Tropical Medicine and International Health
doi:10.1111/tmi.12481
volume 20 no 6 pp 797–806 june 2015
Adverse Drug Reaction reports for cardiometabolic drugs from sub-Saharan Africa: a study in VigiBase Derbew Fikadu Berhe1,2, Kristina Juhlin3, Kristina Star3, Kidanemariam G. M. Beyene4, Mukesh Dheda5, Flora M. Haaijer-Ruskamp1, Katja Taxis6 and Peter G. M. Mol1,7 1 Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands 2 Department of Pharmacy, College of Health Sciences, Mekelle University, Mekelle, Tigray, Ethiopia 3 Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden 4 pharmacovigilince centre, Regulatory Standards Setting and Information Delivery Directorate, Addis Ababa, Ethiopia 5 pharmacovigiliance Unit, Medicines Regulatory Authority, National Department of Health, Pretoria, South Africa 6 Department of Pharmacy, Unit Pharmacotherapy & Pharmaceutical Care, University of Groningen, Groningen, The Netherlands 7 Dutch Medicines Evaluation Board, Utrecht, The Netherlands
Abstract
objective Identifying key features in individual case safety reports (ICSR) of suspected adverse drug reactions (ADRs) with cardiometabolic drugs from sub-Saharan Africa (SSA) compared with reports from the rest of the world (RoW). methods Reports on suspected ADRs of cardiometabolic drugs (ATC: A10[antidiabetic], B01 [antithrombotics] and C[cardiovascular]) were extracted from WHO Global database, VigiBaseâ(1992–2013). We used vigiPoint, a logarithmic odds ratios (log2 OR)-based method to study disproportional reporting between SSA and RoW. Case-defining features were considered relevant if the lower limit of the 99% CI > 0.5. results In SSA, 3773 (9%) of reported ADRs were for cardiometabolic drugs, in RoW for 18%. Of these, 79% originated from South Africa and 81% were received after 2007. Most reports were for drugs acting on the renin–angiotensin system (36% SSA & 14% RoW). Compared with RoW, reports were more often sent for patients 18–44 years old (log2 OR 0.95 [99 CI 0.80; 1.09]) or with non-fatal outcome (log2 OR 1.16 [99 CI 1.10; 1.22]). Eight ADRs (cough, angioedema, lip swelling, face oedema, swollen tongue, throat irritation, drug ineffective and blood glucose abnormal) and seven drugs (enalapril, rosuvastatin, perindopril, vildagliptin, insulin glulisine, nifedipine and insulin lispro) were disproportionally more reported in SSA than in the RoW. conclusions ‘In recent years, the number of adverse drug reactions (ADRs) reported in SubSaharan Africa (SSA) has sharply increased. The data showed the well-known population-based differential ADR profile of ACE inhibitors in the SSA population.’ keywords Adverse drug reactions, cardiometabolic drugs, sub-Saharan Africa, pharmacovigilance, Individual Case Safety Report
Introduction Health care in sub-Saharan Africa (SSA) has prioritised fighting communicable diseases; HIV, TB and malaria [1]. In concert, pharmacovigilance activities that have only fairly recently been established in the region [2, 3], focus on identifying adverse drug reactions ADRs for drugs that are used for these diseases [4, 5, 6]. For example, antiviral agents are used more extensively in SSA than in any other part of the world. Thus, the region is the logical place to look for rare and hitherto unknown ADR’s to such drugs and direct scarce phar-
© 2015 John Wiley & Sons Ltd
macovigilance resources at collecting these types of events. However, non-communicable diseases in the region, WHO predicts, will be the most common cause of death in Africa by 2030 [7, 8]. It is expected that the use of drugs to treat these diseases will expand. However, whether the region should also expand their focus to safety issues of drugs used to treat non-communicable diseases such as cardiometabolic disease remains to be established. Many of the drugs to treat cardiometabolic diseases have already been marketed in the Western world for extensive periods, and their ADR profile is usually well 797
Tropical Medicine and International Health
volume 20 no 6 pp 797–806 june 2015
D. F. Berhe et al. ADRs for cardiometabolic drugs from SSA
