Intensive Hospital-based Adverse Drug Reaction Monitoring Studies On 5482

Patients Of Kashmiri Origin In A Tertiary Care Hospital

Mohammad Ishaq Geer*, M. Y. Shah*, Parvaiz A. Koul**, Shafiqa A. Tanki**

*Dept. of Pharmaceutical Sciences, University of Kashmir, Srinagar, India**Sher-i-Kashmir Institute of Medical

Sciences, Srinagar, IndiaThird International Conference for Improving Use of Medicines, Antalya, Turkey November 14-18, 2011

ABSTRACT PROBLEM STATEMENT: Prior to this study, there was no provision for monitoring drugs for their adverse effects in

any of the leading hospitals of Kashmir division of the Jammu and Kashmir state. OBJECTIVES: To assess the prevalence, preventability, category, costs, and severity of drug-related adverse effects in

Kashmiri patients at a Srinagar-based tertiary care hospital, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar.

DESIGN: Prospective, observational, cohort study with follow-up SETTING: All adult Kashmiri patients admitted to internal medicine IPD, presenting to internal medicine OPD, and those

visiting the accident and emergency department of SKIMS over a 270-day period were included in the study. STUDY POPULATION: A total of 5482 adult, Kashmiri patients of both sexes were screened and monitored on a daily

basis for the occurrence of any ADRs. INTERVENTION: Data was recorded using structured forms and then scrutinized for various assessment parameters by

a multidisciplinary medical team comprising of a senior consultant in medicine, a clinical pharmacologist, and a clinical pharmacist. Interventions relating to detection and management of ADRs were undertaken on a case-to-case basis. This study led to the establishment of a full-fledged pharmacovigilance centre and initiation of pharmaceutical care services in the hospital.

POLICIES: No hospital drug policy or ADR monitoring policy/framework was available in SKIMS at the time of this study.

OUTCOME MEASURES: Causality assessment, severity assessment, preventability assessment, extension of hospital stay, and cost due to ADRs.

RESULTS: ADRs account for 6.23% of adult Kashmiri patients visiting a tertiary care hospital, SKIMS, either for referral or hospitalization, with the majority (81.57%) of these ADRs being preventable; 23.68% of patients had mild ADRs, 69.29% had ADRs of moderate severity, and 7.01% had severe ADRs. The 4 classes of drugs most frequently suspected in admissions due to ADRs were anti-infective agents (40.92%) including anti-tubercular drugs (13.15%), steroids (14.03%), anti-coagulants (8.77%), and NSAIDs (7.89%). Increasing age and female gender were identified as risk factors. The organ systems most commonly affected were gastrointestinal (81%), dermatological (43%), central nervous (40%), hematological (34%), metabolic (33%), cardiovascular (22%), urinary (18%), ENT (18%), immunological (11%), and respiratory (10%) systems. The total cost to the hospital due to hospitalization of patients presenting with ADRs over the 9-month period in the internal medicine IPD was found to be USD 22469.

CONCLUSIONS: The present work is the maiden pharmacovigilance study conducted on Kashmiri patients, especially at a tertiary care teaching hospital such as SKIMS that has provided baseline information about the prevalence of ADRs and their distribution among different age groups, genders, organ systems affected, and therapeutic classes of medicines. The data collected has paved way for long term and more extensive ADR monitoring on Kashmiri patients and will also be useful in framing policies toward the rational use of drugs.

FUNDING SOURCES: Nil

INTRODUCTION/BACKGROUND ADRs are a serious cause of mortality and morbidity in humans inflicting huge

costs to the nation, healthcare system, hospitals & patients. Clinical trials are not sufficient to detect all ADRs. Complete safety profile of a

drug evolves over its lifetime in the market. In India, pharmacovigilance is still in its infancy and is yet to gain the

momentum needed to cope up with the demands of a country that is already under the pressure of overpopulation, malnutrition and high disease burden.

ADR monitoring & reporting scenario in J&K was grim. No such initiative till this study was launched in 2007.

