Original Article
The impact of dosing frequency on medication adherence in chronic cardiovascular disease: Systematic review and meta-analysis
Impacto da frequência posológica na adesão terapêutica em doenças cardiovasculares crónicas: revisão sistemática e meta-análise
a Laboratório de Farmacologia Clínica e Terapêutica, Faculdade Medicina da Universidade de Lisboa, Lisboa, Portugal
b Unidade de Farmacologia Clínica, Instituto Medicina Molecular, Lisboa, Portugal
c Centro de Estudos de Medicina Baseada na Evidência, Faculdade Medicina da Universidade de Lisboa, Lisboa, Portugal
d Centro Colaborador Português da Rede Cochrane Iberoamericana, Portugal
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CI: confidence interval.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cardiovascular disease (CVD) is the leading cause of death and loss of disability-adjusted life years worldwide.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Treatment, control and prevention of the consequences of CVD depend on adherence to interventions as much as on those interventions’ efficacy and tolerability. Adherence to treatment includes patients’ behavior in relation to physicians’ recommendations, such as changes in lifestyle, adoption of a specific diet or taking medication.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The World Health Organization recognizes non-adherence to long-term therapies as a major problem that contributes to morbidity and mortality and their associated direct and indirect costs.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–6</span></a> The magnitude of non-adherence is estimated at 30–50%,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> for which there are a variety of reasons, including the efforts and strategies used by the physician, the individual characteristics of the patient, and the type, complexity and cost of the therapeutic regimen.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In this systematic review we aimed to assess the impact of dosing frequency (single vs. two or more daily doses) on adherence to drug treatment in patients with chronic CVD.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">The electronic databases MEDLINE and the Cochrane Library were searched in November 2013. The search strategy (shown in Supplementary Data Table 1, available online) was adapted from other studies in this area and was extended to searches of references in other systematic reviews and the studies obtained.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The inclusion criteria were randomized controlled trials comparing different daily dosing regimens (single vs. two or more daily doses) in patients with chronic CVD (coronary disease, hypertension, dyslipidemia or persistent arrhythmia) that provided data on adherence to drug therapy. We arbitrarily set a minimum 5-month follow-up period when selecting trials to assess rates of long-term adherence. Placebo-controlled and double-dummy trials were excluded since they do not allow assessment of the impact of dosing frequency on adherence.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The consistency and interpretability of aggregated results of therapeutic interventions are improved by the ability to disregard the adverse events caused by these interventions.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In the light of this, the primary outcome selected was non-adherence to therapy rather than adherence. Non-adherence was defined as taking less than 80–90% of the prescribed medication,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> this definition being assumed for studies in which non-adherence was not defined. Data on discontinuation of therapy were not considered to be equivalent to non-adherence, as there can be various reasons for leaving a trial that are related to the drug therapy but not necessarily to the complexity of the dosing regimen, such as tolerability.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Potentially eligible trials were selected independently by two of the authors (DC and JC) after assessment of the abstract and then the complete text. For each of the eligible studies, a standard data collection form was used to enter the population characteristics, interventions and relevant outcomes. Any disagreement between the investigators was resolved by consensus. The possibility of methodological bias in the selected studies was assessed with the aid of the Cochrane Collaboration's tool for assessing risk of bias.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The results of the individual trials were aggregated by means of a meta-analysis using RevMan software (version 5.2.6; The Nordic Cochrane Centre, The Cochrane Collaboration) to determine the impact of dosing frequency on risk of non-adherence to therapy. Estimates of risk for the combined results and for those of individual studies were assessed using relative risk (RR) rather than absolute risk, since estimates of RR are more consistent between studies with different designs, populations and length of follow-up.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,14</span></a> All the study variables were presented with 95% confidence intervals (CI) for the estimated RR. The overall estimate of the magnitude of the effect was calculated using the inverse variance method. When the estimated risk was significant, an absolute measure of sampling effort, the number needed to treat to benefit (NNTB), was estimated.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The statistical heterogeneity of the results of the different studies was assessed using the I<span class="elsevierStyleSup">2</span> test,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> which calculates the percentage of total variation across studies that is due to heterogeneity rather than chance. When there was significant heterogeneity between studies (I<span class="elsevierStyleSup">2</span>≥50%),<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> we considered whether this could at least partially be due to differences in clinical characteristics (type of intervention, underlying disease, duration of study) or in methodology (quality of studies, study design, type of control). The overall magnitude of the effect was estimated by the DerSimonian and Laird method (random effects approach),<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> whether or not there was heterogeneity. The random effects model assumes that the results of each study are independent of each other, since each study estimates a different treatment effect. This approach is more conservative than the fixed effects model, which assumes that the effect (magnitude and/or direction) of an intervention is the same in different studies and thus that the differences observed between studies are due to chance.