Rationale and design of a European epidemiological post-authorization safety study (PASS) program: rivaroxaban use in routine clinical practice.

BACKGROUND: Rivaroxaban is a highly selective factor Xa inhibitor approved for use in Europe for multiple indications. STUDY DESIGN AND METHODS: The European rivaroxaban epidemiological post-authorization safety study (PASS) program consists of seven complementary observational studies. For four of the studies, data are obtained from health-care databases in the UK, the Netherlands, Germany, and Sweden. These database studies describe patterns of rivaroxaban use and patient characteristics over time, and investigate safety and effectiveness outcomes in new users of rivaroxaban using a cohort analysis and nested case-control analysis. To put these results in context, safety outcomes are also analyzed in new users of standard of care. In addition, a modified prescription event monitoring study conducted in the early post-launch phase in primary care, and two specialist cohort event monitoring studies that investigated rivaroxaban use in the secondary care hospital setting, systematically collected drug utilization and safety data via questionnaires completed by health-care professionals in the UK. DISCUSSION: The European rivaroxaban epidemiological PASS is a comprehensive program of complementary studies generating evidence from patients treated in routine clinical practice that will expand our understanding of the risk-benefit profile of rivaroxaban.

Natural Micronized Progesterone Sustained Release (SR) and Luteal Phase: Role Redefined!!

Role of progesterone in reproductive medicine is evolving with its suggested clinical role for the hormonal and nonhormonal actions in reproductive medicine. The main function of progesterone is to induce 'secretory' changes in endometrium that is further complimented by its immunomodulatory and anti-inflammatory actions. It positively modulates PIBF, NK cells and HOXA 10 genes for better implantation. MHRA recommends Serum Progesterone levels ≥14ng/ml in the mid-luteal phase for supporting pregnancy adequately. Oral Natural Micronized Progesterone SR formulation represents a therapeutic advance in this direction offering 'therapeutic compliance' with oral formulation while avoiding the local side effects related to long-term patient compliance in reproductive disorders. The formulation offers round the clock efficiency and efficacy with single dose administration thereby improving patient convenience and compliance. This formulation has been marketed globally since 1986 utilizing the well validated drug delivery system involving Methylcellulose base. The clinical utility of this formulation is further suggested especially in various conditions related with luteal phase insufficiency and Bad obstetric history (BOH) or luteal phase support in ART. The level of evidence has been quite robust with several clinical studies including Prescription Event Monitoring and Investigator initiated studies supporting the clinical role of oral NMP SR formulation especially in 'Real world' clinic settings for Luteal phase insufficiency that may be physiological or iatrogenic.

Short Term Safety and Tolerability of a Fixed Dose Combination of Olmesartan, Amlodipine and Hydrochlorothiazide.

OBJECTIVE: To assess the short term safety and tolerability of a fixed dose combination (FDC) of olmesartan, amlodipine and hydrochlorothiazide (OAH) in real-world clinical setting in India. MATERIALS AND METHODS: Physicians were requested to provide eight weeks observational clinical event data of the patients prescribed with FDC of Olmesartan (20/40mg), Amlodipine (5mg) and hydrochlorothiazide (12.5mg) in the prescription event monitoring (PEM) forms. Data on patients' demographics, indication for FDC, concomitant medication and other relevant history was also collected and was analysed with descriptive statistics. RESULTS: Two hundred thirty eight physicians provided data of 4763 patients. Mean age of the population was 55±7 years and males were 59.3%. The commonest indication for the FDC was uncontrolled hypertension (60.7%). Diabetes and dyslipidemia were present in 37.9% and 35.1% respectively. Concomitant medications included statins (42.3%), oral anti-diabetic (33.7%) and antiplatelet agents (24.7%). Pedal oedema (0.29%) was the most common adverse event (AE) reported followed by headache (0.16%), giddiness (0.15%), light headedness (0.15) and stroke (0.15%). Other less common (0.04%) reported AEs were tiredness, dizziness, gastritis, hypersomnia, hypoglycaemia, lower respiratory tract infection (LRTI), weakness, diarrhea, labyrinthitis, urinary tract infection, hyponatremia and hypotension. Occurrence of AEs was more common in patients with uncontrolled hypertension (60.74%). CONCLUSION: The FDC of olmesartan, amlodipine and hydrochlorothiazide prescribed most frequently for patients with uncontrolled hypertension and co-morbidities was found to be safe and well tolerated over a short period of observation.

A prescription event monitoring study on the utility of garenoxacin, a newer fluoroquinolone in India.