As per govt. figures Jammu and Kashmir state consumes medicines worth Rs. 600 crores annually, out of which medicines worth 400 crores are consumed by people living in Kashmir valley alone.

Upon literature search for ADR reports from J&K using various database resources like PubMed, Medline, Toxline, Chemical, Biological and Pharmaceutical Abstracts between 1966 to 2009, reports not exceeding a two-digit figure in number from J&K state could be retrieved.

No pharmacovigilance activities were undertaken in any of the leading hospitals like SKIMS, SMHS etc prior to this study.

Study was undertaken to provide baseline data that could help launch a full-fledged pharmacovigilance programme at SKIMS.

AIM AND OBJECTIVESAIMTo assess the prevalence, preventability, category, costs and

severity of drug-related adverse effects in Kashmiri patients, admitted in Internal Medicine IPD, presenting to the Internal Medicine OPD and those visiting the Accident and Emergency Department of SKIMS, Srinagar.

OBJECTIVESTo estimate the incidence and cost of ADRs causing hospital

admissions or occurring whilst in hospital at SKIMS, Srinagar.To estimate the no. of ADRs in patients visiting Internal Medicine

OPD and Emergency Department of SKIMS.To identify risk factors responsible for an increased frequency or

severity of ADRs such as concurrent drugs, disease, age, sex etc.To identify and suggest ways and means for reducing adverse

drug reactions in Kashmiri population.To provide a platform and baseline data for launching a full-

fledged Pharmacovigilance Programme and Pharmaceutical Care Services at SKIMS, Srinagar.

MATERIALS & METHODS

STUDY DESIGN: Prospective, observational, cohort study with follow-up SETTING: All adult Kashmiri patients of both sexes admitted to internal

medicine IPD, presenting to internal medicine OPD, and those visiting the accident and emergency department of a tertiary care centre, SKIMS over a 270-day period between May 1st, 2006 to July 29th, 2006 (90 days) and December 31st, 2006 to June 28th, 2007 (180 days), were included in the study.

STUDY POPULATION: A total of 5482 adult patients of both sexes were screened and monitored on a daily basis for the occurrence of any ADRs.

STUDY HOSPITAL: 650-bedded teaching-cum-service referral, tertiary care centre offering primary and secondary care facilities too.

INTERVENTION: Data was recorded using structured forms and then scrutinized for various assessment parameters like frequency, severity, preventability, category, cost and necessary interventions were suggested by a multidisciplinary medical team consisting of a senior consultant in medicine, a clinical pharmacologist and a pharmacist. Interventions relating to detection and management of ADRs were undertaken on case-to-case basis. This study led to the establishment of a full-fledged pharmacovigilance centre in the hospital and initiation of Pharmaceutical Care Services at its Internal Medicine Ward.

MATERIALS & METHODS DATA COLLECTION: Medication charts, medical records, daily ward rounds,

patient interviews, physician assistance POLICIES: No hospital drug policy or ADR monitoring policy/framework was

available in SKIMS at the time of this study. Present study was the first of its kind. OUTCOME MEASURES: Causality assessment, severity assessment,

preventability assessment, extension of hospital stay, and cost due to ADRs. CAUSALITY ASSESSMENT: Using Naranjo’s Algorithm classified ADRs into

Definite, Probable, Possible, Doubtful. PREVENTABILITY/AVOIDABILITY ASSESMENT: Using Hallas (1990)

methodology classified ADRs into Definitely Avoidable, Possibly Avoidable and Unavoidable.

SEVERITY ASSESMENT: Using Hartwig & Seigel Scale (1992) classified ADRs into mild, moderate, severe, lethal.

FINANCIAL IMPLICATIONS: Using Nicholas (1998) methodology cost of ADRs was calculated by the product of total number of admission days of all patients admitted with the ADR and hospital expenditure per day. Cost of excess hospital days was estimated by multiplying the total number of excess days by the reference daily hospital cost. Direct costs of ADRs calculated for the Internal Medicine ward of SKIMS were then used to extrapolate to annual and hospital-wide rates (Lagnaoui, 2000).

