Trends in prescribing of non-steroidal anti-inflammatory drugs in patients with cardiovascular disease: influence of national guidelines in UK primary care

Trends in prescribing of non-steroidal anti-inflammatory drugs in patients with cardiovascular... Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, but have potential side effects in patients with cardiovascular disease (CVD). Objectives To determine trends in NSAIDs prescribing between 2002 and 2010 in patients with CVD, and ascertain whether prescribing patterns changed following publication of major national (the Medicines and Healthcare products Regulatory Agency (MHRA) and the National Institute for Health and Clinical Excellence (NICE)) guidance to GPs. Methods This was an observational database study of adult patients in 11 practices (Staffordshire, England). NSAIDs were categorised into basic, COX-2 and topical. Study duration was divided on a quarterly basis from 2002-quarter-1 to 2010q4. CVD patients were identified using pre-defined Read Codes recorded in the two years prior to each quarter. Quarterly prevalence was determined. Times of significant changes in prescribing trends were determined using Joinpoint Regression, and compared to dates of the five major guidelines (in 2004q4, 2005q1, 2005q3, 2006q4, 2008q1). Results In CVD patients, the prescription of basic NSAIDs showed a decreasing trend throughout the study period, from 774 (95% CI, 691–863) per 10000 patients in 2002q1 to 245 (204–291) in 2010q4. COX-2 prescribing increased from 232/10000 (187–286) in 2002q1 to 403/10000 (348–464) in 2004q3. Prescribing then fell sharply to 102/10000 (76–134) in 2005q2 before stabilising around 55/10000. Topical NSAIDs prescribing showed a steady increase, starting at 115/10000 (108–123) in 2002q1 and ending at 270/10000 (258–281) in 2010q4. Similar trends were observed in patients without CVD, particularly a sharp drop in COX-2 prescribing also occurred from 2004q4 when initial MHRA guidance was issued. Conclusion Despite guidelines and a trend toward decreased prescribing, the use of potentially harmful NSAIDs continued in CVD patients. The MHRA directives potentially might have affected patients without CVD who may have inappropriately restricted their use of COX-2. Cardiovascular diseases, drug prescribing, electronic health records, NSAID, practice guideline, primary care Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for musculoskeletal conditions such as rheumatoid arthritis or osteoarthritis as they help reduce inflammatory pain and swelling (1). However, there has been increasing concern about their use within the last 15 years. From 2004 to 2006, a series of directives relating to the use of NSAIDs in patients with co-morbid cardiovascular disease (CVD) were issued by the Medicines and Healthcare products Regulatory Agency (MHRA). This advice indicated that NSAIDs, in particular the COX-2 inhibitors, should not be used as they increased the chances of such patients suffering a further cardiovascular event such as a stroke or myocardial infarction (MHRA, 2004 (2), 2005a (3), 2005b (4), 2006 (5); Table 1). A meta-analysis of randomised controlled trials indicated that use of a COX-2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events, compared with placebo (6). CVD is a relatively common problem amongst the population. CVD prevalence amongst the whole of the UK population in 2010 was estimated at 3.4% (1.5 million people) (7). As CVD is more prevalent amongst the elderly, a group also with increased risk of debilitating chronic painful conditions (8), there exists the potential for the inappropriate prescribing of NSAIDs in light of the guidance issued by the MHRA. Additionally, the National Institute for Health and Clinical Excellence (NICE) revised its advice regarding managing osteoarthritis in 2008, advocating a step wise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid medications such as codeine (NICE 2008 (9); Table 1). This guidance, however, does stipulate that NSAIDs should be tailored to the patient such that where a patient may be perceived to be at higher risk, such patients do not receive them, but this is not necessarily an absolute condition of their use. Table 1. Issuance of national guidance with regard to the use of NSAIDs during the study period Intervention  Date  Content  Issue body  1  21 December 2004  Advice to stop using Cox-2 drugs in patients with IHD; Use lowest dose of NSAIDs.  MHRA  2  17 February 2005  Advice to not use Cox-2 drugs in patients with heart disease.  MHRA  3  02 August 2005  Advice to tailor the dose of basic NSAIDs to the individual patient’s risk profile.  MHRA  4  01 October 2006  Advice that basic NSAIDs may be associated with increased thrombotic risk.  MHRA  5  February 2008  NICE OA management guidelines: advice a stepwise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid type medications such as codeine.  NICE  Intervention  Date  Content  Issue body  1  21 December 2004  Advice to stop using Cox-2 drugs in patients with IHD; Use lowest dose of NSAIDs.  MHRA  2  17 February 2005  Advice to not use Cox-2 drugs in patients with heart disease.  MHRA  3  02 August 2005  Advice to tailor the dose of basic NSAIDs to the individual patient’s risk profile.  MHRA  4  01 October 2006  Advice that basic NSAIDs may be associated with increased thrombotic risk.  MHRA  5  February 2008  NICE OA management guidelines: advice a stepwise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid type medications such as codeine.  NICE  MHRA, the Medicines and Healthcare products Regulatory Agency; NICE, the National Institute for Health and Clinical Excellence. View Large Table 1. Issuance of national guidance with regard to the use of NSAIDs during the study period Intervention  Date  Content  Issue body  1  21 December 2004  Advice to stop using Cox-2 drugs in patients with IHD; Use lowest dose of NSAIDs.  MHRA  2  17 February 2005  Advice to not use Cox-2 drugs in patients with heart disease.  MHRA  3  02 August 2005  Advice to tailor the dose of basic NSAIDs to the individual patient’s risk profile.  MHRA  4  01 October 2006  Advice that basic NSAIDs may be associated with increased thrombotic risk.  MHRA  5  February 2008  NICE OA management guidelines: advice a stepwise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid type medications such as codeine.  NICE  Intervention  Date  Content  Issue body  1  21 December 2004  Advice to stop using Cox-2 drugs in patients with IHD; Use lowest dose of NSAIDs.  MHRA  2  17 February 2005  Advice to not use Cox-2 drugs in patients with heart disease.  MHRA  3  02 August 2005  Advice to tailor the dose of basic NSAIDs to the individual patient’s risk profile.  MHRA  4  01 October 2006  Advice that basic NSAIDs may be associated with increased thrombotic risk.  MHRA  5  February 2008  NICE OA management guidelines: advice a stepwise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid type medications such as codeine.  