Worldwide, there are 135 million people who have OA, and it is becoming increasingly common with the aging population seen in most western societies [1]. Consequently, OA is the most frequent cause of disability in older age groups [2] and ranks among the top 10 causes of disability [3]. OA affects twice the number of women (18%) than men (9.6%) aged ≥60 years [2]. NSAIDs are widely prescribed for long-term pain relief and inflammation in arthritis, with guidelines recommending their use after failure with paracetamol [4, 5]. The focus of preventing GI damage with NSAIDs has, until now, been on the upper GI tract. Guidelines recommend the use of a ns-NSAID plus a gastroprotective agent (such as a PPI) or a cyclooxygenase(COX)-2 selective inhibitor alone for patients at increased GI risk [4, 5] with one of the key factors identifying a patient as being at increased risk due to age (>65) [6].

Large trials investigating the gastrointestinal toxicity of NSAIDs do however, suggest that 40-60 % of serious GI toxicity may be in the lower GI tract [7, 8] with large scale epidemiological work [9, 10] and reviews of clinical trial work [11, 12] supporting this picture.

In the lower GI tract, it is proposed that NSAIDs induce changes in local prostaglandin metabolism, together with a topical toxic effect, that may be increased by enterohepatic circulation of the drug[13, 14]. Mucosal cell integrity is compromised as a result, with increases in epithelial permeability allowing bacteria, toxins and bile acids to cause inflammation [15]. The inflammation commonly precipitates subclinical mucosal damage in the distal GI tract, and at least 60-70% of patients taking NSAIDs develop enteropathy [15, 16], which is associated with continuous and mild bleeding. This may in turn result in anaemia, or more obvious clinical damage to the lower bowel (ulcers and bleeds).

The CONDOR (Celecoxib versus Omeprazole aNd Diclofenac for Osteoarthritis and Rheumatoid arthritis patients at increased GI risk) study, published in 2010 was the first large (more than 4,400 arthritis patients at increased GI risk), randomised GI outcomes study to investigate the potential frequency of defined amounts of blood loss [(≥2g/dL) decreases in haemoglobin (hb)] throughout the gastrointestinal tract, in addition to more well recognised clinical endpoints (perforations, obstructions and bleeds) [17]. Use of a ≥2g/dL drop in haemoglobin has been well recognised as a surrogate endpoint in clinical trials investigating the gastrointestinal toxicity of NSAIDs conducted over the last twenty years [17-20].

The trial demonstrated a 4-fold superior risk reduction of clinically significant upper and lower GI events for arthritis patients taking celecoxib alone compared to diclofenac plus omeprazole. Differences were mainly attributable to the frequency of Hb decrease, with fewer patients in the celecoxib group having a significant decrease in Hb (2g/dL or more) than in the diclofenac plus omeprazole group (15 vs 77). The majority of these Hb drops were adjudicated as being of presumed occult GI sources. The study reported that the predefined Hb drop occurred as early as one to two months after starting NSAID treatment in some patients. Of the 92 patients who had a decrease of 2g/dL in Hb, 50 had haemoglobin concentrations lower than 11.5g/dL. (N.B 11.5g/dL was the central labs definition of anaemia for both sexes - and the most conservative estimation of the incidence of ‘true’ anaemia reported in the study)[17].

Whilst there is some contention in the literature [21, 22] most observational cohorts adopt the World Health Organisation (WHO) criteria for anaemia - namely - a Hb concentration<13g/dL in men or <12g/dL in women. Evidence using these values suggests that anaemia is associated with poorer physical performance and greater disability [23], a doubling in the risk of recurrent falls [24], and a greater risk of mortality [25] compared to respective controls with non anaemic Hb levels.

Epidemiological studies have also shown that mildly low or low to normal Hb concentrations that do not meet the definition for anaemia are independently associated with an increased risk of frailty, poor functional outcomes, admission to hospital and mortality [26-28].

The questionnaire described below was designed with the intention of developing an initial understanding of European primary care physician practice for the collection of a complete blood counts (CBC) in osteoarthritis patients. A key goal was to understand how physicians interpret the information obtained, particularly in relation to the parameter of haemoglobin levels as an indicator of patient health (especially patient status as being anaemic/non-anaemic as defined by the WHO). Given that NSAIDs, including COX-2 selective inhibitors have been shown to have a strong causal association with blood loss from the gastrointestinal tract, it was felt that a snapshot survey would be useful to make an initial assessment of primary care physician awareness on this important topic.

The aim of this survey was to provide an initial semi-quantitative view of self-reported physician behaviour in relation to the practice of taking CBC’s and in particular haemoglobin values for patients they are treating who have osteoarthritis. The physicians were screened and excluded using the criteria below with the broad aim of the research being to identify a cohort of physicians who treated osteoarthritis frequently.