established. One could argue that data collected by pharmacovigilance centres in developing countries are not likely to add to our knowledge of these drugs’ risk profiles. Aagaard et al. [9] showed that most ADRs reported from the African continent are for drugs used to treat infectious diseases. Relatively few ADRs were reported for cardiometabolic drugs in Africa compared to the rest of world (RoW). Still, there are several arguments why the safety profile of drugs that are mostly studied in the Western world may not be the same in the SSA setting. ADR prevalence rates may differ as the population at risk is different. In SSA, patients with cardiometabolic disorders may frequently have infectious comorbidities such as malaria, TB and HIV. This may result in patients experiencing medication harm because of drug–drug, drug–disease and disease–disease interactions. Genetic factors may also determine drug–drug interaction induced ADRs [10, 11]. Pharmacogenomics studies in SSA are very challenging to perform as Africans have the world’s greatest genetic variation [12, 13]. Therefore, the SSA population may react to cardiometabolic drugs differently, and the prevalence and type of ADRs may be quite different from that in the RoW population. The aim of this study was to identify key features of ADR reports with cardiometabolic drugs from SSA compared with reports from the RoW. Methods Data were extracted from the WHO Global Individual Case Safety Report (ICSR) database, VigiBaseâ [14, 15], the world’s largest repository of such reports [15]. In April 2014, it held more than 9 million reports since 1968 from the 118 countries that are official members of the WHO Programme for International Drug Monitoring [2, 14]. For this study, the included data were limited to the period 1992 – June 2013, thus including 8.1 million ICSRs. An ICSR is an anonymised report for a single individual who experienced one or more adverse event that may be linked to the use of one or more drugs. In our study, WHO-UMC official members in SSA and RoW within the WHO Programme for International Drug Monitoring were included (Figure 1) [2]. Reports on suspected ADRs, for any drug and separately for cardiometabolic drugs (ATC: A10 [antidiabetes], B01 [antithrombotics] and C [cardiovascular]) were extracted from VigibaseTM. As a reference, we also collected all ADR reports for cardiometabolic drugs in the RoW. Prior to analysis, suspected duplicate reports, as identified by an automated screening, were excluded [16]. ADRs were classified following the Medical Dictionary for Regula798
Number of ICSRs < 100 100 - 499 500 - 999 1,000 - 4,999 5,000 + % Cardiometabolic drugs = 10 Figure 1 Individual Case Safety Reports (ICSRs) per country*, with percentage associated with cardiometabolic drugs. *Only SSA countries that are official WHO-UMC members and contributed reports to VigiBaseTM are indicated in this figure. Note, that the northern African countries were not included in our study.
tory Authorities (MedDRA); grouped at the System Organ Classification (SOC) level and at the individual preferred term (PT) level. Analysis To identify key features of reports on cardiometabolic drugs in SSA, we used vigiPoint, a method developed by WHO-UMC [17]. The method uses disproportionality to compare report features from one data subset of interest with one or more reference data sets. In this study, reports on cardiometabolic drugs in SSA were compared with two references: reports on cardiometabolic drugs outside SSA and reports from SSA with other than cardiometabolic drugs. Included report features were reporting year, notifier (e.g. pharmacist, physician etc.), age, gender, ADR outcome (fatal/non-fatal), reported suspected drugs and the type of reported ADRs. Key features of reports on cardiometabolic drugs in SSA were identified by comparing the range of features for this dataset to
© 2015 John Wiley & Sons Ltd
Tropical Medicine and International Health
volume 20 no 6 pp 797–806 june 2015
D. F. Berhe et al. ADRs for cardiometabolic drugs from SSA
the corresponding features in the two references using shrinkage odds ratios, defined as: log2 OR ¼ log2
aþk ; bc=d þ k
where k is the strength of shrinkage and a, b, c and d are the number of reports with or without a specific feature in the subset of interest and the reference as outlined in the contingency table below.
