DETERMINANT FACTORS FOR GASTRO PROTECTIVE CO PRESCRIPTION: A CROSS SECTIONAL STUDY INVOLVING 303 PATIENTS WITH NON STEROIDAL ANTI INFLAMMATORY DRUGS

DETERMINANT FACTORS FOR GASTRO PROTECTIVE CO

PRESCRIPTION: A CROSS SECTIONAL STUDY INVOLVING 303

PATIENTS WITH NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Ravindra J,Indu TH, Raja D and Roopa B S*

Department of Pharmacy Practice, JSS College of Pharmacy, Ootacamund, JSS University, Mysore.

ABSTRACT

Non-steroidal anti-inflammatory drugs are the core treatment for many pain and inflammatory conditions, but are associated with broad spectrum of side effects, especially Gastro Intestinal ones. This study was undertaken to determine the prescription pattern of gastro protective agents with non-steroidal anti-inflammatory drugs. This is a cross sectional observational study. Chi-square or Fisher’s exact test was used to know the distribution of categorical variables, t-test for comparison of means. Logistic regression parameters using firth procedure by quasi complete separation was used to the penalized likelihood function which makes at least one parameter estimate diverge to ± infinity. Out of 303 patients’ medical record and

prescription reviewed, all the patients received non-selective anti- inflammatory drugs. Diclofenac sodium was highly prescribed anti-inflammatory drugs. 73.6% of patients had at least one gastro intestinal risk factor. Among various factors; age, acute condition and naïve usage of non-steroidal anti-inflammatory drugs were major factors for co prescription of gastro protective agents with non-steroidal anti-inflammatory drugs (P<0.005). In addition

the type of hospital had significant association for the co prescription of gastro protective agents with non-steroidal anti-inflammatory drugs. In multivariate analysis the risk factors; history of ulcer, hypertension and lower respiratory tract infection were significant determinants for prescription of gastro-protective agents with non-steroidal anti-inflammatory drugs. We found profound usage of non-selective non-steroidal anti-inflammatory drugs. The commonly used GPA as prophylaxis was standard dose of H2RA which is ineffective to

Volume 4, Issue 7, 739-750. Research Article ISSN 2277– 7105

*Correspondence for

Author

Roopa B S

Department of Pharmacy

Practice, JSS College of

Pharmacy, Ootacamund,

JSS University, Mysore. Article Received on 23 April 2015,

protect against the non-steroidal anti-inflammatory drugs related gastro intestinal ulcer complications. The study finding shows lesser extent use of Proton Pump Inhibitors.

KEYWORDS: Non-steroidal anti-inflammatory drugs, Gastro Intestinal Risk Factors, Gastro Protective Drugs, and Prescription Pattern.

INTRODUCTION

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the frequently used medications world-wide. It is used to treat pain and inflammatory conditions, including osteoarthritis, inflammatory arthritis, back pain, musculoskeletal injuries, crystal arthritis, metabolic bone diseases and muscle soreness. Individually and together, these drugs associated toxicities have a significant impact on medical outcomes, quality of life and medical expenditures.[1, 2, and 3]

About 60 million population world-wide have been estimated to be the over the counter chronic NSAIDs users and known to have NSAIDs induced gastropathy which is a common cause of hospital admission and death world-wide.[4, 5]The hospitalization due to GI complications caused by NSAIDs is about approximately 107,000 and about 16,500 deaths occur in arthritis patients alone annually, yet the scope of this problem is generally under appreciated. The occurrence of gastric complications which includes peptic ulcer, gastro duodenal hemorrhage, and other conditions like anemia is found to be the major drawback and has limited its use.[6, 7] The incidence of gastric complications with NSAIDs users is about four fold higher than nonusers globally.[8] Presently the use of NSAIDs is increased at the same time resulted in having therapeutic approaches to prevent and decrease the NSAIDs

METHODS

A cross-sectional observational study was performed during the period from September to November 2013 at Government District Head Quarters Hospital, a secondary care hospital in Udhagamandalam and at the private physician’s clinics of Udhagamandalam municipality which comprises of population of about 107,763. The study design was approved by institutional review board of JSS College of Pharmacy, Udhagamandalam and the study was performed in accordance with Good Clinical Practice guidelines.

Inclusion criteria

 Patients of both genders who were older than 18 years and received NSAIDs for more

than 5 days.

Exclusion criteria

 Those who were given NSAIDs on irregular, as required basis were excluded from the

study.

The primary objective of the study is to determine the pattern of use of GPAs, and to find out the determinant and association between risk factors and the co prescription of GPAs with NSAIDs. Computerized medical records of the ambulatory patients available at the pharmacy in the Government Head Quarters Hospital, Udhagamandalam and the prescription given by the physicians at two private clinics were used as the source documents.