STATISTICAL ANALYSIS: Using Student’s t-test with a significance level of P<0.001 and the comparisons of proportions were made using Chi (ᵡ2) square test.

Examined medical records for drugs prescribed, investigations done &

ADRs experienced. Patients were interviewed

and clinical records analyzed to collect

information about the management and outcome

of ADRs.

Followed up all patients until discharge for arriving at a final

conclusion. Wherever reqd. assistance was sought from

prescribing physician

Type of ADR was determined as per the

classification of Wills and Brown

Causality assessment of ADRs was done as per Naranjo’s algorithm,

severity analysis as per modified Hartwig & Seigel Scale, preventability as per

Hallas methodology

Visited ward on daily basis, participated in

ward rounds

METHODOLOGY

RESULTS: TABLE-1: Department-wise break-up of the patients experiencing ADRs

Name of the Department

Number of patients with

ADR/Number of patients

visiting the department

Number of patients with

ADR/Number of patients

visiting the hospital

IPD 240/3899 (6.15%) 240/5482 (4.37%)

OPD 43/556 (7.73%) 43/5482 (0.78%)

Emergency 59/1027 (5.74%) 59/5482 (1.07%)

Total 342/5482 (6.23%) 342/5482 (6.23%)

RESULTS: TABLE-2: Demographic characteristics of the patients

Characteristics

Number of patients

with ADR/Number

of patients visiting

the hospital

Number (%) (n =

121) ADR related

admissions

ADRs occurring

during hospital stay

Male 132/3283 (4.02%)* 21 (0.63%)* 111 (3.38%)*

Female 210/2199 (9.54%)* 47 (2.13%)* 163 (7.41%)*

Adult 187/3985 (4.69%)* 38 (0.95%)* 149 (3.73%)*

Elderly(>65yrs) 155/1497 (10.35%)* 30 (2.00%)* 125 (8.35%)*

Total 342/5482 (6.23%) 68 (1.24%) 274 (5.07%)

*P<0.001 on student’s t-test/chi-square (ᵡ2) test (level=highly significant)

RESULTSTABLE-3: Age-wise incidence of ADRs in 5482 admissions

Age Group No. of Admissions

No. of ADRs Incidence(%; 95% CI)

18 - 38 1748 66* 3.77

39 - 58 2237 121* 5.40

59 - 78 972 89* 9.15

≥ 79 525 66* 12.57

*P<0.001 on student’s t-test/chi-square (ᵡ2) test (level=highly significant)

0

50

100

150

200

250

300

Nu

mb

er

of

AD

Rs

Types of ADverse Drug Reactions

Classification and assessment of ADRs

RESULTSTABLE-5: VARIOUS CLASSES OF DRUGS WITH FREQUENCY OF CAUSING ADRs

Drug Class No. (%) of ADRs Individual Drugs (number)Fluoroquinolones 48 (14.03%) Moxifloxacin (17), Ciprofloxacin

(13), Ofloxacin (7), Gatifloxacin (11)

Beta-lactam antibiotics 30 (8.77%) Benzathine-Penicillin (2), Cefadroxil (4), Ceftriaxone (11), Cefixim (2),

Piperacillin-Tazobactum (5), Meropenem (3),

Imipenem (3)

Anti-tubercular drugs 45 (13.15%) Rifampin (8), Ethambutol (11)Pyrazinamide (3), Streptomycin (12),

Isoniazid (11)Other antibiotics 17 (4.97%) Doxycycline (4), Azithromycin (5),

Vancomycin (3), Aztreonam (1), Clindamycin (4)

Steroids 48 (14.03%) Prednisolone (12), Hydrocortisone (11), Betamethasone (9),

Dexamethasone (16)NSAIDs 27 (7.89%) Diclofenac (7), Aspirin (6),

Serratiopeptidase (11),Ibuprofen (4)

