination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.
Patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dosecombination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.
In the past two years some scientific evidences have suggested a possible negative interference of PPIs on antiplatelet effect of clopidogrel because of the competitive inhibition of the CYP 2C19 isoenzyme.
The success of these drugs, with sales totalling $13.6 billion worldwide in 2009, is not just a result of their potency and effectivenessin improving symptoms and complications of acid-peptic disease. Their safety among pharmacologic agents has been unparalleled.Clopidogrel:on November 17, 2009, the US Food and Drug Administration (FDA) issued an alert to health care professionals and thepublic about the potential interaction between clopidogrel and omeprazole. In this alert, the FDA stated that the use of omeprazoleor esomeprazole (Nexium) with clopidogrel should be avoided.To date, only one prospective randomized controlled trial has specifically investigated the effect of PPIs on cardiovascular outcomesin patients using clopidogrel (Cogent trial). The study ended prematurely, when the sponsor suddenly and unexpectedly lost its financialBacking. Osteoporosis & fractures: Even though the studies had methodologic limitations, on May 25, 2010, the FDA announced a change in the required labeling information for PPIs to indicate a possible risk of fracture with these drugs.Acute interstitial nephritis: A systematic review from 2007 found 64 cases documented in the literature, 12 of which were considered certainly associated, and 9 of which were probably associated.