For the overall reporting in SSA, six countries contributed ≥1000 reports; South Africa, Nigeria, Kenya, Ghana, Namibia and Zimbabwe, and 13 countries contributed fewer than 100 reports (Figure 1). Twenty of the 27 countries contributed at least one report with cardiometabolic drugs, of which four countries; South Africa, Nigeria, Ghana and Madagascar, contributed more than 100 reports. The number of reports from SSA has grown rapidly since 2007 (Figure 2). Individual Case Safety Reports characteristics
Reports not including feature x
a c
b d
Reports for which the value of feature x is missing, for example age unknown, are excluded from this calculation to not distort the distribution of the feature among the reports for which the value is known. As a key feature, we considered a feature for which the lower 99% confidence interval of the log2 odds ratio is greater than 0.5, or the upper 99% confidence interval is lower than 0.5. This threshold corresponds roughly to a 40% increase or decrease of the feature compared to the reference data. For reference, a log2 odds ratio of 0 would mean that the feature was as common in the dataset of interest as in the reference data. Results Overall, 41 870 reports had been received from 27 countries in SSA. Of these, 3773 (9%) were for cardiometabolic drugs, which can be compared to 18% for RoW.
© 2015 John Wiley & Sons Ltd
Type of cardiometabolic drugs reported for ICSRs Cardiometabolic drugs implicated with most ICSRs in SSA and RoW were drugs acting on the renin–angiotensin system (36% SSA versus 14% RoW), lipid-modifying agents (18% vs. 20%), antidiabetics (14% vs. 18%) and antithrombotics (13% vs. 20%). Of these, enalapril 200 000
9000
180 000
8000
160 000
7000
140 000
6000
120 000
5000
100 000
4000
80 000
3000
60 000
2000
40 000
1000
20 000
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
10 000
N in SSA Figure 2 ICSRs reporting trend in SSA and ROW (1992 to June 2013). Cardiometabolic drug ICSRs in SSA (blue); Cardiometabolic drug ICSRs in Row (red); Other drug ICSRs in SSA (green). SSA, Sub-Sahara Africa; ROW, Rest of the world and CMDs, cardiometabolic drugs. Data cover 1992 to June 2013.
The notifier most frequently filing a report for a cardiometabolic drug was a physician both in SSA (83%) and in the RoW (55%). In SSA, most (48%) reports for cardiometabolic drugs were for patients aged 45–64 years, in the RoW (38%). In SSA, reports on non-cardiometabolic drugs generally concerned younger patients, with the largest percentage (56%) of reports for patients aged 18–44 years. More reports for cardiometabolic drugs were for female patients in SSA (57%) than in RoW (53%). Reports from SSA had fewer unspecified items; 1% (notifier), 22% (age) and 4% (gender) compared to 13%, 30% and 7% in the RoW, respectively. ICSRs were mostly non-fatal, 97% (SSA) and 93% (RoW), as shown in Table 1.
N in Row
Subset Reference
Reports on feature x
0
Reporting year
799
Tropical Medicine and International Health
volume 20 no 6 pp 797–806 june 2015
D. F. Berhe et al. ADRs for cardiometabolic drugs from SSA
Table 1 Individual Case Safety Report (ICSR) features of metabolically drugs in SSA and RoW, and of all other drugs in SSA Disproportional reporting for cardiometabolic drugs (log2 OR with 99% CI)
Cardiometabolic drugs SSA, % n = 3773 Notifier (reported by) Physician 82.8 Pharmacist 7.0 Other HCPs 4.9 Consumer/Non HCP 0.4 Literature 0.1 Lawyer 0 Other 4.8 Unspecified* 1.1 Age in year (otherwise specified) 0–27 days 0.2 28 days–23 months 0.2 2–11 1.3 12–17 1.0 18–44 21.3 45–64 48.2 65–74 18.1 ≥75 9.7 Unspecified* 21.9 Gender Female 56.6 Male 43.4 Unspecified* 3.8 Fatality Non-fatal 96.8 Fatal 3.2
RoW, % n = 1 243 110
Other drugs SSA, % n = 38 096
50.4 8.5 5.6 19.6 1.0 0.8 14.0 13.4
55.0 20.8 20.3 0.5 0.3 0 3.0 2.6
0.1 0.7 1.0 0.8 11.7 38.0 25.3 22.4 29.7
0.4 3.7 6.2 3.5 55.6 23.5 4.8 2.2 23.1
53.3 46.7 7.2
63.6 36.4 3.8
93.0 7.0
96.7 3.3
As compared with RoW 2.18 [2.12; 2.25]
4.21 [4.77; 3.72]
As compared with other drugs in SSA 1.93 [1.87; 2.00] 1.67 [1.89; 1.46] 2.11 [2.37; 1.87]
1.51 [1.77; 1.26]