NICE  MHRA, the Medicines and Healthcare products Regulatory Agency; NICE, the National Institute for Health and Clinical Excellence. View Large Previous studies have identified the limited benefit of guidelines (10), whilst others have shown that guidance with multifaceted aspects, incorporating social influence and management support can be substantially more effective in primary care (11,12). In continental Europe, several guidelines and consensuses have recommended avoiding the prescription of NSAIDs in general in patients at high cardiovascular risk (13,14). However, a study from the Netherlands showed that, although patients with a high cardiovascular risk were less likely to be prescribed an NSAID for musculoskeletal consultations compared to patients with a low cardiovascular risk, one in five high cardiovascular risk patients still received an NSAID (15). In the UK, the MHRA and NICE have advised GPs about their appropriate use, but presently it is unknown if they have implemented such advice or continue to prescribe in these conditions. Previously, we showed that MHRA advice to not use COX-2 inhibitors in patients with ischaemic heart disease led to a general reduction in their levels of incident prescribing (16). However, what is not known is whether this reduction was predominantly in the patients targeted by the directive (those with heart disease), or whether prescribing in patients without a higher risk of adverse events and potentially benefitting from NSAID prescriptions, also fell. The first objective of the current study was to determine trends in NSAIDs prescribing between 2002 and 2010 in patients with CVD, and ascertain if prescribing patterns changed following the major national MHRA/NICE guidelines. The second objective was to ascertain whether any observed changes were also apparent in patients without CVD. Methods Database The study was carried out in the Consultations in Primary Care Archive (CiPCA) which contains all recorded primary care data from a subset of general practices in North Staffordshire, UK. The registered populations in the participating practices ranged from 4653 to 12390, with a median size of 8570 (December 2010). The practices are from a mix of urban and rural areas, and whilst North Staffordshire is more deprived than England as a whole, the practices are based in both deprived and more affluent areas. The practices have a research agreement with Keele (Research Institute for Primary Care & Health Sciences) and code clinical activity to a high standard having followed the Keele consultation data audit, training and validation programme (17). The quality of the data is comparable to that of larger national general practice databases (18). Consultation, prescription and demographic data from the 11 practices that have contributed to CiPCA continuously from 2000 – 2010 were analysed for people aged 18 and over. NSAIDs grouping All NSAIDs from British National Formulary (1) chapters 4.7.1, 4.7.2, 10.1.1 and 10.3.2 were included and grouped into three major categories for analysis. Excluded medications include aspirin 75mg (but not ≥300mg). The first group was basic NSAIDs including drugs such as ibuprofen; the second group was COX-2 NSAIDs such as celecoxib; and the third group was topical NSAIDs, for example ibuprofen gel 5%. A list of all drugs and their allocated groups are available at www.keele.ac.uk/mrr. Quarterly prescription prevalence Each year from 2002 to 2010 was divided into quarterly time periods. The quarters were defined on a seasonal basis from the first quarter of 2002 (comprising January, February and March) to the last quarter of 2010 (October, November and December). In UK primary care, problems, including disease labels, are generally recorded using the “Read” system of codes (19). Patients recorded with at least one CVD Read code in the two years prior to each time period were identified from the consultation database using pre-defined Read codes for CVD. For example, when identifying existing CVD patients for the 3rd quarter of 2002 (July, August and September), consultations with a recorded CVD Read code between with 1st July 2000and 30th June 2002 were identified. The CVD codes were agreed through a consensus exercise between JB and RH (available at www.keele.ac.uk/mrr). They covered generalised cardiovascular disease (including heart failure), ischaemic heart disease, myocardial infarction, cerebrovascular disease and abnormal heart rhythm (including atrial fibrillation). The numerators for calculating quarterly prescription prevalence were the number of identified CVD patients receiving at least one prescription within a NSAIDs group within each quarterly time period. Repeat or multiple prescriptions in the same NSAID group following the first prescription for a medication in that group within each quarter were ignored. The registration status for each patient in the studied practices was checked on a half-year basis (1st July and 31st December). Patients included in the denominator were those with confirmation of registration at both flanking check points. Stratified analysis by age group (< 65, ≥ 65 and < 75, ≥ 75 years old) and gender was also carried out. Quarterly prescription prevalence of NSAIDs was also calculated in all registered patients (aged 18 and over) without a CVD record in the previous two years. Major national guidance During the assessment period (2002–2010), four national guidelines regarding the use of NSAIDs in patients with CVD (or with a high-risk profile), and one national guideline with regard to a stepwise use of painkillers in patients with OA were issued. The date, content and issuing body of these interventions are briefly listed in Table 1. Advice issued by the MHRA is sent on an individualized basis using personal letters to all prescribing doctors ensuring that all GPs are aware of the changes suggested in analgesic use. NICE also disseminated their guideline in 2008 to specific groups including all GPs. Changes in GP prescribing behaviour (changes in trends of prescribed NSAIDs) in relation to the five major pieces of national guidance were assessed. If significant changes in trend are identified at the time of guidance being announced, it cannot be assumed to be a causal link, but the fact that both the intervention and change occur within the same time frame suggests strongly that there is some association between the advice and related change in behaviour. Statistical analysis Joinpoint regression was used to identify quarters where a statistically significant change over time in the linear slope of the trend occurred (20,21). Permutation tests using Monte Carlo methods were used to determine the minimum number of joinpoints required to provide an adequate fit to the data. The analysis started with zero joinpoints and tested whether one or more joinpoints improved the model (based on a 5% significance level and up to five joinpoints). Quarterly percentage change in prescribing prevalence was estimated for each time period separated by the identified joinpoints. Joinpoint analyses were performed using the joinpoint regression program (version 4.1.1, Statistical Research and Applications Branch, National Cancer Institute, 2014). The time point for the start of each identified change in the underlying prescribing trend (the joinpoint) was then compared with the dates of the interventions. Results Population characteristics From 2002 to 2010, the total registered population aged 18 and above of the practices ranged from 71713 (2005) to 77056 (2010). The age and gender distributions changed little across all years, with the median ages being 48–49 years old with 51–52% being female (Supplementary Table S1). Therefore, it was not felt necessary to standardize the prevalence figures. Prevalence of CVD The number of patients with CVD identified for each quarter ranged from 3787 (2002 quarter 1) to 5250 (2008 quarter 4). The prevalence of patients with CVD recorded in the previous 2 years increased from 523 (95% CI, 507–540) per 10000 registered population aged 18 and over in 2002 quarter 1 to 722 (95% CI, 704–742) per 10000 in 2006 quarter 2 before decreasing slightly to 663 (95% CI, 645–681) per 10000 in 2010 quarter 4. Males had higher prevalent rates, and both genders displayed similar trends (Supplementary Figure S1). The median age of those patients was from 71 in 2002 quarter 1 rising to 73 in 2010 quarter 4 (Supplementary Table S2). NSAIDs prescription in patients with CVD In patients with CVD, initially there was a generally increasing trend in the prescription of COX-2 inhibitors from 232 (95% CI, 187–286) per 10000 in 2002 quarter 1 to 403 (95% CI, 348–464) per 10000 in 2004 quarter 3. Prescribing then fell sharply to 102 (95% CI, 76–134) per 10000 in 2005 quarter 2 before stabilising around 55 per 10000 (Figure 1). The use of basic NSAIDs overall showed a decreasing trend throughout the study period, starting from 774 (95% CI, 691–863) per 10000 in 2002 quarter 1 and ended at 245 (95% CI, 204–291) per 10000 in 2010 quarter 4. Particularly noticeable was a short-term increase in basic NSAIDs at the same time of the sharp decline in COX-2 inhibitor prescribing (Figure 1). The use of topical NSAIDs showed a steady increase through the study period, with quarterly prevalence starting at 115 (95% CI, 108–123) per 10000 in 2002 quarter 1 and ending at 270 (95% CI, 258–281) per 10000 in 2010 quarter 4 (Figure 1). Figure 1. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in patients (aged 18 and above) with CVD. Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; vertical lines, time of issue of national guidance (intervention); 95% CI, 95% confidence interval; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. Figure 1. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in patients (aged 18 and above) with CVD. Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; vertical lines, time of issue of national guidance (intervention); 95% CI, 95% confidence interval; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. The time points of advisory interventions on NSAIDs (national guidance) and the NSAIDs’ prescribing trends are shown in Figure 1. The joinpoint regression analysis for any significant change in the trend in prescription of NSAIDs (basic oral NSAIDs, COX-2 inhibitor, topical NSAIDs and basic oral and COX-2 inhibitor NSAIDs combined) in patients with CVD is shown in Table 2. For example, the quarterly percentage change for COX-2 inhibitors during 2004 quarter 3 to 2005 quarter 2 was −39 (95% CI, −50 to −26), that is, a decrease of 39% in each quarter during the period. Table 2. Joinpoint regression analysis of quarterly prevalence of NSAIDs (basic NSAIDs, Cox-2, topical NSAIDs and basic and Cox-2 NSAIDs) prescribing in patients with CVD (aged 18 and over)   Average QPC 2002–2010  Trend 1  Trend 2  Trend 3  Trend 4      Period 1  QPC  Period 2  QPC  Period 3  QPC  Period 4  QPC  In patients with CVD  Basic  −3.0† (−4.3, −1.6)  02Q1–04Q3  −3.8† (−5.0, −2.5)  04Q3–05Q2  4.9 (−11.2, 24.0)  05Q2–10Q4  −3.6† (−4.0, −3.2)  —  —  Cox-2  −3.9† (−5.7, −2.0)  02Q1–04Q3  5.6† (4.3, 7.0)  04Q3–05Q2  −39.2† (−50.2, −25.7)  05Q2–09Q1  −4.5† (−5.9, −2.9)  09Q1 – 10Q4  2.6 (-1.6, 6.9)  Topical  2.7† (2.3, 3.0)  02Q1–07Q1  1.7† (1.2, 2.2)  07Q1–10Q4  3.9† (3.3, 4.5)  —  —  —  —  Basic and Cox-2  −3.2† (−4.2, −2.2)  02Q1–04Q2  −0.4 (−1.5, 0.7)  04Q2–05Q1  −8.6 (−19.0, 3.2)  05Q1–10Q4  −3.5† (−3.9, −3.2)  —  —    Average QPC 2002–2010  Trend 1  Trend 2  Trend 3  Trend 4      Period 1  QPC  Period 2  QPC  Period 3  QPC  Period 4  QPC  In patients with CVD  Basic  −3.0† (−4.3, −1.6)  02Q1–04Q3  −3.8† (−5.0, −2.5)  04Q3–05Q2  4.9 (−11.2, 24.0)  05Q2–10Q4  −3.6† (−4.0, −3.2)  —  —  Cox-2  −3.9† (−5.7, −2.0)  02Q1–04Q3  5.6† (4.3, 7.0)  04Q3–05Q2  −39.2† (−50.2, −25.7)  05Q2–09Q1  −4.5† (−5.9, −2.9)  09Q1 – 10Q4  2.6 (-1.6, 6.9)  Topical  2.7† (2.3, 3.0)  02Q1–07Q1  1.7† (1.2, 2.2)  07Q1–10Q4  3.9† (3.3, 4.5)  —  —  —  —  Basic and Cox-2  −3.2† (−4.2, −2.2)  02Q1–04Q2  −0.4 (−1.5, 0.7)  04Q2–05Q1  −8.6 (−19.0, 3.2)  05Q1–10Q4  −3.5† (−3.9, −3.2)  —  —  NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor; CVD, cardiovascular disease; QPC, quarterly percentage change indicates the percentage change in prescribing prevalence per quarter over the stated time period. A positive percentage indicates an increase in prevalence; †QPC significantly different from 0 (0 indicating no change in prevalence, significant cut-off point P = 0.05); End quarter of each period signifies a joinpoint. View Large Table 2. Joinpoint regression analysis of quarterly prevalence of NSAIDs (basic NSAIDs, Cox-2, topical NSAIDs and basic and Cox-2 NSAIDs) prescribing in patients with CVD (aged 18 and over)   Average QPC 2002–2010  Trend 1  Trend 2  Trend 3  Trend 4      Period 1  QPC  Period 2  QPC  Period 3  QPC  Period 4  QPC  In patients with CVD  Basic  −3.0† (−4.3, −1.6)  02Q1–04Q3  −3.8† (−5.0, −2.5)  04Q3–05Q2  4.9 (−11.2, 24.0)  05Q2–10Q4  −3.6† (−4.0, −3.2)  —  —  Cox-2  −3.9† (−5.7, −2.0)  02Q1–04Q3  5.6† (4.3, 7.0)  04Q3–05Q2  −39.2† (−50.2, −25.7)  05Q2–09Q1  −4.5† (−5.9, −2.9)  09Q1 – 10Q4  2.6 (-1.6, 6.9)  Topical  2.7† (2.3, 3.0)  02Q1–07Q1  1.7† (1.2, 2.2)  07Q1–10Q4  3.9† (3.3, 4.5)  —  —  —  —  Basic and Cox-2  −3.2† (−4.2, −2.2)  02Q1–04Q2  −0.4 (−1.5, 0.7)  04Q2–05Q1  −8.6 (−19.0, 3.2)  05Q1–10Q4  −3.5† (−3.9, −3.2)  —  —    Average QPC 2002–2010  Trend 1  Trend 2  Trend 3  Trend 4      Period 1  QPC  Period 2  QPC  Period 3  QPC  Period 4  QPC  In patients with CVD  Basic  −3.0† (−4.3, −1.6)  02Q1–04Q3  −3.8† (−5.0, −2.5)  04Q3–05Q2  4.9 (−11.2, 24.0)  05Q2–10Q4  −3.6† (−4.0, −3.2)  —  —  Cox-2  −3.9† (−5.7, −2.0)  02Q1–04Q3  5.6† (4.3, 7.0)  04Q3–05Q2  −39.2† (−50.2, −25.7)  05Q2–09Q1  −4.5† (−5.9, −2.9)  09Q1 – 10Q4  2.6 (-1.6, 6.9)  Topical  2.7† (2.3, 3.0)  02Q1–07Q1  1.7† (1.2, 2.2)  07Q1–10Q4  3.9† (3.3, 4.5)  —  —  —  —  Basic and Cox-2  −3.2† (−4.2, −2.2)  02Q1–04Q2  −0.4 (−1.5, 0.7)  04Q2–05Q1  −8.6 (−19.0, 3.2)  05Q1–10Q4  −3.5† (−3.9, −3.2)  —  —  NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor; CVD, cardiovascular disease; QPC, quarterly percentage change indicates the percentage change in prescribing prevalence per quarter over the stated time period. A positive percentage indicates an increase in prevalence; †QPC significantly different from 0 (0 indicating no change in prevalence, significant cut-off point P = 0.05); End quarter of each period signifies a joinpoint. View Large In general, the trend in prescribing was similar by age group. However, higher prevalence of basic NSAIDs prescribed in younger patients with CVD and topical NSAIDs in older patients was observed (Figure 2). No difference in COX-2 inhibitor prescribing was seen among the age groups (Figure 2). Figure 2. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in CVD patients stratified by age-group. Age group, ≥18 and <65 years in Black, ≥65 and <75 years in Blue, ≥75 years in Red; Dash line, 95% confidence interval; Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. Figure 2. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in CVD patients stratified by age-group. Age group, ≥18 and <65 years in Black, ≥65 and <75 years in Blue, ≥75 years in Red; Dash line, 95% confidence interval; Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. The prescribing patterns were largely similar between males and females. However, higher prevalence of COX-2 inhibitors and topical NSAIDs was seen among females (Supplementary Figure S2), although this may be due to more females in older age groups. NSAIDs prescription in patients without CVD Figure 3 shows the NSAIDs prescribing in all registered population (aged 18 and above) without CVD from 2002 to 2010. A sharp drop in COX-2 inhibitor prescribing starting from 2002 quarter 4 also occurred, similar to those with CVD. The joinpoint regression analysis for non-CVD patients is summarized in Supplementary Table S3. Figure 3. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in patients (aged 18 and above) without CVD. Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; vertical lines, time of issue of national guidance (intervention); 95% CI, 95% confidence interval; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. Figure 3. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in patients (aged 18 and above) without CVD. Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; vertical lines, time of issue of national guidance (intervention); 95% CI, 95% confidence interval; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. Discussion Main findings This is the first study in UK primary care to investigate trends in the prevalence of NSAIDs prescribing in patients with CVD and particularly to assess the association with major national guidance issued during the study period 2002 – 2010. We have shown there was a shift in use between oral (basic and COX-2 inhibitors) and topical NSAIDs. 