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Appropriate prescription, adherence and safety of non-steroidal anti-inflammatory drugs
Prescripción apropiada, adherencia y seguridad de los antiinflamatorios no esteroideos
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"documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2016;146:273-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Guideline development process checklist" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "273" "paginaFinal" => "277" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Lista de comprobación del proceso de elaboracio¿n de guías de práctica clínica" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2030 "Ancho" => 3007 "Tamanyo" => 462403 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Outline of the clinical practice guidelines development process.The different steps and the participation of the guideline development group members (GDG) are interrelated and are not necessarily sequential. The clinical practice guideline (CPG) panel and support groups (such as, for example, methodologists, health economists, the systematic review team and the administrative support secretariat) work collaboratively and are informed by users and interest groups, usually supervised by a monitoring committee. For example, while deciding how to incorporate interest groups early during the process to select and prioritise the subjects, the GDG also needed to consider that the development of formal relations with interest groups will facilitate effective dissemination and implementation and provide support for updating the CPG. In addition, considerations for the organisation, planning and training cover the entire CPG development project, and measures such as documentation of the methodology used and the decisions taken as well as the consideration of conflicts of interest, need to be present throughout the process. (Translated with permission from Schünemann et al.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a>).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Itziar Etxeandia-Ikobaltzeta, Romina Brignardello-Petersen, Alonso Carrasco-Labra, Pablo Alonso-Coello" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Itziar" "apellidos" => "Etxeandia-Ikobaltzeta" ] 1 => array:2 [ "nombre" => "Romina" "apellidos" => "Brignardello-Petersen" ] 2 => array:2 [ "nombre" => "Alonso" "apellidos" => "Carrasco-Labra" ] 3 => array:2 [ "nombre" => "Pablo" "apellidos" => "Alonso-Coello" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S002577531500593X" "doi" => "10.1016/j.medcli.2015.09.023" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S002577531500593X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616301930?idApp=UINPBA00004N" "url" => "/23870206/0000014600000006/v3_201704140441/S2387020616301930/v3_201704140441/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020616301917" "issn" => "23870206" "doi" => "10.1016/j.medcle.2016.05.005" "estado" => "S300" "fechaPublicacion" => "2016-03-18" "aid" => "3447" "copyright" => "Elsevier España, S.L.U." 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"apellidos" => "Ramos" ] 5 => array:2 [ "nombre" => "Héctor" "apellidos" => "Pinargote" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775315006296" "doi" => "10.1016/j.medcli.2015.11.008" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775315006296?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616301917?idApp=UINPBA00004N" "url" => "/23870206/0000014600000006/v3_201704140441/S2387020616301917/v3_201704140441/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Appropriate prescription, adherence and safety of non-steroidal anti-inflammatory drugs" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "267" "paginaFinal" => "272" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Carlos Sostres, Ángel Lanas" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Carlos" "apellidos" => "Sostres" "email" => array:1 [ 0 => "carlossostres@gmail.com" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Ángel" "apellidos" => "Lanas" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Universidad de Zaragoza, Instituto de Investigación Sanitaria (IIS) Aragón, Zaragoza, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Prescripción apropiada, adherencia y seguridad de los antiinflamatorios no esteroideos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1530 "Ancho" => 2951 "Tamanyo" => 185938 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Summary of the most important secondary effects of the nonsteroidal anti-inflammatory drugs that are most commonly used in clinical practice. ASA: acetylsalicylic acid; OAC: oral anticoagulants. <span class="elsevierStyleItalic">Source</span>: Modified from Lanas et al.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pain is one of the main factors contributing to the global burden of disease, measured by years lived with disability. Patients in pain, especially musculoskeletal pain, represent a significant percentage of the population and demand treatment; the most commonly used medication for this scenario are nonsteroidal anti-inflammatory drugs (NSAIDs), of the analgesic variety.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Traditional NSAIDs are associated with a significantly increased risk of gastrointestinal (GI) events, which varies depending on the NSAID and dose, and the existence of risk factors.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> Within NSAIDs, COX-2 inhibitors, also known as coxibs, have a better GI safety profile, but as a result of their marketing it became known that these, and subsequently other non-selective NSAIDs, increased cardiovascular (CV) risk, which led to different regulatory agencies stating that NSAIDs in general may pose a significant risk to health.