Physicians were excluded if they had practiced medicine for <3 or >30 years, were employed in any capacity by a pharmaceutical company/Clinical Research Organisation, saw fewer than 7 OA patients per month, or did not recognise themselves as being involved in the initiation or switching of pain medications for the treatment of osteoarthritis. In addition, physicians who self-recognised as prescribing less than 7 prescriptions for a COX-2 selective inhibitor (e.g. etoricoxib/celecoxib) were also de-selected from further follow up.

All information presented was gathered through the form of a short online questionnaire with doctors from 8 European countries (Belgium, France, Germany, Italy, Portugal, Spain, Switzerland, and UK) who were self-identified as working in a primary care environment. The exception was Portugal where the interviews were conducted face to face. One hundred physicians were questioned from France, Germany, Italy, Portugal, Spain, and the UK, with 50 physicians sampled from Switzerland and Belgium. All interviews took place in November and December 2009. The interviews were designed to be as short as possible (no interview/online interaction lasted greater than 15 minutes), and no physician demographics were captured other than the screener questions designed to assess their suitability for entry into the survey.

Physicians meeting the criteria above were asked the questions presented in the two exhibits below:

Approximately 50 % of the 700 physicians surveyed suggested that OA patients would have a complete blood count (CBC) ‘routinely’ conducted with the percentage varying from 32 % of Swiss doctors, to 64 % of Italian doctors (see Table 1 for full country by country variations).

The most frequently observed definition of routine were based on a periodicity of every 6-12 months (39% of physicians sampled - see Table 2 for full description of variations in periodicity) or every 5-6 months (22% of physicians sampled).

The most common reasons (detailed data not shown) for conducting routine measurements were to compare to a previous measurement in the same patient (59 % of doctors) and to assess the absolute haemoglobin (Hb) level at the time of the test (30 % of doctors). Personal preference was cited by 28% of physicians, with following guidelines (type of guidelines not specified) cited by 18% of doctors.

In the other group of approximately 50 % of physicians that only conducted a CBC on an ‘ad hoc’ basis, for 90% a key potential reason cited was suspected anaemia in the patient concerned, with physicians also being concerned by blood loss (80 % of physicians sampled) or by the patient showing signs of fatigue or weakness (78% of physicians sampled).

The survey of doctors from across Western Europe reported here, suggests there is insufficient awareness of the need to monitor for NSAID-related blood loss, potentially increasing the risk of patients suffering GI problems (anaemia and other clinical manifestations of harm). The inclusion criteria for this survey were designed to capture the views of doctors with at least a reasonable degree of familiarity of the classes of medicine under investigation and their associated toxicities, perhaps suggesting that had the inclusion criteria being less exacting the findings would have been even more marked. Whilst the findings are only intended to provide a spontaneous snapshot of physician practice and understanding, the sample is of a reasonable size, and is the first attempt, to the authors’ knowledge, at investigating the views of primary care physicians from across several European countries. Given that OA is a condition primarily treated by this physician group the findings are important, and highlight that more could be done to raise awareness of the importance of Hb as a haematological parameter that may be altered unfavourably by medicines used to treat the condition.

The survey does have weaknesses. It lacks the benefit of a more formalised design, where information would be independently verified rather than just reported by the physician questioned. Capturing a greater quality and quantity of information on physician and patient phenotypes would allow better interrogation of some of the differences tentatively identified here, including the high awareness and concern with lower GI toxicity observed in Spain and Portugal (answer to question 4), that appears to be matched by an erroneous belief that proton pump inhibitors mitigate the problem (see question 5).

A more detailed qualitative design may also help explain whether the relatively low level of concern illustrated by French primary care physicians (answers to question 4) is explained by genuine physician beliefs, or some form of existing general practice/guideline that physicians believe meet this area of medical need (and therefore mitigates concern). To date the authors are not aware of any guidelines for OA in the countries surveyed that recommend Hb monitoring.

Reducing the risk of bleeding throughout the entire GI tract in OA patients being treated with NSAIDs can improve the health of individual patients affected, and reduce expenditure on further investigations and care. The survey presented here suggests the potential for the more subtle forms of bleeding that may occur with NSAID use, particularly from the lower gastrointestinal tract, are an under recognised problem. Further research is still required to supplement the one study that begins to suggest what the risk factors for gastrointestinal harm are beyond the duodenum [30]. Given that OA is an increasingly prevalent disease in societies with aging populations it may also be time to develop guideline recommendations on monitoring Hb levels in the growing populations of elderly OA patients who use NSAIDs.