The informed consent form was obtained in the local language from patient or care taker prior to the data collection. A specially designed patient pro forma was used to collect the data on patient’s demographics (age, gender, habit of smoking and drinking), medical history

(indications of NSAIDs, history of ulcer, concomitant medication and diseases) and treatment details including NSAIDs and GPAs along with dosage and durations. During the data collection risk factors (RF) for GI complications which were identified by literature and are defined as.

RF 1 - Age ≥ 65 years old

RF 2 - Social habits of smoking and alcohol intake

RF 3 - Concomitant medications of steroids, anti-coagulants and anti-platelet drugs RF 4 - H. pylori infection

RF 6 - Chronic usage of NSAIDs

RF 7 - Previous history of gastro duodenal ulcer or GI bleeding

RF 8 – Co-morbid condition such as cardiovascular, renal or hepatic impairment, diabetes and hypertension.

DATA ANALYSIS

The data obtained was analyzed using GraphPad Prism version 6.04 for Windows (GraphPad Software, La Jolla California USA, www.graphpad.com) and SPSS version 22.0 (SPSS Inc., Chicago II, USA) for windows. An exploratory analysis was carried out to compare groups with and without GPAs prescription. Pearson Chi-square or Fisher’s exact tests were used to analyse statistical significant relationship. A difference with a P (< 0.05) was considered to have significant association. Variables that are significant in the exploratory analysis were included in a multiple logistic regression model to assess the factors that are found to be determinants with for co prescription for GPAs.

Logistic regression parameters were estimated by firth procedure using the penalized likelihood function. Advantage of this method enables to estimate parameters in small samples with strongly predictive covariates, where the phenomenon of quasi-complete separation makes at least one parameter estimate diverge to ± infinity. A manual selection approach was used in selecting significant variables P-value (< 0.05) of the penalized log-likelihood ratio test.

RESULTS

Exploratory Analysis

Information of 303 patients who were given NSAIDs was collected during the period September to November 2013. The factors that might be associated with the prescription of GPAs while prescribing NSAIDs were separated into 3 groups: those related to patients’ demographic characteristics, those related to patient’s clinical conditions and those related to

clinical settings and are summarized in Table 1. Among them 135 patients were male (44.6%)

social habits there was no significant association for the GPAs prescription in NSAIDs users. Only non-selective NSAIDs like dicofenac (29%) and paracetamol (16.5%) were prescribed more frequently and low dose of aspirin 75mg once daily (19.5%) used towards the management of cardiovascular risk events were prescribed more frequently. Hypertension, ischemic heart disease, myalgia, and lower respiratory infections were more frequently reported diseases for which NSAIDs were prescribed, (Table 2). Prescription of GPA with co morbid conditions in NSAIDs use was relatively less. There is no significant association for GPA co prescription considering various disease conditions. Even though female patients

reported more concomitant disease like myalgia, ischemic heart disease, osteoarthritis, hypertension and osteoporosis for which the NSAIDs was prescribed, there was no significant difference of GPA usage when compared with male patients. Both naive and chronic NSAIDs users were included in the study, 41.25 % of study population had renewal of prescription and 58.75% was on initial NSAIDs prescription. Precisely 17.5 % received the prescription of NSAIDs for greater than equal to 28 days and are considered as chronic users. Patients with acute indication are more likely to receive GPAs along with NSAIDs (OR: 2.2662; 95% CI: 1.0390-4.9426) and also patients who received NSAID for first time are associated with GPA prescription (OR: 2.0997; 95% CI: 1.0096-4.3671). Out of 223 patients, 88.34% of study population had no history of ulcer/bleeding and were prescribed with NSAIDs along with GPAs; whereas among 71 patients who had history of ulcer/bleeding 91.55% were prescribed with NSAID along with GPA and almost all patients having history of bleeding received GPA co-prescription. Nearly 73.6% (n= 223) of patients had at least one GI risk factors and are identified as at high risk of developing GI complications, 85.20% of them received GPA co-prescription. Nearly 56.5% patients received ranitidine of dosage 150mg twice daily as GPA with specified frequency followed whereas only 16.67% received PPIs which attributed to lesser extent of overall GPA prescription. It was observed that there was significant association between the hospital

settings (P=0.0334) towards GPA prescription with NSAIDs. 87.8% of patients at Government District Head Quarters Hospital Udhagamandalam were prescribed with GPAs

was significant association between GPA prescription with NSAID alone and antibiotics (P=0.037) but no significant association was found between GPAs prescription with NSAIDs alone and with anti-hypertensive drugs (Amlodipine and Nifedipine) or anti-diabetic drug (Metformin) as represented in Table 3.