BACKGROUND: Prescription event monitoring (PEM) study is conducted worldwide. The main objective of such study is to monitor the adverse events when a drug is being prescribed in "real life clinical" settings. PEM studies are being looked upon as an essential observational tool of postmarketing surveillance. Garenoxacin, a newer fluoroquinolone offers an excellent spectrum of antimicrobial coverage, which includes Gram-positive, Gram-negative, anaerobes and atypical microorganism. This broad spectrum of activity is attributed to its unique structure. AIM: The aim was to assess the safety profile of garenoxacin in Indian settings. MATERIALS AND METHODS: A total of 400 doctors across the country participated in the study. Data from 12,498 patients was obtained. Monitoring of each patient was done for any adverse events. RESULTS: As an initial line of therapy garenoxacin was preferred in majority of cases of community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis. Adverse events were reported in 159 patients which included 0.5% cases with nausea/vomiting, 0.1% cases with diarrhea. Central nervous system side-effects like drowsiness or dizziness was reported in 0.02% of the cases. All the adverse events were of mild to moderate severity and did not require hospitalization. CONCLUSION: Garenoxacin a novel desfluoroquinolone appears to be an ideal antimicrobial agent for the treatment of various respiratory tract infections including CAP. With superior safety profile, excellent antimicrobial coverage and a convenient once a day dosing garenoxacin appears to improve the patient compliance.

Pharmacologic reperfusion therapy with indigenous tenecteplase in 15,222 patients with ST elevation myocardial infarction - the Indian Registry.

OBJECTIVE: To study the efficacy and safety of single intravenous bolus administration of indigenously developed tenecteplase (TNK-tPA) in the management of patients with ST-elevation myocardial infarction (STEMI) in clinical practice. METHODS: Observational, prescription-event monitoring study. RESULTS: Data of 15,222 patients who had STEMI and received weight adjusted TNK injection was analyzed. Overall 95.43% patients had clinically successful thrombolysis (CST). In the different subgroups, hypertensives, diabetics, smokers and hyperlipidemic patients had CST rates comparable to the general patient data. CST rates were significantly lower in the elderly patients (>70 years; 92.11%; p < 0.0001), in patients with history of Ischemic Heart Disease (IHD, 93.86%; p = 0.0004) and in patients receiving delayed treatment (>6 h after onset of chest pain; 85.38%; p < 0.0001). CST was significantly higher in patients who received an early thrombolysis (<3 h after onset of chest pain; 96.54%; p = 0.006). Overall mortality was 1.69%, while it was significantly higher in the elderly (4.42%), patients with history of IHD (2.67%), females (2.93%) and in those who received delayed treatment (4.98%). The overall incidences of intracranial hemorrhage (ICH), bleeding excluding ICH, stroke and ventricular tachyarrhythmia were 0.39%, 2.01%, 0.16% and 2.35% respectively. Age >70 years, diabetes, hyperlipidemia and history of IHD were associated with a higher incidence of heart failure, myocardial re-infarction or ventricular tachyarrhythmias. However, incidence of ICH and bleeding other than ICH was comparable amongst all patient subgroups. CONCLUSION: This study confirms the safety and efficacy of indigenous tenecteplase in Indian patients with STEMI, including high risk subgroups. It also highlights the fact that delayed treatment denotes denial of benefits of pharmacologic reperfusion therapy.

Health outcome and safety assessment of a fixed dose combination of Amantadine, Paracetamol, Chlorpheniramine maleate, and Phenylephrine introduction in India: A prescription event monitoring study.

To assess the likely impact of a fixed dose combination (FDC) of Amantadine, Paracetamol, Chlorpheniramine maleate, and Phenylephrine on the health outcome and safety profile arising from the complementary action of amantadine and other ingredients, we conducted a Prescription Event Monitoring study for patients with suspected Influenza symptoms who were prescribed this FDC in 'real life clinical settings' or clinical practice. Between August 2010 and March 2011, Questionnaires were sent to doctors who provided data on the health outcome or safety profile. Sedation and allergy, including rash, were noted in few of the patients. None of the patients reported any major events. Most of the patients (60%) were initiated on FDC therapy within the first 24 hours of symptom onset. Even as a significant proportion of the patients (24.9%) had a concurrent history of allergy / rhinitis including asthma, few of them (4.1%) reported lack of improvement and had to be complemented with antibiotics. The FDC of Amantadine, Chlorpheniramine, Paracetamol, and Phenylephrine was found to be safe and well-tolerated when administered to patients within the first 24 to 48 hours of symptom onset.