RESULTSTABLE-5: VARIOUS CLASSES OF DRUGS WITH FREQUENCY OF CAUSING ADRs

Drug Class No. (%) of ADRs Individual Drugs (number)

Anti-coagulants 30 (8.77%) Heparin (8)Warfarin (19)

Acenocoumarol (3)Diuretics 12 (3.5%) Furosemide (3)

Spiranolactone (3)Bumetanide (2)Amiloride (2)

Indapamide (2)Anti-hypertensives 12 (3.5%) Enalapril (9)

Amlodipine (3)Drugs used in hypotension 9 (2.63%) Dopamine (7)

Hormones 12 (3.5%) Parathyroid hormone (2)Thyroxine (6)

Insulin (4)Beta-Blockers 9 (2.63%) Atenolol (3)

Carvedilol (2)Sotalol (1)

Propranolol (3)

RESULTSTABLE-5: VARIOUS CLASSES OF DRUGS WITH FREQUENCY OF CAUSING ADRs

Drug Class No. (%) of ADRs Individual Drugs (number)

Anti-depressants 6 (1.75%) Escitalopram (6)

Opioid analgesics 3 (0.87%) Morphine (3)

Multi-vitamins 5 (1.46%) Vitamin B1, B6, B12 (5)

Anti-histaminics 2 (0.58%) Diphenhydramine (2)

Sedatives 2 (0.58%) Diazepam (2)

RESULTSTABLE-5: VARIOUS CLASSES OF DRUGS WITH FREQUENCY OF CAUSING ADRs

Drug Class No. (%) of ADRs Individual Drugs (number)

Phenothiazines 3(0.87%) Trifluperazine (1), Olanzapine (2)

Cardiac stimulants 3 (0.87%) Digoxin (3)

Anti-epileptics 6 (1.75%) Phenytoin (6)

Oral hypoglycemic agents 6(1.75%) Glimepiride (2), Glyburide (4)

Haematinics 3(0.87%) Ferrous fumarate(2), Ferrous sulphate (1)

Anti-asthmatics 4 (1.16%) Salbutamol (4)

RESULTS

Moxifloxa

cin

Ciprofloxa

cin

Gatifloxa

cin

Ceftrixone

Etham

abuto

l

Strepto

mycin

Isoniaz

id

Rifampin

Predniso

lone

Hydro

corti

sone

Betameth

asone

Dexameth

asone

Serra

tiopeptidase

Warf

arin

Heparin

Enala

pril

Aspirin

Furo

semide

Diclofenac

0

2

4

6

8

10

12

14

16

18

20

Most common drugs causing ADRs

Nu

mb

er

of

AD

Rs

Ca

us

ed

RESULTS

GastritisSkin Rashes

HypokalemiaHypersensitivity

HepatotoxicityEncephalopathy

LeucopeniaGastric Bleeding

DiarrhoeaVomiting

HypotensionMuscle Weakness

ThrombocytopeniaTachycardia

Cochlear ToxicityItching/Pruritis

DyspepsiaAnemia

EosinophiliaHyponatremia

0 5 10 15 20 25

2012

1111

101010

988

76

5555

4444

Most common Adverse Drug Reactions

RESULTS

Gastrointestinal

Skin

CNS

Hematological

Metabolic

CVS

Urinary/Renal

ENT

Respiratory

Immunological

Skeletal

Muscular

Hormonal

Opthalmological

Gynaecological

0 10 20 30 40 50 60 70 80 90

81

43

40

34

33

22

18

18

10

11

8

7

5

4

1

Organ Systems affected by ADRs

No. of Adverse Drug Reactions

RESULTS

40.92

14.03

8.77

7.89

3.5

3.5

3.5

2.63

15.26

Classes of drugs responsible for causing ADRs (numbers indicate

percentage)

Anti-infectivesSteroidsAnti-coagulantsNSAIDsDiureticsAnti-hypertensivesHormonesBeta-BlockersOthers

IMPLICATIONS/CONCLUSIONS ADRs continue to represent a considerable burden on our healthcare system,

accounting for 6.23% Kashmiri patients visiting a tertiary care hospital like SKIMS, either for referral or hospitalization and a majority (81.57%) of these ADRs were preventable.