1.31 [1.52; 1.11]
1.82 1.64 1.12 2.15 1.53 1.85 1.74
[2.44; 1.29] [2.10; 1.23] [1.61; 0.69] [2.29; 2.01] [1.43;1.62] [1.69;2.00] [1.52;1.94]
1.16 [1.10;1.22] 0.98 [1.29; 0.70]
% reports within a variable (per column), SSA: Sub-Sahara Africa; RoW: Rest of the world; HCPs: Healthcare professionals. Log2 OR (Logarithmic shrinkage odds ratio in base two) are presented for ICSR characteristics that are disproportionally associated with ICSRs in SSA compared to RoW that is either more often associated, lower bound of the 99% confidence interval (LCI) >0.5, or less often associated, upper bound of the 99% confidence interval 2% of Individual Case Safety Reports (ICSR). Reports originating from Sub-Saharan Africa (SSA) as black bars and originating from the rest of the world in grey bars. One ICSR may contain multiple potential ADR’s. MedDRA SOC level; A, blood and lymphatic system disorders; B, cardiac disorders; C, gastrointestinal disorders; D, general disorders and administration site conditions; E, investigations; F, metabolism and nutrition disorders; G, musculoskeletal and connective tissue disorders; H, nervous system disorders; I, respiratory, thoracic and mediastinal disorders; J, skin and subcutaneous tissue disorders; K, vascular disorders. MedDRA PTs are presented in descending order within each MedDRA SOC of SSA reports.
Key features As presented in Table 1, ICSRs with cardiometabolic drugs were more frequently reported by physicians in
© 2015 John Wiley & Sons Ltd
SSA, while consumers/non-Health Care Professionals and ‘others’ less often provided ICSRs compared to the RoW. In SSA, more reports with cardiometabolic drugs were received for patients 18–44 years old and fewer for 801
Tropical Medicine and International Health
volume 20 no 6 pp 797–806 june 2015
D. F. Berhe et al. ADRs for cardiometabolic drugs from SSA
patients aged 75 and older. There were no differences in gender, but reports in SSA had more often a non-fatal outcome. We found a higher level of reporting in SSA for the following eight ADRs (lip swelling, cough, angioedema, face oedema, swollen tongue, throat irritation, blood glucose abnormal and drug ineffective) and seven drugs (enalapril, rosuvastatin, perindopril, vildagliptin, insulin glulisine, nifedipine and insulin lispro) than in the RoW (Figure 5). Less often reported potential ADRs in SSA were death, congestive cardiac failure, flushing, myocardial infarction and blood glucose increase. A lower percentage of ADRs in SSA than in the RoW was reported to be related to warfarin, digoxin,
diltiazem, metoprolol, heparin, exenatide, nicotinic acid and rosiglitazone. Features for SSA reports with and without cardiometabolic drugs were also compared. The most notable differences were that physicians reported more frequently ADRs on cardiometabolic drugs and pharmacists and other HCPs less frequently. The patients in the cardiometabolic drug group were older (above 45 years old) than patients reported with other drugs in SSA (Table 1). Discussion In recent years, the number of potential ADRs reported for cardiometabolic and other drugs within the WHO
Drug Enalapril Rosuvastatin Perindopril Vildagliptin Insulin glulisine Nifedipine Insulin lispro . Warfarin Digoxin Diltiazem Metoprolol Heparin Exenatide Nicotinic acid Rosiglitazone .. ADR Lip swelling Cough Angioedema Face oedema Swollen tongue Throat irritation Blood glucose abnormal Drug ineffective ... Death Cardiac failure congestive Flushing Myocardial infarction Blood glucose increased –3
–2
Figure 5 Disproportionally reported drugs and ADRs for reports with cardiometabolic drugs in Sub-Saharan Africa versus the rest of the world, sorted by the value of the log2 OR. More often reported, lower bound of the 99% confidence interval >0.5, or less often reported, upper bound of the 99% confidence interval
doi:10.1111/tmi.12481
volume 20 no 6 pp 797–806 june 2015