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Thus, despite the undoubted beneficial effects of NSAIDs to control pain and inflammation in musculoskeletal diseases, the presence of adverse GI events and CV risk mean that the ‘ideal’ choice of NSAID is a sometimes complicated decision in routine clinical practice. Recently a consensus document was published by 3 Spanish scientific societies on the appropriate prescription based on the secondary effects of different NSAIDs.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> This article also discussed other issues that decisively affect the end safety of patients being prescribed NSAIDs, while also referring to the appropriateness of the prescription and adherence to treatment by patients.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Nonsteroidal anti-inflammatory drugs and gastrointestinal damage</span><p id="par0015" class="elsevierStylePara elsevierViewall">The main indication of NSAIDs is the reduction of pain. Clinical practice guidelines recommend their prescription after assessing other non-pharmacological or paracetamol options.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> The response to NSAIDs varies from patient to patient, but no NSAID (including coxibs) has proven to be more effective than another.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> Today it is widely accepted that NSAIDs (traditional and coxibs) can damage the entire GI tract, although there are clear differences between traditional NSAIDs and coxibs in this regard. The spectrum of lesions is variable, ranging from ulcers or erosions to severe complications such as bleeding and perforation. Many of these lesions are asymptomatic. However, more than 40% of NSAID takers have reported symptoms in the upper GI tract during treatment, the most frequent being gastroesophageal reflux and dyspeptic symptoms.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> Approximately 1–4% of patients will have symptomatic GI ulcers or complications from treatment with NSAIDs. Observational studies have shown that the average relative risk (RR) of developing a peptic ulcer complication is 4–5 times higher in patients treated with NSAIDs compared to those who are not.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> There is less evidence available of damage to the lower GI tract caused by NSAIDs than for the upper GI tract. It has recently been shown that hospital admissions for lower GI complications are increasing, while upper GI tract complications are decreasing.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The risk of GI complications is not the same for all patients, but depends–aside from the dose and type of NSAID–on a series of risk factors that must be taken into account when deciding on treatment. Age, >60 years-old, is an independent risk factor for the occurrence of GI complications. Risk increases progressively with age. The presence of a history of gastroduodenal peptic ulcer has proven to be the most important risk factor for developing GI complications in patients taking NSAIDs.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> The <span class="elsevierStyleItalic">combination of 2 or more NSAIDs</span> increases the risk of bleeding associated for each NSAID individually. This increased risk is also observed with the involvement of a classic NSAID or coxib with acetylsalicylic acid (ASA) at low doses, a combination very often used in clinical practice. Based on these risk factors, patients requiring NSAIDs have been categorised into 3 groups<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a>:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1.</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">High risk</span>: a complicated personal history of peptic ulcers; use of anticoagulants or combination of >2 accepted risk factors.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2.</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Medium risk</span>: patients without a history of complicated ulcer and no anticoagulation with some other isolated risk factor.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3.</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Low risk</span>: patients without risk factors. No consumption of ASA.</p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Nonsteroidal anti-inflammatory drugs and cardiovascular damage</span><p id="par0040" class="elsevierStylePara elsevierViewall">The patient who requires NSAIDs also requires a CV risk assessment. CV risk is currently measured by following the <span class="elsevierStyleItalic">Systematic Coronary Risk Evaluation</span><a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> model, based on studies with European populations. It is well established that the administration of NSAIDs increases the risk of developing acute coronary syndrome or other CV risk episodes of an atherothrombotic nature. This has been certified by data published since coxibs entered the market, current clinical practice guidelines, consensus documents and regulatory agencies.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4,11,12</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The most recent large meta-analysis study indicates that coxibs and NSAIDs have an increased cardiovascular risk compared to placebo, with no significant differences between them in general. From all the traditional NSAIDs, the one that posed a greater risk of CV risk was diclofenac, presenting a similar risk to that of coxibs. Naproxen at doses of 500<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h was not associated with an increased CV risk, unlike ibuprofen and diclofenac.