10% of patients with CVD received oral (basic or COX-2 inhibitors) and 4% topical NSAIDs per quarter in 2002, while such rates changed to 3% for oral and 8% for topical NSAIDs in 2010. The overall reduction in use of oral NSAIDs can be attributed to both basic and COX-2 inhibitor drugs. Particularly, following the MHRA 2004–2005 interventions, COX-2 inhibitor prescribing showed a sharp reduction within 6 months, with the rates dropping from 4% to 1%, suggesting a marked effectiveness of the guidance. During the same period, a short-term increase in basic NASIDs prescribing was seen, which may reflect basic NASIDs as one of the major alternatives to COX-2 inhibitors. In the following years, the trends were more stable, therefore, no obvious association of later guidance with prescribing change was determined. Overall, during 2002–2010 there was a reduction in use of NSAIDs. Our results are in line with Koffeman et al. (15) and a US study which indicated that there was still a large proportion of CVD patients using NSAIDs despite a decline after a Food and Drug Administration warning in 2005 (22). We have shown that a significant drop in COX-2 inhibitor prescribing also occurred in the population without pre-existing CVD when MHRA published the guidance during later 2004 and early 2005. This is surprising as the guidance was directed at patients with cardiovascular problems. To some extent, this implied that the guidance may be over looked as the GPs tended to not prescribe COX-2 inhibitor drugs to any patients. It also suggested that GPs might have been under treating patients who may benefit from COX-2 when there was no reason not to give it to them. Indeed, some patients being given basic NSAIDs perhaps should have had COX-2 as this is less risky for them in terms of gastrointestinal adverse events such as peptic ulceration. It is unknown whether such a decision was made based on more careful review of patients’ cardiovascular risk, or it was just easier to do for the GPs to use a blanket approach to NSAIDs due to the perceived risks and worry that litigation from patients who might not have CVD could occur. On the other hand, after several national guidances issued during 2004–2008, there were still some CVD patients receiving COX-2 inhibitors with a quarterly prevalence at approximately 50 per 10000. Whether or not these prescriptions were appropriate is unknown. Further research will be needed to look at the demographic, lifestyle and co-morbid characteristics of these patients and to assess the reason behind these COX-2 inhibitor prescriptions. We have also shown that in patients with CVD, NSAIDs prescribing trends were similar in different age and gender groups. However, patients with younger age tended to receive basic oral NSAIDs instead of topical NSAIDs perhaps because they were perceived to be less likely to suffer complications from the oral drugs compared to the older patients. However, other age-related factors, which may influence drug prescription such as severity of pain, disability level or patient preference, has yet to be investigated. Limitations Our study has several limitations. First, although the demographic structure of the population from our study was comparable to the general population of UK, this population was from more deprived areas compared to England as a whole. Here, we have shown that the average prevalence of CVD in our population was approximately 6% that was higher than the national figure (3.5%) (7), although the method of identifying patients was different. Second, we were unable to identify the use of over-the-counter (OTC) NSAIDs, and GPs may advise purchase of OTC NSAIDs rather than prescribe them. This might potentially lead to under reporting of NSAIDs use in the studied population. However, since 90% of English prescriptions are issued free to patients, the amount of missing data on NSAIDs use should not have had a large impact on our results. Third, the data used in this study were derived from the years 2002–2010 and trends in prescribing may have changed more recently. Impact of the study Despite guidelines and a trend toward decreased prescribing, the use of potentially harmful NSAIDs continued in patients with CVD. The MHRA directives had similar effects on both patient groups such that COX-2 prescribing became very infrequent, and basic NSAIDs decreased, based on our data up to 2010. Further advice appears to be needed regarding the correct use of NSAIDs since CVD patients might still be using them inappropriately, and non-CVD patients, who might benefit, have had their use inappropriately restricted. Supplementary material Supplementary material is available at Family Practice online. Declaration Funding: The Keele GP Research Partnership and the Informatics team at the Arthritis Research UK Primary Care Centre. CiPCA funded by the North Staffordshire Primary Care Research Consortium and Keele University Research Institute for Primary Care and Health Sciences. Ethical approval: Ethical approval for download and research using these databases was originally gained from the North Staffordshire Research Ethics Committee. Conflict of interest: None of the authors has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper. References 1. Joint Formulary Committee. British National Formulary 2011 . London: BMJ Group and Pharmaceutical Press, 2011. 2. The Medicines and Healthcare products Regulatory Agency [Internet]. Advice on the use of Celecoxib and other selective cox-2 inhibitors in light of concerns about cardiovascular safety. http://webarchive.nationalarchives.gov.uk/20141206131601/http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con019466.pdf (accessed on 2 August 2017). 3. The Medicines and Healthcare products Regulatory Agency [Internet]. MHRA issues updated advice on the safety of selective cox-2 inhibitors. http://webarchive.nationalarchives.gov.uk/20141206131519/http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con019458.pdf (accessed on 2 August 2017). 4. The Medicines and Healthcare products Regulatory Agency [Internet]. Review of the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs). http://webarchive.nationalarchives.gov.uk/20141205212332/http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON1004301 (accessed on 2 August 2017). 5. The Medicines and Healthcare products Regulatory Agency [Internet]. Safety of selective and non-selective NSAIDs. http://webarchive.nationalarchives.gov.uk/20141206130348/http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2025036.pdf (accessed on 2 August 2017). 6. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ  2006; 332: 1302– 8. Google Scholar CrossRef Search ADS PubMed  7. British Heart Foundation [Internet]. Coronary heart disease statistics 2010 edition. https://www.bhf.org.uk/publications/statistics/coronary-heart-disease-statistics-2010 (accessed on 2 August 2017). 8. Jordan KP, Kadam UT, Hayward R, Porcheret M, Young C, Croft P. Annual consultation prevalence of regional musculoskeletal problems in primary care: an observational study. BMC Musculoskelet Disord  2010; 11: 144. Google Scholar CrossRef Search ADS PubMed  9. National Institute for Health and Clinical Excellence [Internet]. CG59 Osteoarthritis: full guidance [updated and replaced by CG177. https://www.nice.org.uk/guidance/cg177 (accessed on 2 August 2017). 10. Farmer AP, Légaré F, Turcot Let al.   Printed educational materials: effects on professional practice and health care outcomes. Cohrance Database Syst Rev . 2008; 3: CD004398. 11. Braybrook S, Walker R. Influencing NSAID prescribing in primary care using different feedback strategies. Pharm World Sci  2000; 22: 39– 46. Google Scholar CrossRef Search ADS PubMed  12. Wensing M, van der Weijden T, Grol R. Implementing guidelines and innovations in general practice: which interventions are effective? Br J Gen Pract  1998; 48: 991– 7. Google Scholar PubMed  13. Chan FK, Abraham NS, Scheiman JM, Laine L; First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents. Management of patients on nonsteroidal anti-inflammatory drugs: a clinical practice recommendation from the First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents. Am J Gastroenterol  2008; 103: 2908– 18. Google Scholar CrossRef Search ADS PubMed  14. Warlé-van Herwaarden MF, Kramers C, Sturkenboom MC, van den Bemt PM, De Smet PA; Dutch HARM-Wrestling Task Force. Targeting outpatient drug safety: recommendations of the Dutch HARM-Wrestling Task Force. Drug Saf  2012; 35: 245– 59. Google Scholar CrossRef Search ADS PubMed  15. Koffeman AR, Valkhoff VE, Jong GWet al.   