Adverse Drug Reaction reports for cardiometabolic drugs from sub-Saharan Africa: a study in VigiBase Derbew Fikadu Berhe1,2, Kristina Juhlin3, Kristina Star3, Kidanemariam G. M. Beyene4, Mukesh Dheda5, Flora M. Haaijer-Ruskamp1, Katja Taxis6 and Peter G. M. Mol1,7 1 Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands 2 Department of Pharmacy, College of Health Sciences, Mekelle University, Mekelle, Tigray, Ethiopia 3 Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden 4 pharmacovigilince centre, Regulatory Standards Setting and Information Delivery Directorate, Addis Ababa, Ethiopia 5 pharmacovigiliance Unit, Medicines Regulatory Authority, National Department of Health, Pretoria, South Africa 6 Department of Pharmacy, Unit Pharmacotherapy & Pharmaceutical Care, University of Groningen, Groningen, The Netherlands 7 Dutch Medicines Evaluation Board, Utrecht, The Netherlands
Abstract
objective Identifying key features in individual case safety reports (ICSR) of suspected adverse drug reactions (ADRs) with cardiometabolic drugs from sub-Saharan Africa (SSA) compared with reports from the rest of the world (RoW). methods Reports on suspected ADRs of cardiometabolic drugs (ATC: A10[antidiabetic], B01 [antithrombotics] and C[cardiovascular]) were extracted from WHO Global database, VigiBaseâ(1992–2013). We used vigiPoint, a logarithmic odds ratios (log2 OR)-based method to study disproportional reporting between SSA and RoW. Case-defining features were considered relevant if the lower limit of the 99% CI > 0.5. results In SSA, 3773 (9%) of reported ADRs were for cardiometabolic drugs, in RoW for 18%. Of these, 79% originated from South Africa and 81% were received after 2007. Most reports were for drugs acting on the renin–angiotensin system (36% SSA & 14% RoW). Compared with RoW, reports were more often sent for patients 18–44 years old (log2 OR 0.95 [99 CI 0.80; 1.09]) or with non-fatal outcome (log2 OR 1.16 [99 CI 1.10; 1.22]). Eight ADRs (cough, angioedema, lip swelling, face oedema, swollen tongue, throat irritation, drug ineffective and blood glucose abnormal) and seven drugs (enalapril, rosuvastatin, perindopril, vildagliptin, insulin glulisine, nifedipine and insulin lispro) were disproportionally more reported in SSA than in the RoW. conclusions ‘In recent years, the number of adverse drug reactions (ADRs) reported in SubSaharan Africa (SSA) has sharply increased. The data showed the well-known population-based differential ADR profile of ACE inhibitors in the SSA population.’ keywords Adverse drug reactions, cardiometabolic drugs, sub-Saharan Africa, pharmacovigilance, Individual Case Safety Report
Introduction Health care in sub-Saharan Africa (SSA) has prioritised fighting communicable diseases; HIV, TB and malaria [1]. In concert, pharmacovigilance activities that have only fairly recently been established in the region [2, 3], focus on identifying adverse drug reactions ADRs for drugs that are used for these diseases [4, 5, 6]. For example, antiviral agents are used more extensively in SSA than in any other part of the world. Thus, the region is the logical place to look for rare and hitherto unknown ADR’s to such drugs and direct scarce phar-
© 2015 John Wiley & Sons Ltd
macovigilance resources at collecting these types of events. However, non-communicable diseases in the region, WHO predicts, will be the most common cause of death in Africa by 2030 [7, 8]. It is expected that the use of drugs to treat these diseases will expand. However, whether the region should also expand their focus to safety issues of drugs used to treat non-communicable diseases such as cardiometabolic disease remains to be established. Many of the drugs to treat cardiometabolic diseases have already been marketed in the Western world for extensive periods, and their ADR profile is usually well 797
Tropical Medicine and International Health
volume 20 no 6 pp 797–806 june 2015
D. F. Berhe et al. ADRs for cardiometabolic drugs from SSA