How to Minimize ‘Lost to Follow-up’ in a Cohort Study in Pharmacoepidemiology? : / 薬剤疫学

<b>Objective</b> : To find methods to minimize ‘lost to follow-up’ in the long-term follow-up in a pilot study of Prescription-Event Monitoring in Japan (J-PEM) where hypertensive subjects who took losartan or a control drug and gave informed consent to the study were directly followed by researcher for years.<br><b>Design</b> : Cohort Study<br><b>Methods</b> : We conducted the follow-up survey twice, in which questionnaires were sent to hypertensive patients who had consented to being involved in the survey and returned it by mail. In the questionnaire, we asked about the use of the monitoring drug, change of medical institutions for the treatment of hypertension, significant health-related events. In the second survey, we reminded the non-responders by a letter of reminder and by telephone. When no information was obtained from the subject, we sent a letter, together with a copy of the informed consent given by the subject, to the municipal office where the subject's home was registered to inquire about the subject's current address and related information including the vital status. We calculated Standardized Mortality Ratio (SMR) using the information on death obtained from the mailed questionnaires, telephone and information in the municipal office.<br><b>Results</b> : In a pilot study of J-PEM on losartan, 4344 and 3517 questionnaires were sent to pharmacists and doctors, respectively. The doctors handed the informed consent form to the patients and 422 patients agreed to participate the study and sent back the signed form to the study office. In the first and second surveys, a questionnaire was mailed to the subject approximately 1 and 5 years after the first prescription of losartan or a control drug, respectively. The response rate was 73 and 60% in the 1 st and 2 nd survey, respectively. In the manuscript, the results of the 2 nd survey were mainly presented. The reminders by mail and telephone increased the response rate from 60 to 81% and provided the information on the vital status for 86% of the subjects. The response rate was further increased to 84% and the vital status was known for 99% when the information in the municipal office was used. SMR was estimated to be 0.59 (95% CI : 0.34-1.01) before reminding subjects, 0.78 (0.52-1.17) after reminding subjects by a letter and telephone and 0.92 (0.65-1.31) after further addition of the information from the municipal office. During the 5 years of the observation, 21% of 343 subjects who sent back a filled questionnaire did and 70% did not change the clinic/hospital where they received the care for hypertension, while 9% did not answer the relevant question.<br><b>Conclusion</b> : The method of the systematic survey may be useful in minimizing the ‘lost to follow-up’ subjects in the long-term pharmacoepidemiology studies in Japan where a patient can change the clinic/hospital for his/her own health care without any letter of reference. In the systematic survey, the researchers may try to follow the subjects by using several methods including reminders like a letter or telephone as well as the use of the information in the municipal office. To facilitate better follow-up, a careful design of the study including the proper design of the informed consent form is essential to maximize the amount and quality of the available information, particularly when the subject has a serious event or dies in a hospital or institution apart from that where the patient has been registered.

Study on British Prescription-events Monitoring System / 中国药房

OBJECTIVE:To facilitate the evolvement of Chinese ADR monitoring.METHODS:Approaches concerning prescription-event monitoring in England and its progresses were investigated.RESULTS:Early warning signals that of precaution effect were available through prescription-event monitoring on primary safeguarded newly marketed drugs.CON?CLUSION:Voluntary ADR reporting system is now prevalent in China,the prescription-event monitoring system assumed by England set a good example for us to follow.

The Need to Complement the Information Obtained from Pharmacists in the Community Pharmacy by That in the Hospital Pharmacy in Prescription-Event Monitoring in Japan (J-PEM) / 薬剤疫学

Objective : To evaluate the necessity to complement the information obtained from pharmacists in the community pharmacy by that from the hospital pharmacy in Prescription-Event Monitoring in Japan (J-PEM) by using data in a J-PEM pilot study.<BR>Methods : For each patient, two questionnaires were sent to the prescribing doctor and the pharmacist who registered the patient ID code in the pilot study. If the patient ID code was registered by the pharmacist in the community pharmacy and if a pharmacist inside the hospital where the prescription was issued was willing to co-operate, a third questionnaire for the same patient was sent to the pharmacist in the hospital pharmacy. The information given by pharmacists was analyzed for 150 pairs of questionnaires (on 150 patients) sent back from pharmacists in both community and hospital pharmacies. The questions in the questionnaire were categorized into [1] those on drugs used by patients (concurrent drugs, daily dose of the drug monitored, and compliance), [2] those on events which the patient had experienced after the prescription of the drug monitored, [3] those on patients (the first date of prescription, reason of prescribing the drug monitored, initial date when the disease developed, underlying diseases or complications and whether and when the patient was lost to follow-up). The questionnaires were examined to determine whether the answer was given to each question. When the answer was given, its quality and quantity were then assessed. The answer to each question given by the pharmacist in the community pharmacy (C) and that by the pharmacist in the hospital pharmacy (H) were compared by the McNemar test after the pairs of answers were classified into the following categories : [1] C is better than H, [2] H is better than C, [3] C and H are similar to each other, and [4] impossible to classify. The difference was considered to be significant where p<0.05.<BR>Results and conclusion : For the initial date when the disease developed and 'underlying diseases or complications', H was significantly better than C. However, for concurrent drugs, compliance and events, C was significantly better than H. Otherwise, the difference was not statistically significant. Being compatible with the superiority of C over H in regard to concurrent drugs and events, the fraction of patients lost to follow-up during the observation period was small not only in H but also in C. This observation may be associated with the fact that almost all prescriptions were issued by a single hospital in more than 60% of community pharmacies in the pilot study, and most patients identified in the study were probably a regular visitor to one of such community pharmacies. The most important information to be provided by the pharmacists in J-PEM is that on events and drugs used by patients. It is thought to be not necessary to complement the information obtained from the community pharmacy by that from the hospital pharmacy.

