Oral Diclofenac Plus Omeprazole Biology Essay

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Published in the lancet June 2010. The Lancet has an impact factor of 38·28. The journal is currently ranked second out of 153 journals in the general medicine category (2011 Journal Citation Reports®, Thomson Reuters 2012).

COX-2 selective NSAIDs were developed to provide

anti-infl ammatory therapy; avoiding COX-1 inhibition

and sparing the enzyme in the gut supports mucosal

integrity. Several large outcome studies 19,27,28 have shown

reductions in upper gastrointestinal tract ulceration and

complications for patients using these drugs compared

with non-selective NSAIDs. Although PPIs eff ectively

reduce upper gastrointestinal ulceration, 4,5

a double-blind, triple-dummy, parallel group randomised trial

Clinical trials are a special kind of cohort study in which the selection of treatment groups, nature of interventions, and management during follow-up are specified by the investigator for the purpose of making unbiased comparisons. (Research Methods G.J.Ebrahim Editor Journal of Tropical Pediatrics, Oxford University Press)

Randomisation is a process for allocating subjects between the different trial interventions. Each subject has the same chance of being allocated to any group, which ensures similarity in characteristics between the arms. This minimises the effect of both known and unknown confounders, and thus has a distinct advantage over observational studies in which statistical adjustments can only be made for known confounders. (Allan Hackshaw 2009)

Parallel Design Trial

A parallel designed trial compares the results of an intervention on two different groups of patients. http://www.ukmi.nhs.uk/Research/CliniTrialType.asp

In double blind studies neither the participant nor the researchers know which treatment is being tested at any one time. Blinding was done using the triple dummy" method.

4402 Patients were assigned in a 1:1 ratio Reporting Groups

Celecoxib

200 mg BID plus omeprazole placebo and diclofenac SR placebo

Oral Diclofenac Plus Omeprazole

Oral diclofenac SR (75 mg BID) plus omeprazole (20 mg QD) and celecoxib placebo.

Patients and researchers were masked to treatment allocation. The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events adjudicated by an independent committee.

Reductions in serious GI outcomes (perforations, ulcers and bleeds) have been demonstrated with the Cox-2 selective agents; however, data to date is limited with mixed results. Clinical data regarding long-term (>12 months) use in high-risk patients is not yet available.

6 month treatment duration is sufficient As The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events 6 months duration.

1. the statistical significance level, alpha (typically 5% (sometimes written =0.05);

also known as the false-positive rate.

2. the power - adequate power for a trial is widely accepted as 0.8 (or 80%). Power is

defined as 1-where , the false-negative rate, in this case would be 0.2 (or 20%).

The trial is sufficiently powered (sample size of 4402 would achieve 80% power to detect the treatment difference at a 0.05 significance using the χ² test) as the total n= 4484 patients

Inclusion Criteria:

Subjects with a clinical diagnosis of osteoarthritis or rheumatoid arthritis and who are expected to require regular anti-inflammatory therapy for arthritis symptom management

Subjects must be aged 60 years or older with or without a history of gastroduodenal ulceration; or be of any age 18 years or older and have had documented evidence of gastroduodenal ulceration 90 days or more prior to the screening visit

Exclusion Criteria:

Active ulceration within 90 days of the screening visit.

Concomitant use of low dose aspirin

Previous MI, stroke or significant vascular disease.

The population is representative of the patient with high gastrointestinal risk

patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk, 

Celecoxib 200 mg BID Oral diclofenac SR (75 mg BID) plus omeprazole (20 mg QD) and celecoxib placebo.

Primary Outcome Measures:

Number of Subjects With Clinically Significant Upper and/or Lower Gastrointestinal Events Time Frame: 6 month treatment duration 

CSULGIE=any of the following: gastroduodenal (GD) hemorrhage; gastric outlet obstruction; GD, small or large bowel perforation; small or large bowel hemorrhage; clinically significant anemia of defined GI origin; acute GI hemorrhage of unknown origin, including presumed small bowel hemorrhage; clinically significant anemia of presumed occult GI origin including possible small bowel blood loss. Subjects were assessed by an independent GI Events Adjudication Committee, who were blinded to study treatment assignments.

Previous studies have demonstrated that COX-2-selective NSAIDs and non-selective NSAIDs plus a proton-pump inhibitor (PPI) have comparable side effects in the upper gastrointestinal tract, but adverse effects in the entire gastrointestinal tract (including the lower part) might be less common with selective drugs than with non-selective drugs. This is because acid suppression does not avert damage to the lower gastrointestinal tract. In this study, the scientists aimed to compare risk of gastrointestinal events associated with celecoxib (COX-2 selective NSAID) versus diclofenac slow release (a non-selective NSAID) plus omeprazole (a PPI).

Primary Outcome Measures:

Number of Subjects With Clinically Significant Upper and/or Lower Gastrointestinal Events Time Frame: 6 month treatment duration 

CSULGIE=any of the following: gastroduodenal (GD) hemorrhage; gastric outlet obstruction; GD, small or large bowel perforation; small or large bowel hemorrhage; clinically significant anemia of defined GI origin; acute GI hemorrhage of unknown origin, including presumed small bowel hemorrhage; clinically significant anemia of presumed occult GI origin including possible small bowel blood loss. Subjects were assessed by an independent GI Events Adjudication Committee, who were blinded to study treatment assignments.

guidelines (which currently recommend selection of anti-inflammatory therapy on the basis of the patient's upper gastrointestinal and cardiovascular risks), As the trail suggest that risk of lower gastrointestinal bleeding could be as important a as is risk of upper gastrointestinal bleeding. However, risk of gastrointestinal adverse events was driven by haemoglobin decrease, not by documented lower gastrointestinal bleeding

When offering treatment with an oral NSAID/COX-2 inhibitor, the first choice should be either a standard NSAID or a COX-2 inhibitor. In either case, these should be coprescribed with a proton pump inhibitor (PPI), choosing the one with the lowest acquisition cost.

1.4.4.4 All oral NSAIDs/COX-2 inhibitors have analgesic effects of a similar magnitude but vary in their potential gastrointestinal, liver and cardio-renal toxicity; therefore, when choosing the agent and dose, healthcare professionals should take into account individual patient risk factors, including age. When prescribing these drugs, consideration should be given to appropriate assessment and/or ongoing monitoring of these risk factors.

(http://publications.nice.org.uk/rheumatoid-arthritis-cg79/guidance#pharmacological-management)

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