Ischaemic cardiovascular risk and prescription of non-steroidal anti-inflammatory drugs for musculoskeletal complaints. Scand J Prim Health Care  2014; 32: 90– 8. Google Scholar CrossRef Search ADS PubMed  16. Bedson J, Belcher J, Martino OIet al.   The effectiveness of national guidance in changing analgesic prescribing in primary care from 2002 to 2009: an observational database study. Eur J Pain  2013; 17: 434– 43. Google Scholar CrossRef Search ADS PubMed  17. Porcheret M, Hughes R, Evans Det al.  ; North Staffordshire General Practice Research Network. Data quality of general practice electronic health records: the impact of a program of assessments, feedback, and training. J Am Med Inform Assoc  2004; 11: 78– 86. Google Scholar CrossRef Search ADS PubMed  18. Jordan K, Clarke AM, Symmons DPet al.   Measuring disease prevalence: a comparison of musculoskeletal disease using four general practice consultation databases. Br J Gen Pract  2007; 57: 7– 14. Google Scholar PubMed  19. Stuart-Buttle CD, Read JD, Sanderson HF, Sutton YM. A language of health in action: Read Codes, classifications and groupings. Proc AMIA Annu Fall Symp . 1996; 75– 9. 20. Fay MP, Tiwari RC, Feuer EJ, Zou Z. Estimating average annual percent change for disease rates without assuming constant change. Biometrics  2006; 62: 847– 54. Google Scholar CrossRef Search ADS PubMed  21. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med  2000; 19: 335– 51. Google Scholar CrossRef Search ADS PubMed  22. Castelli G, Petrone A, Xiang J, Shrader C, King D. Rates of nonsteroidal anti-inflammatory drug use in patients with established cardiovascular disease: A retrospective, cross-sectional study from NHANES 2009-2010. Am J Cardiovasc Drugs  2017; 17: 243– 9. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Family Practice Oxford University Press

Trends in prescribing of non-steroidal anti-inflammatory drugs in patients with cardiovascular disease: influence of national guidelines in UK primary care

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Abstract

Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, but have potential side effects in patients with cardiovascular disease (CVD). Objectives To determine trends in NSAIDs prescribing between 2002 and 2010 in patients with CVD, and ascertain whether prescribing patterns changed following publication of major national (the Medicines and Healthcare products Regulatory Agency (MHRA) and the National Institute for Health and Clinical Excellence (NICE)) guidance to GPs. Methods This was an observational database study of adult patients in 11 practices (Staffordshire, England). NSAIDs were categorised into basic, COX-2 and topical. Study duration was divided on a quarterly basis from 2002-quarter-1 to 2010q4. CVD patients were identified using pre-defined Read Codes recorded in the two years prior to each quarter. Quarterly prevalence was determined. Times of significant changes in prescribing trends were determined using Joinpoint Regression, and compared to dates of the five major guidelines (in 2004q4, 2005q1, 2005q3, 2006q4, 2008q1). Results In CVD patients, the prescription of basic NSAIDs showed a decreasing trend throughout the study period, from 774 (95% CI, 691–863) per 10000 patients in 2002q1 to 245 (204–291) in 2010q4. COX-2 prescribing increased from 232/10000 (187–286) in 2002q1 to 403/10000 (348–464) in 2004q3. Prescribing then fell sharply to 102/10000 (76–134) in 2005q2 before stabilising around 55/10000. Topical NSAIDs prescribing showed a steady increase, starting at 115/10000 (108–123) in 2002q1 and ending at 270/10000 (258–281) in 2010q4. Similar trends were observed in patients without CVD, particularly a sharp drop in COX-2 prescribing also occurred from 2004q4 when initial MHRA guidance was issued. Conclusion Despite guidelines and a trend toward decreased prescribing, the use of potentially harmful NSAIDs continued in CVD patients. The MHRA directives potentially might have affected patients without CVD who may have inappropriately restricted their use of COX-2. Cardiovascular diseases, drug prescribing, electronic health records, NSAID, practice guideline, primary care Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for musculoskeletal conditions such as rheumatoid arthritis or osteoarthritis as they help reduce inflammatory pain and swelling (1). However, there has been increasing concern about their use within the last 15 years. From 2004 to 2006, a series of directives relating to the use of NSAIDs in patients with co-morbid cardiovascular disease (CVD) were issued by the Medicines and Healthcare products Regulatory Agency (MHRA). This advice indicated that NSAIDs, in particular the COX-2 inhibitors, should not be used as they increased the chances of such patients suffering a further cardiovascular event such as a stroke or myocardial infarction (MHRA, 2004 (2), 2005a (3), 2005b (4), 2006 (5); Table 1). A meta-analysis of randomised controlled trials indicated that use of a COX-2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events, compared with placebo (6). CVD is a relatively common problem amongst the population. CVD prevalence amongst the whole of the UK population in 2010 was estimated at 3.4% (1.5 million people) (7). As CVD is more prevalent amongst the elderly, a group also with increased risk of debilitating chronic painful conditions (8), there exists the potential for the inappropriate prescribing of NSAIDs in light of the guidance issued by the MHRA. Additionally, the National Institute for Health and Clinical Excellence (NICE) revised its advice regarding managing osteoarthritis in 2008, advocating a step wise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid medications such as codeine (NICE 2008 (9); Table 1). This guidance, however, does stipulate that NSAIDs should be tailored to the patient such that where a patient may be perceived to be at higher risk, such patients do not receive them, but this is not necessarily an absolute condition of their use. Table 1. Issuance of national guidance with regard to the use of NSAIDs during the study period Intervention  Date  Content  Issue body  1  21 December 2004  Advice to stop using Cox-2 drugs in patients with IHD; Use lowest dose of NSAIDs.  MHRA  2  17 February 2005  Advice to not use Cox-2 drugs in patients with heart disease.  MHRA  3  02 August 2005  Advice to tailor the dose of basic NSAIDs to the individual patient’s risk profile.  MHRA  4  01 October 2006  Advice that basic NSAIDs may be associated with increased thrombotic risk.  MHRA  5  February 2008  NICE OA management guidelines: advice a stepwise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid type medications such as codeine.  NICE  Intervention  Date  Content  Issue body  1  21 December 2004  Advice to stop using Cox-2 drugs in patients with IHD; Use lowest dose of NSAIDs.  MHRA  2  17 February 2005  Advice to not use Cox-2 drugs in patients with heart disease.  MHRA  3  02 August 2005  Advice to tailor the dose of basic NSAIDs to the individual patient’s risk profile.  MHRA  4  01 October 2006  Advice that basic NSAIDs may be associated with increased thrombotic risk.  MHRA  5  February 2008  NICE OA management guidelines: advice a stepwise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid type medications such as codeine.  NICE  MHRA, the Medicines and Healthcare products Regulatory Agency; NICE, the National Institute for Health and Clinical Excellence. View Large Table 1. Issuance of national guidance with regard to the use of NSAIDs during the study period Intervention  Date  Content  Issue body  1  21 December 2004  Advice to stop using Cox-2 drugs in patients with IHD; Use lowest dose of NSAIDs.  MHRA  2  17 February 2005  Advice to not use Cox-2 drugs in patients with heart disease.  MHRA  3  02 August 2005  Advice to tailor the dose of basic NSAIDs to the individual patient’s risk profile.  MHRA  4  01 October 2006  Advice that basic NSAIDs may be associated with increased thrombotic risk.  MHRA  5  February 2008  NICE OA management guidelines: advice a stepwise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid type medications such as codeine.  