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> More recently the Spanish Medicines Agency (AEMPS) has warned that available data indicate the need to emphasise that ibuprofen at high doses (2400<span class="elsevierStyleHsp" style=""></span>mg/day) and dexibuprofen (1200<span class="elsevierStyleHsp" style=""></span>mg/day) (medications that are widely used in Spain and available without prescription) present a CV risk similar to coxibs at standard doses, such that, except at doses at or below 1200<span class="elsevierStyleHsp" style=""></span>mg/day or 600<span class="elsevierStyleHsp" style=""></span>mg/day, respectively, and used for only short periods of time, these molecules should be taken with the same precautions than coxibs.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Prescribing recommendations based on gastrointestinal and cardiovascular risk</span><p id="par0050" class="elsevierStylePara elsevierViewall">The main objective of managing patients treated with NSAIDs is preventing the development of complications. For this, a GI and CV risk profile must be made for each case before prescribing the ‘ideal’ NSAID, in addition to a gastroprotection strategy if necessary. This full profile would be what guides the type, dose and schedule for NSAIDs administered in each case (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">We know that the GI safety profile of coxibs is superior to that of traditional NSAIDs.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> A recent meta-analysis study showed that compared with traditional NSAIDs, celecoxib is associated with a significantly lower risk of all clinically significant GI events throughout the entire GI tract.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> Naproxen has the lowest CV risk, while other medications like diclofenac and etoricoxib pose the greatest risk at present. This was confirmed by a recent meta-analysis study<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> which showed that CV risks from diclofenac and ibuprofen at high doses are comparable to coxibs, while doses of 500<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h of naproxen are associated with lower CV risks. In any case, if coxibs (especially celecoxib at doses of 200<span class="elsevierStyleHsp" style=""></span>mg/day) has the safest GI profile, naproxen has the safest CV risk profile. Celecoxib and diclofenac do not interfere with antiplatelet activity of ASA at low-dosis<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> or clopidogrel. This would make celecoxib at low-doses the most suitable NSAID for patients receiving ASA; however, the EMA (European Medicines Agency) maintains contraindication of its use in patients taking ASA for secondary prevention. There are conflicting data regarding the interference of the antiplatelet effect of ASA in the presence of naproxen; in any case, this interaction appears to be lower than that observed with ibuprofen.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Current recommendations are reflected in a consensus document prepared by three Spanish scientific societies.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> Based on these recommendations, any NSAID is acceptable in patients with low CV and GI risk. Patients at high GI risk should avoid treatment with NSAIDs; if it is necessary, <span class="elsevierStyleItalic">Helicobacter pylori</span> should be eradicated in patients with history of ulcers and infected ulcers and prescribed celecoxib<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>proton-pump inhibitor (PPI) if CV risk is low. In patients with high CV risk the best treatment option is naproxen with or without PPI, depending on the GI risk. Naproxen with PPI is a reasonable option, but its possible interference with low-dose ASA–until we have more conclusive data–means that its use should be restricted to less time if NSAIDs must necessarily be used in this particular context. Taking naproxen 2<span class="elsevierStyleHsp" style=""></span>h after ASA could reduce the impact of such interference, but its effect on chronic to long-term treatments is unknown.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a><a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> summarises the main characteristics of the clinical impact of the most prescribed NSAIDs in Spain.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Prescription of nonsteroidal anti-inflammatory drugs, gastroprotection and adherence to treatment. Do we do it properly?</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Proper prescription</span><p id="par0065" class="elsevierStylePara elsevierViewall">An important question is whether the recommendations of clinical practice guidelines are followed in routine practice. The data indicate that in most countries prescriptions do not comply with guidelines recommendations or those of regulatory agencies.</p><p id="par0070" class="elsevierStylePara elsevierViewall">A Dutch retrospective study showed that the vast majority (>80%) of patients with GI risk did not follow their treatment properly (coxib or traditional NSAID<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>PPI). Another recent study in the US found that less than half patients conducted a correct prescription and that only 37% of high-risk GI patients were taking appropriate preventive measures. Another Spanish observational study<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> showed that 86.6% of patients with osteoarthritis had at least one GI risk factor (22.3% were patients with high GI risk). CV risk was high in 44%, and average in 28.5% of patients. 