Multiple Logistic Regressions

The variables that were significantly associated with GPA prescription in the univariate analysis were included into multiple logistic regression model, whereas other variables had incomplete data for selected covariates. The firth bias corrected logistic regression method was used, as there was quasi-complete separation in the data. The adjusted odds ratios for selected model variables of multiple logistic regression analysis are summarized in Table 4. After adjustment in models, patients who had history of ulcer, disease conditions like hypertension and lower respiratory infection were predictors of GPA prescription. Patients with history of ulcer are more likely to receive GPAs than those without history of ulcer (OR, 8.488). Patients with concomitant diseases like hypertension and lower respiratory infection

are more likely to be prescribed with GPAs along with NSAIDs than other diseases (OR: 8.761 and 7.958 respectively). (Table 4)

Table 1: Patients demographic characteristics.

Characteristics Stratum

total (n)

No GPA Prescription n (%)

GPA

Prescription n (%)

P -value**

Age (yrs) <45 120 10 (8.33) 110 (91.67)

0.0029

45-65 135 11 (8.15) 124 (91.85)

≥65 48 12 (25) 36 (75)

Gender Female 168 18 (10.71) 150 (89.29) 0.9122

Male 135 15 (11.11) 120 (88.89)

Smoking habits No 234 24 (10.26) 210 (89.74) 0.5132

Yes 69 9 (13.04) 60 (86.96)

Drinking habits No 245 26 (10.61) 219 (89.39) 0.8145

Yes 58 7 (12.07) 51 (87.93)

Smoking & drinking

None 225 23 (10.22) 202 (89.78)

0.8122 Either Smoking/Drinking 30 4 (13.33) 26 (86.67)

Smoking and Drinking 48 6 (12.5) 42 (87.5)

Risk factors

0 80 0 (0) 80 (100)

<0.0001

1 106 5 (4.72) 101 (95.28)

2 66 10 (15.15) 56 (84.85)

≥3 51 18 (35.29) 33 (64.71)

History of ulcer/ bleeding.

No 223 26 (11.66) 197 (88.34)

0.6939

Yes 71 6 (8.45) 65 (91.55)

Bleeding 9 1 (11.11) 8 (88.89)

Center Government Hospital 270 33 (12.22) 237 (87.78) 0.0334

**P-value is based on a chi-square test or Fisher’s exact test, ns not significant.

Table 2: Indications of use of NSAIDs. Disease

No GPA Drug Prescription

GPA

Drug Prescription

Stratum total

P-value

n (%) n (%) n (%)

No Comorbid conditions 27(10.50) 230 (89.50) 257 (84.81) Ref Comorbid conditions 6 (18.18) 40 (14.81) 46 (15.18) 0.6088 Ischemic Heart Disease 7 (21.21) 32 (11.85) 39 (12.87) 0.1805

Myalgia 5 (15.15) 77 (28.51) 82 (27.06) 0.2834

Lower Respiratory tract

Infection 2 (6.06) 19 (7.04) 21 (6.93) 1.000

Hypertension 6 (18.18) 20 (7.41) 26 (8.58) 0.0987

Other disease 7 (21.21) 82 (30.37) 89 (29.37) 0.5414

Table 3: GPA prescription with other concomitant medications. Concomitant medication

No GPA Prescription

GPA

Prescription Stratum total P- value

n (%) n (%) n (%)

NSAIDs alone 13 (39.39%) 167 (61. 85 %) 180 (59.41%) Ref

Any Concomitant Medication 20 (60.61%) 103 (38.15 %) 123 (40.59 %) 0.0131

Antibiotic 12 (36.36%) 62 (22.96 %) 75 (24.75%) 0.037

Antihypertensive

(Amlodipine and Nifedipine) 5 (15.15%) 24 (8.89 %) 30 (9.90%) 0.0836 Antidiabetic (Metformin) 3 (9.09%) 13 (4.81%) 16 (5.28%) 0.1292

Table 4: Multivariate analysis of determinants of GPA co prescription

Effect Adjusted

Odds Ratio 95% Confidence Limits

Hist_ulcer 1 vs 0 8.488 2.213-32.554

No of Risk Factors

1 0.067 0.007-0.692

2 0.007 <0.001-0.090

3 <0.001 <0.001-0.011

Hypertension 8.761 1.215-63.189

Lower respiratory infection 7.958 1.143-55.425

NSAID Dosage 1.004 1.001-1.008

DISCUSSION

NSAIDs and to find out the determinant risk factors and its association while prescribing the GPAs.