NICE  Intervention  Date  Content  Issue body  1  21 December 2004  Advice to stop using Cox-2 drugs in patients with IHD; Use lowest dose of NSAIDs.  MHRA  2  17 February 2005  Advice to not use Cox-2 drugs in patients with heart disease.  MHRA  3  02 August 2005  Advice to tailor the dose of basic NSAIDs to the individual patient’s risk profile.  MHRA  4  01 October 2006  Advice that basic NSAIDs may be associated with increased thrombotic risk.  MHRA  5  February 2008  NICE OA management guidelines: advice a stepwise use of painkillers, initially using simple analgesics such as paracetamol or topical NSAIDs, followed by adding oral NSAIDs and finally opioid type medications such as codeine.  NICE  MHRA, the Medicines and Healthcare products Regulatory Agency; NICE, the National Institute for Health and Clinical Excellence. View Large Previous studies have identified the limited benefit of guidelines (10), whilst others have shown that guidance with multifaceted aspects, incorporating social influence and management support can be substantially more effective in primary care (11,12). In continental Europe, several guidelines and consensuses have recommended avoiding the prescription of NSAIDs in general in patients at high cardiovascular risk (13,14). However, a study from the Netherlands showed that, although patients with a high cardiovascular risk were less likely to be prescribed an NSAID for musculoskeletal consultations compared to patients with a low cardiovascular risk, one in five high cardiovascular risk patients still received an NSAID (15). In the UK, the MHRA and NICE have advised GPs about their appropriate use, but presently it is unknown if they have implemented such advice or continue to prescribe in these conditions. Previously, we showed that MHRA advice to not use COX-2 inhibitors in patients with ischaemic heart disease led to a general reduction in their levels of incident prescribing (16). However, what is not known is whether this reduction was predominantly in the patients targeted by the directive (those with heart disease), or whether prescribing in patients without a higher risk of adverse events and potentially benefitting from NSAID prescriptions, also fell. The first objective of the current study was to determine trends in NSAIDs prescribing between 2002 and 2010 in patients with CVD, and ascertain if prescribing patterns changed following the major national MHRA/NICE guidelines. The second objective was to ascertain whether any observed changes were also apparent in patients without CVD. Methods Database The study was carried out in the Consultations in Primary Care Archive (CiPCA) which contains all recorded primary care data from a subset of general practices in North Staffordshire, UK. The registered populations in the participating practices ranged from 4653 to 12390, with a median size of 8570 (December 2010). The practices are from a mix of urban and rural areas, and whilst North Staffordshire is more deprived than England as a whole, the practices are based in both deprived and more affluent areas. The practices have a research agreement with Keele (Research Institute for Primary Care & Health Sciences) and code clinical activity to a high standard having followed the Keele consultation data audit, training and validation programme (17). The quality of the data is comparable to that of larger national general practice databases (18). Consultation, prescription and demographic data from the 11 practices that have contributed to CiPCA continuously from 2000 – 2010 were analysed for people aged 18 and over. NSAIDs grouping All NSAIDs from British National Formulary (1) chapters 4.7.1, 4.7.2, 10.1.1 and 10.3.2 were included and grouped into three major categories for analysis. Excluded medications include aspirin 75mg (but not ≥300mg). The first group was basic NSAIDs including drugs such as ibuprofen; the second group was COX-2 NSAIDs such as celecoxib; and the third group was topical NSAIDs, for example ibuprofen gel 5%. A list of all drugs and their allocated groups are available at www.keele.ac.uk/mrr. Quarterly prescription prevalence Each year from 2002 to 2010 was divided into quarterly time periods. The quarters were defined on a seasonal basis from the first quarter of 2002 (comprising January, February and March) to the last quarter of 2010 (October, November and December). In UK primary care, problems, including disease labels, are generally recorded using the “Read” system of codes (19). Patients recorded with at least one CVD Read code in the two years prior to each time period were identified from the consultation database using pre-defined Read codes for CVD. For example, when identifying existing CVD patients for the 3rd quarter of 2002 (July, August and September), consultations with a recorded CVD Read code between with 1st July 2000and 30th June 2002 were identified. The CVD codes were agreed through a consensus exercise between JB and RH (available at www.keele.ac.uk/mrr). They covered generalised cardiovascular disease (including heart failure), ischaemic heart disease, myocardial infarction, cerebrovascular disease and abnormal heart rhythm (including atrial fibrillation). The numerators for calculating quarterly prescription prevalence were the number of identified CVD patients receiving at least one prescription within a NSAIDs group within each quarterly time period. Repeat or multiple prescriptions in the same NSAID group following the first prescription for a medication in that group within each quarter were ignored. The registration status for each patient in the studied practices was checked on a half-year basis (1st July and 31st December). Patients included in the denominator were those with confirmation of registration at both flanking check points. Stratified analysis by age group (< 65, ≥ 65 and < 75, ≥ 75 years old) and gender was also carried out. Quarterly prescription prevalence of NSAIDs was also calculated in all registered patients (aged 18 and over) without a CVD record in the previous two years. Major national guidance During the assessment period (2002–2010), four national guidelines regarding the use of NSAIDs in patients with CVD (or with a high-risk profile), and one national guideline with regard to a stepwise use of painkillers in patients with OA were issued. The date, content and issuing body of these interventions are briefly listed in Table 1. Advice issued by the MHRA is sent on an individualized basis using personal letters to all prescribing doctors ensuring that all GPs are aware of the changes suggested in analgesic use. NICE also disseminated their guideline in 2008 to specific groups including all GPs. Changes in GP prescribing behaviour (changes in trends of prescribed NSAIDs) in relation to the five major pieces of national guidance were assessed. If significant changes in trend are identified at the time of guidance being announced, it cannot be assumed to be a causal link, but the fact that both the intervention and change occur within the same time frame suggests strongly that there is some association between the advice and related change in behaviour. Statistical analysis Joinpoint regression was used to identify quarters where a statistically significant change over time in the linear slope of the trend occurred (20,21). Permutation tests using Monte Carlo methods were used to determine the minimum number of joinpoints required to provide an adequate fit to the data. The analysis started with zero joinpoints and tested whether one or more joinpoints improved the model (based on a 5% significance level and up to five joinpoints). Quarterly percentage change in prescribing prevalence was estimated for each time period separated by the identified joinpoints. Joinpoint analyses were performed using the joinpoint regression program (version 4.1.1, Statistical Research and Applications Branch, National Cancer Institute, 2014). The time point for the start of each identified change in the underlying prescribing trend (the joinpoint) was then compared with the dates of the interventions. Results Population characteristics From 2002 to 2010, the total registered population aged 18 and above