Rate of incidence of ADR was found to be higher (7.73%) in patients presenting to the OPD clinic of Internal Medicine, followed by 6.15% in patients admitted to the Internal Medicine ward and 5.74% patients visiting the Accident and Emergency Department of SKIMS during the period of study.

Out of a total of 342 patients experiencing various kinds of ADRs, 70.17% patients were those admitted to the Internal Medicine ward whereas 12.57% patients were those that presented to the OPD clinic of Internal Medicine and 17.25% patients were those that visited the Accident and Emergency Department of SKIMS during the period of study.

It was seen that 81/342 (23.68%) patients had mild ADRs while 237/342 (69.29%) patients had ADRs of moderate severity and 24/342 (7.01%) patients had severe ADRs. Thus a majority of the ADRs detected were of moderate severity.

The four classes of drugs most frequently suspected in admissions due to ADRs were anti-infective agents (40.92%) including anti-tubercular drugs (13.15%), steroids (14.03%), anti-coagulants (8.77%) and NSAIDs (7.89%).

IMPLICATIONS/CONCLUSIONSThe most common drugs related to ADRs were Moxifloxacin (17),

Ciprofloxacin (13), Gatifloxacin (11), Ceftriaxone (16), Ethambutol (11), Streptomycin (13), Isoniazid (11), Rifampin (8), Prednisolone (10), Hydrocortisone (8), Betamethasone (14), Dexamethasone (16), Serratiopeptidase (11), Warfarin (19), Heparin (8) and Enalapril (9).

Most common adverse drug reactions were gastritis (n=20), skin rashes (n=12), hypokalemia (n=11), hypersensitivity (n=11), hepatotoxicity (n=10), gastric bleeding (n=9), hypotension (n=7), thrombocytopenia (n=5), tachycardia (n=5), cochlear toxicity (n=5), anemia (n=4), diarrhea (n=8), vomiting (n=8), encephalopathy (n=10), leucopenia (n=10), itching/pruritis (n=5), dyspepsia (n=4), muscle weakness (n=6), eosinophilia (n=4) and hyponatremia (n=4).

The organ-systems most commonly affected were gastrointestinal (81%), dermatological (43%), central nervous (40%), hematological (34%), metabolic (33%), cardiovascular (22%), urinary (18%), ENT (18%), immunological (11%) and respiratory (10%) systems.

The average cost per patient hospitalized with an ADR was INR 3,285/- (USD 65$). The total cost to the hospital due to hospitalization of patients presenting with ADRs over the 9 month period in the IPD of General Medicines at SKIMS, Srinagar was found to be INR 11,23,470/- (USD 22469).

IMPLICATIONS/CONCLUSIONS The number of suspected adverse drug reactions was significantly

higher in females as compared to males in all age groups above 18 years of age, and the size of the increased risk was relatively consistent across all the age-bands.

Adverse drug reaction recording rates increased further in the age group of 80s and 90s. The highest rate of ADRs in males was recorded in the >79 year age group and in females in the age group of 59-78 years.

Considering that 81.57% ADRs were found to be preventable, adequate measures need to be taken to decrease the unnecessary burden of ADRs.

Qualified pharmacists too must be involved in the process of achieving drug safety by allowing them to contribute towards the prevention, identification, documentation, and reporting of ADRs.

They must be included in the daily ward rounds and assigned suitable duties in areas of Clinical, Hospital and Community Pharmacy.

Present study paved way for the establishment of a full-fledged Pharmacovigilance centre in the tertiary care hospital and lead to the initiation of Pharmaceutical Care Services in its Internal Medicine Ward.

AcknowledgementAuthors are thankful to the medical

and nursing staff of the study departments at Sher-i-Kashmir

Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India

for their support and cooperation.