From the demographics, predominance use of NSAIDs was higher in female over male which is similar to reported and the social habits like smoking and drinking were not considered for the prescription of GPAs with NSAIDs.[6, 14]

The widespread use of NSAIDs indicates the increased chance of GI adverse effects which may be a significant health concern.[15] The development of NSAIDs inducted GI complications increases with age.[14, 16] The Dutch study[17] reported that 14% of the geriatric population was prescribed with GPAs along with NSAIDs and low dose of aspirinwhereas in this study 75 % of the geriatric populations were GPA co prescribed. The larger usage (91.85 %) of GPAs with NSAIDs were in the age group of 45-65 years followed by the age group <45 years (91.67%)

Wherein the 25% of geriatric population are still not given adequate preventive measures when NSAIDs are used, this finding is similar to other study reports.[4, 18] The reason for lesser extent of GPA prescription in geriatrics can’t be drawn and hence the emphasis to the

physician is needed to practice GPAs prescription with NSAIDs in elderly consulting the guidelines.

Unlike other studies our study had the advantage of considering both acute and chronic usage of NSAIDs, 17.5% of the population was chronic users (≥ 28 days) and 29% of study population were on diclofenac sodium, this trend is similar with Netherlands.[19]We found that none of patients received selective COX-2I. This report is consistent with the study reported by Bianco M et al.[11] The major reason for this could be the need for careful evaluation before initiation, as the cardiac and renal adverse effects are associated with selective COX-2I in elderly population.[15, 16, 20]

It was observed that the use of NSAIDs was high in the disease conditions viz hypertension, ischemic heart disease, myalgia, and lower respiratory infection.[21]The aspirin in low dose of 75 mg for antiplatelet action was prescribed in 19.5% of study population in the management of Ischemic heart disease and hypertension. Many physician believe that the low dose of aspirin does not provide adequate ground for GPA co prescription but as per Derry S et al many studies have demonstrated that odds of bleeding is 1.68 times higher with aspirin even

concomitant corticosteroids, here about 3.9% of study population was found and no significant association was observed between them and GPAs prescription. But only antibiotic prescription with NSAID alone has a significant association with GPA prescription which was a similar finding to Eva M van Soest et al.[23]

The American College of Gastroenterology and the American College of Rheumatology guidelines recommends that patients with at least one risk factor including low dose of aspirin in NSAIDs users should also be co-prescribed with gastro protective agent.[2, 9, 24, 25] However in the present study we found that 14.8% did not receive any GPAs out of 223 patients who had at least one risk factor.

The guidelines recommends standard dose of PPIs or high dose (double the standard dose) of H2RA will be effective in NSAIDs, low or high dose of antiplatelet drug aspirin associated ulcer complications.[24,25] The extent of prophylactic use of GPAs along with NSAIDs was 89.1% in the present study out of which 56.5% of patients received H2RA ranitidine 150 mg twice daily (standard dose) and the 16.67% received PPIs indicating the need for either increasing the dose of ranitidine or change to standard dose of PPIs in this population as they are at the risk of developing ulcer complications.Misoprostol as gastro protecting agent was not prescribed in the study population may be due its adverse effects and the frequency of dosing need to be two to four times a day which is inconvenient and may cause non adherence. The clinical setting was found to be significant factor for prescription of GPAs with NSAIDs, as all patients who visited private clinics received the GPAs in comparison to

Government hospital (87.8%).

In multivariate analysis, the certain risk factors like history of ulcer, hypertension and lower respiratory infection were identified and considered as significant determinants for the co- prescription of GPA. This result indicates that the physicians are aware of certain risk factors

but not considered all of them for co-prescription of GPA along with NSAIDs; however the abundantly used GPA is standard dose of ranitidine which was found to be ineffective in

preventing NSAIDs induced upper GI toxicity as per the currently available literature and guidelines recommendations.

Some of the limitations of the study includes that the information of Helicobacter pylori infection (one of the RF) was not obtained for which conflicting results have been reported

esophageal reflux disease was not seen in the study period which may also have influenced the pattern of GPAs prescription, if present. The negligible OTC use of NSAIDs or GPAs was not considered and the adherence data was not collected for GPAs or NSAIDs in our study as our primary objective is to evaluate the prescription pattern by physicians. Further investigation in a larger population is needed to identify the pattern of prophylactic use of GPAs with NSAIDs in Indian scenario; however this study was one of its first kinds performed in the Nilgiris population.

CONCLUSION

Only non-selective NSAIDs were prescribed in the study settings, the commonly used GPA that was prescribed as prophylaxis was 150 mg of ranitidine (H2RA) which is ineffective to protect against the GI adverse effects caused by NSAIDs and low dose of aspirin. We found PPIs were used in a lesser extent against the Cochrane review and American College of Gastroenterology guidelines which suggests standard dose of PPIs are effective in prevention of NSAIDs related GI complications.

In multivariate analysis the physicians considered factors; history of ulcer, disease conditions like hypertension and lower respiratory infection as significant determinants for GPAs prescription with NSAIDs.

ACKNOWLEDGEMENT: The authors thank Bhavyashree G. M Sc. Biostatistics for her contribution in statistical analysis.

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