established. One could argue that data collected by pharmacovigilance centres in developing countries are not likely to add to our knowledge of these drugs’ risk profiles. Aagaard et al. [9] showed that most ADRs reported from the African continent are for drugs used to treat infectious diseases. Relatively few ADRs were reported for cardiometabolic drugs in Africa compared to the rest of world (RoW). Still, there are several arguments why the safety profile of drugs that are mostly studied in the Western world may not be the same in the SSA setting. ADR prevalence rates may differ as the population at risk is different. In SSA, patients with cardiometabolic disorders may frequently have infectious comorbidities such as malaria, TB and HIV. This may result in patients experiencing medication harm because of drug–drug, drug–disease and disease–disease interactions. Genetic factors may also determine drug–drug interaction induced ADRs [10, 11]. Pharmacogenomics studies in SSA are very challenging to perform as Africans have the world’s greatest genetic variation [12, 13]. Therefore, the SSA population may react to cardiometabolic drugs differently, and the prevalence and type of ADRs may be quite different from that in the RoW population. The aim of this study was to identify key features of ADR reports with cardiometabolic drugs from SSA compared with reports from the RoW. Methods Data were extracted from the WHO Global Individual Case Safety Report (ICSR) database, VigiBaseâ [14, 15], the world’s largest repository of such reports [15]. In April 2014, it held more than 9 million reports since 1968 from the 118 countries that are official members of the WHO Programme for International Drug Monitoring [2, 14]. For this study, the included data were limited to the period 1992 – June 2013, thus including 8.1 million ICSRs. An ICSR is an anonymised report for a single individual who experienced one or more adverse event that may be linked to the use of one or more drugs. In our study, WHO-UMC official members in SSA and RoW within the WHO Programme for International Drug Monitoring were included (Figure 1) [2]. Reports on suspected ADRs, for any drug and separately for cardiometabolic drugs (ATC: A10 [antidiabetes], B01 [antithrombotics] and C [cardiovascular]) were extracted from VigibaseTM. As a reference, we also collected all ADR reports for cardiometabolic drugs in the RoW. Prior to analysis, suspected duplicate reports, as identified by an automated screening, were excluded [16]. ADRs were classified following the Medical Dictionary for Regula798
Number of ICSRs < 100 100 - 499 500 - 999 1,000 - 4,999 5,000 + % Cardiometabolic drugs = 10 Figure 1 Individual Case Safety Reports (ICSRs) per country*, with percentage associated with cardiometabolic drugs. *Only SSA countries that are official WHO-UMC members and contributed reports to VigiBaseTM are indicated in this figure. Note, that the northern African countries were not included in our study.
tory Authorities (MedDRA); grouped at the System Organ Classification (SOC) level and at the individual preferred term (PT) level. Analysis To identify key features of reports on cardiometabolic drugs in SSA, we used vigiPoint, a method developed by WHO-UMC [17]. The method uses disproportionality to compare report features from one data subset of interest with one or more reference data sets. In this study, reports on cardiometabolic drugs in SSA were compared with two references: reports on cardiometabolic drugs outside SSA and reports from SSA with other than cardiometabolic drugs. Included report features were reporting year, notifier (e.g. pharmacist, physician etc.), age, gender, ADR outcome (fatal/non-fatal), reported suspected drugs and the type of reported ADRs. Key features of reports on cardiometabolic drugs in SSA were identified by comparing the range of features for this dataset to
© 2015 John Wiley & Sons Ltd
Tropical Medicine and International Health
volume 20 no 6 pp 797–806 june 2015
D. F. Berhe et al. ADRs for cardiometabolic drugs from SSA
the corresponding features in the two references using shrinkage odds ratios, defined as: log2 OR ¼ log2
aþk ; bc=d þ k
where k is the strength of shrinkage and a, b, c and d are the number of reports with or without a specific feature in the subset of interest and the reference as outlined in the contingency table below.