15.5% of these patients had a high GI and CV risk. These data imply that most patients on chronic NSAID therapy should also receive preventive measures. These data were confirmed in another study<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> that included 17,105 patients with osteoarthritis (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Globally, more than 90% of patients were at risk of GI and/or CV, and for 51% of them the treatment prescribed to them was not in accordance with the indications of clinical practice guidelines.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">A European multicentre<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> study with patients at risk of GI taking NSAIDs showed that the rate of gastroprotection was variable and unacceptably low. A German database covering 9 million people showed a significant deficit of PPI co-prescription for elderly patients who were starting treatment with traditional NSAIDs. However, not all data are negative. A Spanish retrospective observational study found that 90% of patients did take gastroprotection, the most frequent being chronic takers with associated risk factors. Another study that includes data from 3 European countries, showed an increase in the correct prescription of up to 20% between the 90s and the first decade of the 21st century. Despite this, about 35–40% of the population taking NSAIDs is doing so without a proper prescription and are exposed to side effects.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Adherence to treatment</span><p id="par0080" class="elsevierStylePara elsevierViewall">A Dutch study showed that only 15% of patients with at least one GI risk factor taking NSAIDs followed the gastroprotective treatment prescribed to them, and that the risk of GI complications increased by 16% for every 10% decrease in adherence to that gastroprotective treatment. Patients who were not undergoing gastroprotective treatment had between 2.5 and 4 times more risk of developing high GI complications than those who were. More recently, the study of a cohort of 618,684 NSAID takers in 3 different European countries (Holland, Italy and the UK) found that the risk of GI bleeding and/or GI ulcer was significantly higher (RR 2.39 [95% CI 1.09–3.28]) in patients not taking proper gastroprotection compared to those who did take it.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Another study showed similar results in patients treated with coxibs (an increase of 9% for every 10% decrease of adherence to treatment).</p><p id="par0085" class="elsevierStylePara elsevierViewall">A Spanish prospective study<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> assessed adherence to treatment of NSAID<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>PPI, as well as the causes and consequences of non-adherence to the treatment. It was observed that the optimum adherence reported by patients to NSAIDs and PPIs was 79.7% (95% CI 76.9–82.2) and 84.1% (95% CI 81.7–86.3), respectively (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Patients who did not properly adhere to PPI showed a greater number of GI adverse events compared to those who complied with treatment (22.1 compared to 1.9%, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001). The most common causes for non-adherence was the absence of rheumatic pain for NSAIDs and forgetting to take medication for PPIs. Another Swedish study included 3649 patients who had upper gastrointestinal bleeding secondary to taking NSAIDs. Patients with low adherence to gastroprotective treatment<span class="elsevierStyleMonospace">(<</span>20% of the days) had a greater risk of high GI complications (OR 1.88 [95% CI 1.22–2.88]) compared with patients with good adherence (>80% of the days).</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Proposals to improve suitable prescription and patient adherence to treatment</span><p id="par0090" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">1.</span><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Suitable prescription.</span> Evidence available in this field is scarce. A Canadian study found that factors associated with a worse prescription included the doctors’ age and the number of years since they graduated. A double-blind randomised study for taking diclofenac or etoricoxib<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> that included 23,504 chronic NSAIDs takers. 69% had a high-risk of GI and they were prescribed treatment with PPI (free). Halfway through the study, a letter was sent to their doctors indicating the need to continue the prescription with PPI. The inclusion of a direct communication that urged a written response significantly increased correct prescription (43–61%), although without reaching adequate prescription levels <span class="elsevierStyleMonospace">(<</span>50%). In a Spanish study<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> in which 456 specialists and 3728 patients participated, data on the correct prescription of PPIs were collected before and after attending an update symposium on evidence of secondary GI damage from taking NSAIDs as well as on indications of gastroprotection. The study concluded that the update seminar programme did not change the results of suitable prescription. Finally, a Dutch study<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> found an increase in prescriptions of PPIs in patients treated with NSAIDs between 2001 and 2007 (from 40 to 70%). In turn, it observed a clear decrease in the number of hospitalisations secondary to high GI bleeding due to peptic ulcer in the last decade,<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> being at least partly due to a better prescription of gastroprotection in the population.