of the practices ranged from 71713 (2005) to 77056 (2010). The age and gender distributions changed little across all years, with the median ages being 48–49 years old with 51–52% being female (Supplementary Table S1). Therefore, it was not felt necessary to standardize the prevalence figures. Prevalence of CVD The number of patients with CVD identified for each quarter ranged from 3787 (2002 quarter 1) to 5250 (2008 quarter 4). The prevalence of patients with CVD recorded in the previous 2 years increased from 523 (95% CI, 507–540) per 10000 registered population aged 18 and over in 2002 quarter 1 to 722 (95% CI, 704–742) per 10000 in 2006 quarter 2 before decreasing slightly to 663 (95% CI, 645–681) per 10000 in 2010 quarter 4. Males had higher prevalent rates, and both genders displayed similar trends (Supplementary Figure S1). The median age of those patients was from 71 in 2002 quarter 1 rising to 73 in 2010 quarter 4 (Supplementary Table S2). NSAIDs prescription in patients with CVD In patients with CVD, initially there was a generally increasing trend in the prescription of COX-2 inhibitors from 232 (95% CI, 187–286) per 10000 in 2002 quarter 1 to 403 (95% CI, 348–464) per 10000 in 2004 quarter 3. Prescribing then fell sharply to 102 (95% CI, 76–134) per 10000 in 2005 quarter 2 before stabilising around 55 per 10000 (Figure 1). The use of basic NSAIDs overall showed a decreasing trend throughout the study period, starting from 774 (95% CI, 691–863) per 10000 in 2002 quarter 1 and ended at 245 (95% CI, 204–291) per 10000 in 2010 quarter 4. Particularly noticeable was a short-term increase in basic NSAIDs at the same time of the sharp decline in COX-2 inhibitor prescribing (Figure 1). The use of topical NSAIDs showed a steady increase through the study period, with quarterly prevalence starting at 115 (95% CI, 108–123) per 10000 in 2002 quarter 1 and ending at 270 (95% CI, 258–281) per 10000 in 2010 quarter 4 (Figure 1). Figure 1. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in patients (aged 18 and above) with CVD. Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; vertical lines, time of issue of national guidance (intervention); 95% CI, 95% confidence interval; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. Figure 1. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in patients (aged 18 and above) with CVD. Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; vertical lines, time of issue of national guidance (intervention); 95% CI, 95% confidence interval; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. The time points of advisory interventions on NSAIDs (national guidance) and the NSAIDs’ prescribing trends are shown in Figure 1. The joinpoint regression analysis for any significant change in the trend in prescription of NSAIDs (basic oral NSAIDs, COX-2 inhibitor, topical NSAIDs and basic oral and COX-2 inhibitor NSAIDs combined) in patients with CVD is shown in Table 2. For example, the quarterly percentage change for COX-2 inhibitors during 2004 quarter 3 to 2005 quarter 2 was −39 (95% CI, −50 to −26), that is, a decrease of 39% in each quarter during the period. Table 2. Joinpoint regression analysis of quarterly prevalence of NSAIDs (basic NSAIDs, Cox-2, topical NSAIDs and basic and Cox-2 NSAIDs) prescribing in patients with CVD (aged 18 and over)   Average QPC 2002–2010  Trend 1  Trend 2  Trend 3  Trend 4      Period 1  QPC  Period 2  QPC  Period 3  QPC  Period 4  QPC  In patients with CVD  Basic  −3.0† (−4.3, −1.6)  02Q1–04Q3  −3.8† (−5.0, −2.5)  04Q3–05Q2  4.9 (−11.2, 24.0)  05Q2–10Q4  −3.6† (−4.0, −3.2)  —  —  Cox-2  −3.9† (−5.7, −2.0)  02Q1–04Q3  5.6† (4.3, 7.0)  04Q3–05Q2  −39.2† (−50.2, −25.7)  05Q2–09Q1  −4.5† (−5.9, −2.9)  09Q1 – 10Q4  2.6 (-1.6, 6.9)  Topical  2.7† (2.3, 3.0)  02Q1–07Q1  1.7† (1.2, 2.2)  07Q1–10Q4  3.9† (3.3, 4.5)  —  —  —  —  Basic and Cox-2  −3.2† (−4.2, −2.2)  02Q1–04Q2  −0.4 (−1.5, 0.7)  04Q2–05Q1  −8.6 (−19.0, 3.2)  05Q1–10Q4  −3.5† (−3.9, −3.2)  —  —    Average QPC 2002–2010  Trend 1  Trend 2  Trend 3  Trend 4      Period 1  QPC  Period 2  QPC  Period 3  QPC  Period 4  QPC  In patients with CVD  Basic  −3.0† (−4.3, −1.6)  02Q1–04Q3  −3.8† (−5.0, −2.5)  04Q3–05Q2  4.9 (−11.2, 24.0)  05Q2–10Q4  −3.6† (−4.0, −3.2)  —  —  Cox-2  −3.9† (−5.7, −2.0)  02Q1–04Q3  5.6† (4.3, 7.0)  04Q3–05Q2  −39.2† (−50.2, −25.7)  05Q2–09Q1  −4.5† (−5.9, −2.9)  09Q1 – 10Q4  2.6 (-1.6, 6.9)  Topical  2.7† (2.3, 3.0)  02Q1–07Q1  1.7† (1.2, 2.2)  07Q1–10Q4  3.9† (3.3, 4.5)  —  —  —  —  Basic and Cox-2  −3.2† (−4.2, −2.2)  02Q1–04Q2  −0.4 (−1.5, 0.7)  04Q2–05Q1  −8.6 (−19.0, 3.2)  05Q1–10Q4  −3.5† (−3.9, −3.2)  —  —  NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor; CVD, cardiovascular disease; QPC, quarterly percentage change indicates the percentage change in prescribing prevalence per quarter over the stated time period. A positive percentage indicates an increase in prevalence; †QPC significantly different from 0 (0 indicating no change in prevalence, significant cut-off point P = 0.05); End quarter of each period signifies a joinpoint. View Large Table 2. Joinpoint regression analysis of quarterly prevalence of NSAIDs (basic NSAIDs, Cox-2, topical NSAIDs and basic and Cox-2 NSAIDs) prescribing in patients with CVD (aged 18 and over)   Average QPC 2002–2010  Trend 1  Trend 2  Trend 3  Trend 4      Period 1  QPC  Period 2  QPC  Period 3  QPC  Period 4  QPC  In patients with CVD  Basic  −3.0† (−4.3, −1.6)  02Q1–04Q3  −3.8† (−5.0, −2.5)  04Q3–05Q2  4.9 (−11.2, 24.0)  05Q2–10Q4  −3.6† (−4.0, −3.2)  —  —  Cox-2  −3.9† (−5.7, −2.0)  02Q1–04Q3  5.6† (4.3, 7.0)  04Q3–05Q2  −39.2† (−50.2, −25.7)  05Q2–09Q1  −4.5† (−5.9, −2.9)  09Q1 – 10Q4  2.6 (-1.6, 6.9)  Topical  2.7† (2.3, 3.0)  02Q1–07Q1  1.7† (1.2, 2.2)  07Q1–10Q4  3.9† (3.3, 4.5)  —  —  —  —  Basic and Cox-2  −3.2† (−4.2, −2.2)  02Q1–04Q2  −0.4 (−1.5, 0.7)  04Q2–05Q1  −8.6 (−19.0, 3.2)  05Q1–10Q4  −3.5† (−3.9, −3.2)  —  —    Average QPC 2002–2010  Trend 1  Trend 2  Trend 3  Trend 4      Period 1  QPC  Period 2  QPC  Period 3  QPC  Period 4  QPC  In patients with CVD  Basic  −3.0† (−4.3, −1.6)  02Q1–04Q3  −3.8† (−5.0, −2.5)  04Q3–05Q2  4.9 (−11.2, 24.0)  05Q2–10Q4  −3.6† (−4.0, −3.2)  —  —  Cox-2  −3.9† (−5.7, −2.0)  02Q1–04Q3  5.6† (4.3, 7.0)  04Q3–05Q2  −39.2† (−50.2, −25.7)  05Q2–09Q1  −4.5† (−5.9, −2.9)  09Q1 – 10Q4  2.6 (-1.6, 6.9)  Topical  2.7† (2.3, 3.0)  02Q1–07Q1  1.7† (1.2, 2.2)  07Q1–10Q4  3.9† (3.3, 4.5)  —  —  —  —  Basic and Cox-2  −3.2† (−4.2, −2.2)  02Q1–04Q2  −0.4 (−1.5, 0.7)  04Q2–05Q1  −8.6 (−19.0, 3.2)  05Q1–10Q4  −3.5† (−3.9, −3.2)  —  —  NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor; CVD, cardiovascular disease; QPC, quarterly percentage change indicates the percentage change in prescribing prevalence per quarter over the stated time period. A positive percentage indicates an increase in prevalence; †QPC significantly different from 0 (0 indicating no change in prevalence, significant cut-off point P = 0.05); End quarter of each period signifies a joinpoint. View Large In general, the trend in prescribing was similar by age group. However, higher prevalence of basic NSAIDs prescribed in younger patients with CVD and topical NSAIDs in older patients was observed (Figure 2). No difference in COX-2 inhibitor prescribing was seen among the age groups (Figure 2). Figure 2. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in CVD patients stratified by age-group. Age group, ≥18 and <65 years in Black, ≥65 and <75 years in Blue, ≥75 years in Red; Dash line, 95% confidence interval; Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. Figure 2. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in CVD patients stratified by age-group. Age group, ≥18 and <65 years in Black, ≥65 and <75 years in Blue, ≥75 years in Red; Dash line, 95% confidence interval; Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. The prescribing patterns were largely similar between males and females. However, higher prevalence of COX-2 inhibitors and topical NSAIDs was seen among females (Supplementary Figure S2), although this may be due to more females in older age groups. NSAIDs prescription in patients without CVD Figure 3 shows the NSAIDs prescribing in all registered population (aged 18 and above) without CVD from 2002 to 2010. A sharp drop in COX-2 inhibitor prescribing starting from 2002 quarter 4 also occurred, similar to those with CVD. The joinpoint regression analysis for non-CVD patients is summarized in Supplementary Table S3. Figure 3. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in patients (aged 18 and above) without CVD. Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; vertical lines, time of issue of national guidance (intervention); 95% CI, 95% confidence interval; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. Figure 3. View largeDownload slide Quarterly prevalence of NSAIDs prescribing (basic oral NSAIDs, Cox-2, topical NSAIDs, and basic and Cox-2 NSAIDs combined) in patients (aged 18 and above) without CVD. Vertical axis, quarterly prevalence (per 10000); horizontal axis, quarters from 2002 to 2010; vertical lines, time of issue of national guidance (intervention); 95% CI, 95% confidence interval; CVD, cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs; Cox-2, cyclooxygenase-2 inhibitor. Discussion Main findings This is the first study in UK primary care to investigate trends in the prevalence of NSAIDs prescribing in patients with CVD and particularly to assess the association with major national guidance issued during the study period 2002 – 2010. We have shown there was a shift in use between oral (basic and COX-2 inhibitors) and topical NSAIDs. 10% of patients with CVD received oral (basic or COX-2 inhibitors) and 4% topical NSAIDs per quarter in 2002, while such rates changed to 3% for oral and 8% for topical NSAIDs in 2010. The overall reduction in use of oral NSAIDs can be attributed to both basic and COX-2 inhibitor drugs. Particularly, following the MHRA 2004–2005 interventions, COX-2 inhibitor prescribing showed a sharp reduction within 6 months, with the rates dropping from 4% to 1%, suggesting a marked effectiveness of the guidance. During the same period, a short-term increase in basic NASIDs prescribing was seen, which may reflect basic NASIDs as one of the major alternatives to COX-2 inhibitors. In the following years, the trends were more stable, therefore, no obvious association of later guidance with prescribing change was determined. Overall, during 2002–2010 there was a reduction in use of NSAIDs. Our results are in line with Koffeman et al. (15) and a US study which indicated that there was still a large proportion of CVD patients using NSAIDs despite a decline after a Food and Drug Administration warning in 2005 (22). We have shown that a significant drop in COX-2 inhibitor prescribing also occurred in the population without pre-existing CVD when MHRA published the guidance during later 2004 and early 2005. This is surprising as the guidance was directed at patients with cardiovascular problems. To some extent, this implied that the guidance may be over looked as the GPs tended to not prescribe COX-2 inhibitor drugs to any patients. It also suggested that GPs might have been under treating patients who may benefit from COX-2 when there was no reason not to give it to them. Indeed, some patients being given basic NSAIDs perhaps should have had COX-2 as this is less risky for them in terms of gastrointestinal adverse events such as peptic ulceration. It is unknown whether such a decision was made based on more careful review of patients’ cardiovascular risk, or it was just easier to do for the GPs to use a blanket approach to NSAIDs due to the perceived risks and worry that litigation from patients who might not have CVD could occur. On the other hand, after several national guidances issued during 2004–2008, there were still some CVD patients receiving COX-2 inhibitors with a quarterly prevalence at approximately 50 per 10000. Whether or not these prescriptions were appropriate is unknown. Further research will be needed to look at the demographic, lifestyle and co-morbid characteristics of these patients and to assess the reason behind these COX-2 inhibitor prescriptions. We have also shown that in patients with CVD, NSAIDs prescribing trends were similar in different age and gender groups. However, patients with younger age tended to receive basic oral NSAIDs instead of topical NSAIDs perhaps because they were perceived to be less likely to suffer complications from the oral drugs compared to the older patients. However, other age-related factors, which may influence drug prescription such as severity of pain, disability level or patient preference, has yet to be investigated. Limitations Our study has several limitations. First, although the demographic structure of the population from our study was comparable to the general population of UK, this population was from more deprived areas compared to England as a whole. Here, we have shown that the average prevalence of CVD in our population was approximately 6% that was higher than the national figure (3.5%) (7), although the method of identifying patients was different. Second, we were unable to identify the use of over-the-counter (OTC) NSAIDs, and GPs may advise purchase of OTC NSAIDs rather than prescribe them. This might potentially lead to under reporting of NSAIDs use in the studied population. However, since 90% of English prescriptions are issued free to patients, the amount of missing data on NSAIDs use should not have had a large impact on our results. Third, the data used in this study were derived from the years 2002–2010 and trends in prescribing may have changed more recently. Impact of the study Despite guidelines and a trend toward decreased prescribing, the use of potentially harmful NSAIDs continued in patients with CVD. The MHRA directives had similar effects on both patient groups such that COX-2 prescribing became very infrequent, and basic NSAIDs decreased, based on our data up to 2010. Further advice appears to be needed regarding the correct use of NSAIDs since CVD patients might still be using them inappropriately, and non-CVD patients, who might benefit, have had their use inappropriately restricted. Supplementary material Supplementary material is available at Family Practice online. Declaration Funding: The Keele GP Research Partnership and the Informatics team at the Arthritis Research UK Primary Care Centre. CiPCA funded by the North Staffordshire Primary Care Research Consortium and Keele University Research Institute for Primary Care and Health Sciences. Ethical approval: Ethical approval for download and research using these databases was originally gained from the North Staffordshire Research Ethics Committee. Conflict of interest: None of the authors has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper. References 1. Joint Formulary Committee. British National Formulary 2011 . London: BMJ Group and Pharmaceutical Press, 2011. 2. The Medicines and Healthcare products Regulatory Agency [Internet]. Advice on the use of Celecoxib and other selective cox-2 inhibitors in light of concerns about cardiovascular safety. http://webarchive.nationalarchives.gov.uk/20141206131601/http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con019466.pdf (accessed on 2 August 2017). 3. The Medicines and Healthcare products Regulatory Agency [Internet]. 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Farmer AP, Légaré F, Turcot Let al.   Printed educational materials: effects on professional practice and health care outcomes. Cohrance Database Syst Rev . 2008; 3: CD004398. 11. Braybrook S, Walker R. Influencing NSAID prescribing in primary care using different feedback strategies. Pharm World Sci  2000; 22: 39– 46. Google Scholar CrossRef Search ADS PubMed  12. Wensing M, van der Weijden T, Grol R. Implementing guidelines and innovations in general practice: which interventions are effective? Br J Gen Pract  1998; 48: 991– 7. Google Scholar PubMed  13. Chan FK, Abraham NS, Scheiman JM, Laine L; First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents. 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Family PracticeOxford University Press

Published: Jan 22, 2018

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