For the overall reporting in SSA, six countries contributed ≥1000 reports; South Africa, Nigeria, Kenya, Ghana, Namibia and Zimbabwe, and 13 countries contributed fewer than 100 reports (Figure 1). Twenty of the 27 countries contributed at least one report with cardiometabolic drugs, of which four countries; South Africa, Nigeria, Ghana and Madagascar, contributed more than 100 reports. The number of reports from SSA has grown rapidly since 2007 (Figure 2). Individual Case Safety Reports characteristics
Reports not including feature x
a c
b d
Reports for which the value of feature x is missing, for example age unknown, are excluded from this calculation to not distort the distribution of the feature among the reports for which the value is known. As a key feature, we considered a feature for which the lower 99% confidence interval of the log2 odds ratio is greater than 0.5, or the upper 99% confidence interval is lower than 0.5. This threshold corresponds roughly to a 40% increase or decrease of the feature compared to the reference data. For reference, a log2 odds ratio of 0 would mean that the feature was as common in the dataset of interest as in the reference data. Results Overall, 41 870 reports had been received from 27 countries in SSA. Of these, 3773 (9%) were for cardiometabolic drugs, which can be compared to 18% for RoW.
© 2015 John Wiley & Sons Ltd
Type of cardiometabolic drugs reported for ICSRs Cardiometabolic drugs implicated with most ICSRs in SSA and RoW were drugs acting on the renin–angiotensin system (36% SSA versus 14% RoW), lipid-modifying agents (18% vs. 20%), antidiabetics (14% vs. 18%) and antithrombotics (13% vs. 20%). Of these, enalapril 200 000
9000
180 000
8000
160 000
7000
140 000
6000
120 000
5000
100 000
4000
80 000
3000
60 000
2000
40 000
1000
20 000
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
10 000
N in SSA Figure 2 ICSRs reporting trend in SSA and ROW (1992 to June 2013). Cardiometabolic drug ICSRs in SSA (blue); Cardiometabolic drug ICSRs in Row (red); Other drug ICSRs in SSA (green). SSA, Sub-Sahara Africa; ROW, Rest of the world and CMDs, cardiometabolic drugs. Data cover 1992 to June 2013.
The notifier most frequently filing a report for a cardiometabolic drug was a physician both in SSA (83%) and in the RoW (55%). In SSA, most (48%) reports for cardiometabolic drugs were for patients aged 45–64 years, in the RoW (38%). In SSA, reports on non-cardiometabolic drugs generally concerned younger patients, with the largest percentage (56%) of reports for patients aged 18–44 years. More reports for cardiometabolic drugs were for female patients in SSA (57%) than in RoW (53%). Reports from SSA had fewer unspecified items; 1% (notifier), 22% (age) and 4% (gender) compared to 13%, 30% and 7% in the RoW, respectively. ICSRs were mostly non-fatal, 97% (SSA) and 93% (RoW), as shown in Table 1.
N in Row
Subset Reference
Reports on feature x
0
Reporting year
799
Tropical Medicine and International Health
volume 20 no 6 pp 797–806 june 2015
D. F. Berhe et al. ADRs for cardiometabolic drugs from SSA
Table 1 Individual Case Safety Report (ICSR) features of metabolically drugs in SSA and RoW, and of all other drugs in SSA Disproportional reporting for cardiometabolic drugs (log2 OR with 99% CI)
Cardiometabolic drugs SSA, % n = 3773 Notifier (reported by) Physician 82.8 Pharmacist 7.0 Other HCPs 4.9 Consumer/Non HCP 0.4 Literature 0.1 Lawyer 0 Other 4.8 Unspecified* 1.1 Age in year (otherwise specified) 0–27 days 0.2 28 days–23 months 0.2 2–11 1.3 12–17 1.0 18–44 21.3 45–64 48.2 65–74 18.1 ≥75 9.7 Unspecified* 21.9 Gender Female 56.6 Male 43.4 Unspecified* 3.8 Fatality Non-fatal 96.8 Fatal 3.2
RoW, % n = 1 243 110
Other drugs SSA, % n = 38 096
50.4 8.5 5.6 19.6 1.0 0.8 14.0 13.4
55.0 20.8 20.3 0.5 0.3 0 3.0 2.6
0.1 0.7 1.0 0.8 11.7 38.0 25.3 22.4 29.7
0.4 3.7 6.2 3.5 55.6 23.5 4.8 2.2 23.1
53.3 46.7 7.2
63.6 36.4 3.8
93.0 7.0
96.7 3.3
As compared with RoW 2.18 [2.12; 2.25]