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">2.</span><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Increase adherence.</span> If proper prescription is important, so is increasing adherence to treatment, as this is inversely related to the occurrence of GI complications.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> The most common cause of non-adherence is forgetting to take the medication; other causes described include the absence of prescription of PPIs by doctors after 2 years or more of treatment, the female sex and the absence of side effects. To try to prevent/reduce non-adherence, one single tablet/capsule has been designed that contains both NSAID and PPI. The fixed dose combination of naproxen and esomeprazole combines the effectiveness of naproxen with a favourable CV safety profile dose of 500<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h, a lower incidence of ulcers associated with NSAIDs and better tolerability in the upper digestive tract because of the esomeprazole. Its effectiveness in osteoarthritis is equivalent to that of coxibs, it has shown that it maintains its GI and CV safety profile even in the long-term, and has a favourable pharmacoeconomic profile in the Spanish population.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> There are no direct data of improvement in adherence with the use of this combination. However, indirect published data comparing a combination of ibuprofen and famotidine with ibuprofen in mono-dose showed that a significantly greater number of patients adhered to treatment when their medication was combined.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> In turn, data from other specialties<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> evidenced a clear improved adherence with the use of “polypills’.</p></li></ul></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0105" class="elsevierStylePara elsevierViewall">The need for treatment with NSAIDs and an increase in rheumatic diseases in an ageing population such as the Spanish one remains high. The need for a suitable prescription to prevent side effects in patients treated with NSAIDs is evident, not only because it has been endorsed by several scientific societies and regulatory agencies, and requires individual assessment of GI and CV risk. Thus, the most common options (but not the only ones) recommended today for the treatment of rheumatic diseases are prescribing celecoxib with or without PPI, depending on the GI risk, and naproxen for patients with high CV risk, with or without PPI, depending on the GI risk. Two problems in the proper treatment of patients requiring NSAIDs have been identified: one is suitable prescription by the doctor, and the other is patient adherence to prescribed treatment.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Although proper prescription of NSAIDs and gastroprotective treatment has improved in recent years, the current rate in this area is far from acceptable. The presence of secondary GI and CV effects and existing co-morbidities in the population in need of NSAIDs make the decision-making process increasingly complicated. This is why strategies to improve doctors’ education and training are required as well as making tools that facilitate the decision-making process (simplified algorithms, risk calculators, clinical practice guidelines) available in clinical practice. Increasing patient adherence to treatment is also necessary. The appearance on the market of pills that combine medications is a step in the right direction. In summary, therapeutic innovation in its many facets and innovation in the availability of appropriate tools to facilitate clinical decision-making are essential elements on which to build a safer future for pain treatment.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">Dr. Ángel Lanas has participated in studies funded by <span class="elsevierStyleGrantSponsor" id="gs1">AstraZeneca</span> and has conducted investigator-driven research that has been partially or fully funded by AstraZeneca, without the company taking part in development of the study. Finally, he has received small payments for participating as a speaker at meetings supported by AstraZeneca, Bayer and Pfizer.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres828439" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec824640" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres828438" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec824641" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Nonsteroidal anti-inflammatory drugs and gastrointestinal damage" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Nonsteroidal anti-inflammatory drugs and cardiovascular damage" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Prescribing recommendations based on gastrointestinal and cardiovascular risk" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Prescription of nonsteroidal anti-inflammatory drugs, gastroprotection and adherence to treatment. Do we do it properly?" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Proper prescription" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Adherence to treatment" ] ] ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Proposals to improve suitable prescription and patient adherence to treatment" ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-06-16" "fechaAceptado" => "2015-09-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec824640" "palabras" => array:4 [ 0 => "Non-steroidal anti-inflammatory drugs" 1 => "Safety profile" 2 => "Side effects" 3 => "Adherence" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec824641" "palabras" => array:4 [ 0 => "Antiinflamatorios no esteroideos" 1 => "Seguridad" 2 => "Efectos secundarios" 3 => "Adherencia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Non-steroidal anti-inflammatory drugs (NSAIDs) are the most numerous category of drugs sharing the same mechanism of action and therapeutic activities (anti-inflammatory, analgesic and anti-pyretic). Despite having similar efficacy for pain relieve, the different available NSAIDs show variability in its safety profile. The risk of gastrointestinal and cardiovascular complications varies depending on the dose of NSAID and also the presence of different risk factors. It is necessary, therefore, an individualised case assessment before establishing the indication of the best NSAID for each patient, taking account of the best gastroprotection strategy. Improved prescription and enhanced treatment adherence are central objectives to reduce NSAID-related complications. A recent consensus of the Spanish Association of Gastroenterology and the Spanish societies of Cardiology and Rheumatology intends to promote the rational use of NSAIDs according to new recent studies. This review provides additional aspects to facilitate the optimal decision-making process in the routine use of these drugs in clinical practice.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los antiinflamatorios no esteroideos (AINE) configuran la familia más numerosa de fármacos que comparten los mismos mecanismos de acción y actividades terapéuticas (antiinflamatoria, analgésica y antipirética). A pesar de tener una eficacia similar para controlar el dolor, los diferentes AINE disponibles presentan variabilidad en su perfil de seguridad. El riesgo de complicaciones gastrointestinales y cardiovasculares varía en función del AINE y de la dosis que utilicemos, además de la presencia de factores de riesgo. Es necesaria una evaluación individualizada de cada caso antes de sentar tanto la indicación del AINE «ideal» como la estrategia de prevención gastrointestinal si fuera necesaria. Una correcta prescripción y una adecuada adherencia al tratamiento gastroprotector son los objetivos que hay que plantearse para conseguir reducir las complicaciones secundarias al tratamiento con AINE. Recientemente se han publicado unas recomendaciones de prescripción adecuada fruto de la colaboración de la Asociación Española de Gastroenterología y las sociedades españolas de Reumatología y Cardiología que tiene por objeto impulsar un uso racional de los AINE en función de los últimos estudios publicados. Esta revisión completa aspectos adicionales necesarios para facilitar la toma de decisiones óptima en el uso habitual de estos fármacos en la práctica clínica diaria.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Sostres C, Lanas Á. Prescripción apropiada, adherencia y seguridad de los antiinflamatorios no esteroideos. Med Clin (Barc). 2016;146:267–272.</p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2162 "Ancho" => 3312 "Tamanyo" => 235411 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Therapeutic algorithm for patients requiring simplified nonsteroidal anti-inflammatory drugs in the long term depending on gastrointestinal risk and cardiovascular risk factors. ASA: acetylsalicylic acid; NSAIDs: nonsteroidal anti-inflammatory drugs; PPI: proton-pump inhibitor; CV risk: cardiovascular risk; GI risk: gastrointestinal risk. Naproxen at doses of 500<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h. <span class="elsevierStyleItalic">Helicobacter pylori</span> infection should be investigated and treated in patients with a history of peptic ulcers. <span class="elsevierStyleItalic">Source</span>: Modified from Lanas et al.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1530 "Ancho" => 2951 "Tamanyo" => 185938 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Summary of the most important secondary effects of the nonsteroidal anti-inflammatory drugs that are most commonly used in clinical practice. ASA: acetylsalicylic acid; OAC: oral anticoagulants. <span class="elsevierStyleItalic">Source</span>: Modified from Lanas et al.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1529 "Ancho" => 2587 "Tamanyo" => 139097 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Rates of unsuitable prescription of nonsteroidal anti-inflammatory drugs and proton-pump inhibitors according to gastrointestinal and cardiovascular risk levels. CV: cardiovascular risk; GI: gastrointestinal. <span class="elsevierStyleItalic">Source</span>: Modified from Lanas et al.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1442 "Ancho" => 2137 "Tamanyo" => 265069 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Distribution and causes of non-adherence to prescribed treatment by patients with osteoarthritis and risk factors who are receiving nonsteroidal anti-inflammatory drugs and proton-pump inhibitors. NSAIDs: nonsteroidal anti-inflammatory drugs; PPI: proton-pump inhibitor; Tt: treatment. <span class="elsevierStyleItalic">Source</span>: Modified from Lanas et al.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a></p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New insights into the use of currently available non-steroidal anti-inflammatory drugs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K. Brune" 1 => "P. 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