Feasibility of Conducting Event Monitoring in Japan Similar to Prescription-Event Monitoring in England : A Report on a Health Sciences Research to Ministry of Health and Welfare Japan in 1997 / 薬剤疫学

Background : With a support from Ministry of Health and Welfare (MHW) Japan, we embarked on a pilot study for Prescription-Event Monitoring (PEM) adapted to Japanese environment. <BR>Methods : A pilot study was conducted according to the report on this subject to MHW in 1996. <BR>Results and Conclusion : PEM using monthly claims called as “Rezept” issued by individual hospitals and clinics is judged to be difficult unless the use of the claims for epidemiological studies is legally separated from the examination process of the medical cost claimed. PEM using the prescriptions dispensed by individual pharmacies is easier to conduct. Some progress has been attained by employing the latter scheme in the pilot study where approximately 1300 patients with a new antidiabetic agent, troglitazone, are compared with 1300 patients who have recently started one of “old” antidiabetics.

Activity Report of the Liaison Meetings of Reserchers Interested in Health Insurance Claims as Data Source / 薬剤疫学

Background : Health insurance claims contain invaluable data for epidemiological survey. However their use for research purposes has been hampered by both bureaucratic red-tape and technical limitations. These include the lack of legal rationale for disclosure and the lack of electronic data transfer. In response to the recent advancement in these field, such as the governmental policy change to allow disclosure of the claims to patients and a rapid computerization of the claims, researchers interested in health insurance claims held liaison meetings to exchange views and know-hows to facilitate the epidemiological research using health insurance claims.<BR>Reports on the Meeting : The liason meetings have so far been held twice as part of Japan Public Health Association annual assembly, at Yamagata in 1995 and at Yokohama in 1997, both sponsored by the author. Fourteen researchers presented their research activities using health insurance claims and discussed with the attendants on their experience to overcome the bureaucratic red-tape and technical limitations. Two of the presenters beside the author were pharmacoepidemiologists : Dr. Hayashi addressed the value and possibilities of the claims as data source for pharmacoepidemiology and Dr. Kubota proposed PEM (Prescription Event Monitoring) using health insurance claims as triggers to complement the present voluntary ADR reporting.<BR>Implications : Since the bureaucratic and technical obstacles may be better handled through a coordinated and liaisoned action of the researchers, it is necessary to form a consortium of researchers and professionals who have any interest in health insurance claims regardless of their purposes and make guidelines and recommendations to assure legitimate and appropriate utilization of the potentially sensitive but useful individual information.

Feasibility of Conducting Event Monitoring in Japan Similar to Prescription-Event Monitoring in England : A Report on a Health Sciences Research to Ministry of Health and Welfare Japan in 1996 / 薬剤疫学

Background : With a suppport from Ministry of Health and Welfare (MHW) Japan, we studied the feasibility of conducting event monitoring in Japan similar to Prescription-Event Monitoring in England. The manuscript presented is a report to MHW in 1996.<BR>Methods : Means available in Japan to identify drug, patient and doctor are examined. In addition, any modification needed to make on a questionnaire sent to doctors in PEM conducted in Japan is examined.<BR>Results and Conclusion : Monthly claims called as “Rezept” issued by individual hospitals and clinics and sent to insurers and outpatient prescriptions issued by hospitals to be dispensed by the pharmacies outside the hospitals are considered to be two available means to identify drug, patient and doctor. To have a sample representative of all drug users, the use of “Rezept” is needed as only a fraction of outpatient prescriptions are dispensed by independent pharmacies. However, the use of prescriptions dispensed by the independent pharmacies together with the cooperation of individual pharmacies is capable of finding a contemporary control which is a group of patients who have recently started “old” drugs comparable to the new “test drug”. In Japan no doctor may have a complete list of the hospitals and clinics a patient has visited and it is mandatory to ask doctors the last date when the patient visited the doctor. To clarify what problems arise when a PEM-like study is introduced to Japan, a pilot study is going to be done during 1997 and the feasibility will be examined further based on the results.