4.21 [4.77; 3.72]
As compared with other drugs in SSA 1.93 [1.87; 2.00] 1.67 [1.89; 1.46] 2.11 [2.37; 1.87]
1.51 [1.77; 1.26]
1.31 [1.52; 1.11]
1.82 1.64 1.12 2.15 1.53 1.85 1.74
[2.44; 1.29] [2.10; 1.23] [1.61; 0.69] [2.29; 2.01] [1.43;1.62] [1.69;2.00] [1.52;1.94]
1.16 [1.10;1.22] 0.98 [1.29; 0.70]
% reports within a variable (per column), SSA: Sub-Sahara Africa; RoW: Rest of the world; HCPs: Healthcare professionals. Log2 OR (Logarithmic shrinkage odds ratio in base two) are presented for ICSR characteristics that are disproportionally associated with ICSRs in SSA compared to RoW that is either more often associated, lower bound of the 99% confidence interval (LCI) >0.5, or less often associated, upper bound of the 99% confidence interval 2% of Individual Case Safety Reports (ICSR). Reports originating from Sub-Saharan Africa (SSA) as black bars and originating from the rest of the world in grey bars. One ICSR may contain multiple potential ADR’s. MedDRA SOC level; A, blood and lymphatic system disorders; B, cardiac disorders; C, gastrointestinal disorders; D, general disorders and administration site conditions; E, investigations; F, metabolism and nutrition disorders; G, musculoskeletal and connective tissue disorders; H, nervous system disorders; I, respiratory, thoracic and mediastinal disorders; J, skin and subcutaneous tissue disorders; K, vascular disorders. MedDRA PTs are presented in descending order within each MedDRA SOC of SSA reports.
Key features As presented in Table 1, ICSRs with cardiometabolic drugs were more frequently reported by physicians in
© 2015 John Wiley & Sons Ltd
SSA, while consumers/non-Health Care Professionals and ‘others’ less often provided ICSRs compared to the RoW. In SSA, more reports with cardiometabolic drugs were received for patients 18–44 years old and fewer for 801
Tropical Medicine and International Health
volume 20 no 6 pp 797–806 june 2015
D. F. Berhe et al. ADRs for cardiometabolic drugs from SSA
patients aged 75 and older. There were no differences in gender, but reports in SSA had more often a non-fatal outcome. We found a higher level of reporting in SSA for the following eight ADRs (lip swelling, cough, angioedema, face oedema, swollen tongue, throat irritation, blood glucose abnormal and drug ineffective) and seven drugs (enalapril, rosuvastatin, perindopril, vildagliptin, insulin glulisine, nifedipine and insulin lispro) than in the RoW (Figure 5). Less often reported potential ADRs in SSA were death, congestive cardiac failure, flushing, myocardial infarction and blood glucose increase. A lower percentage of ADRs in SSA than in the RoW was reported to be related to warfarin, digoxin,
diltiazem, metoprolol, heparin, exenatide, nicotinic acid and rosiglitazone. Features for SSA reports with and without cardiometabolic drugs were also compared. The most notable differences were that physicians reported more frequently ADRs on cardiometabolic drugs and pharmacists and other HCPs less frequently. The patients in the cardiometabolic drug group were older (above 45 years old) than patients reported with other drugs in SSA (Table 1). Discussion In recent years, the number of potential ADRs reported for cardiometabolic and other drugs within the WHO
Drug Enalapril Rosuvastatin Perindopril Vildagliptin Insulin glulisine Nifedipine Insulin lispro . Warfarin Digoxin Diltiazem Metoprolol Heparin Exenatide Nicotinic acid Rosiglitazone .. ADR Lip swelling Cough Angioedema Face oedema Swollen tongue Throat irritation Blood glucose abnormal Drug ineffective ... Death Cardiac failure congestive Flushing Myocardial infarction Blood glucose increased –3
–2
Figure 5 Disproportionally reported drugs and ADRs for reports with cardiometabolic drugs in Sub-Saharan Africa versus the rest of the world, sorted by the value of the log2 OR. More often reported, lower bound of the 99% confidence interval >0.5, or less often reported, upper bound of the 99% confidence interval