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The risk of publication bias was assessed using Egger's test.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">On the basis of the inclusion criteria, four clinical trials were selected for analysis.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20–23</span></a> The results of the assessment and selection process are shown in <a class="elsevierStyleCrossRef" href="#fig0015">Figure 1</a>. These trials analyzed 2557 patients with chronic CVD, including patients with hypertension and/or dyslipidemia and high cardiovascular risk. Sample size ranged between 133 and 1921 patients, and follow-up between five and 12 months. In one study the intervention was the polypill (vs. usual care),<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and in the others it was antihypertensive medication.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Based on the aim of the review and the inclusion criteria, the main source of methodological bias in all the selected studies was the fact that they were open; the UMPIRE trial<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> was the only one in which investigators were blinded to the treatment results, and even here adherence and non-adherence were reported by the patients themselves, which introduces a different type of risk of bias. A qualitative evaluation of the studies is shown in Supplementary Data Figure 1, available online.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The main characteristics and results of the selected studies are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Risk of non-adherence to therapy</span><p id="par0070" class="elsevierStylePara elsevierViewall">Dosing regimens in which patients with chronic CVD take their drugs once daily were associated with a significant reduction (57%) in risk for non-adherence (RR: 0.44; 95% CI: 0.35–0.54). There was no significant heterogeneity between study results (I<span class="elsevierStyleSup">2</span>=25%). <a class="elsevierStyleCrossRef" href="#fig0020">Figure 2</a> shows the results of the meta-analysis.</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">In absolute terms, this reduction translates into a difference of 19% in the proportion of non-adherent patients (95% CI: 12–26%; I<span class="elsevierStyleSup">2</span>=50%). We also calculated the NNTB that would result in one less non-adherent patient, adjusted to the baseline risk of non-adherent patients prescribed a single daily dose and using the previously obtained RRs. This gave an NNTB of 5 (95% CI: 4–6) over a period of nine months.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Although there was no significant heterogeneity between study results, data in the largest study (UMPIRE<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>), hence with the most weight in the analysis, were obtained by a self-administered questionnaire and are thus subject to various types of information bias.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In addition, different methods of estimating non-adherence (questionnaires and electronic monitoring) do not always produce a high degree of concordance.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26,27</span></a> We accordingly performed a sensitivity analysis excluding the UMPIRE trial from the analysis in order to evaluate the consistency of the data. The result was similar (RR for non-adherence: 0.50; 95% CI: 0.38–0.67), without statistical heterogeneity (I<span class="elsevierStyleSup">2</span>=0%).</p><p id="par0085" class="elsevierStylePara elsevierViewall">The result of Egger's test did not suggest publication bias (p=0.335), although the small number of studies means this possibility cannot be excluded.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">In this systematic review and meta-analysis we found that once-daily administration vs. two or more daily administrations is associated with a reduction of about 50% in risk of non-adherence to treatment. Although this subject has been extensively studied in other contexts such as psychiatric disease and HIV infection,<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28,29</span></a> there are few long-term clinical trials assessing the impact of dosing frequency on medication adherence in chronic CVD.</p><p id="par0095" class="elsevierStylePara elsevierViewall">On the basis of the four randomized trials selected, we found that less frequent dosing is associated with a significant reduction in non-adherence to treatment, as found in other areas. However, on the basis of the available evidence, it is still difficult to estimate the precise clinical impact in CVD of the better adherence to therapy seen with less frequent dosing.</p><p id="par0100" class="elsevierStylePara elsevierViewall">A recent systematic review and meta-analysis of epidemiological studies estimated that 9% of all cardiovascular events in Europe could be attributed to poor adherence to vascular medications alone. The results of the largest study included here (UMPIRE), probably the only one with the statistical power to reveal differences in clinical outcomes between groups, showed better control of hypertension of hypercholesterolemia in patients prescribed the polypill.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In 2010 a study was performed in Portugal specifically on adherence to therapy.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Of the 561 patients with chronic conditions analyzed, a third had CVD. Patients’ responses to the questionnaires showed that the main reasons for non-adherence related to the drugs themselves were adverse effects and symptomatic improvement followed by discontinuation. The need to take many different medications and/or the complexity of the therapeutic regimen was the main reason for non-adherence in 8.7% of patients. Even for those who did not indicate complexity of the therapy as the main reason for non-adherence, it was considered an important factor affecting adherence by over 40%. Complexity of the therapeutic regimen is thus a significant risk factor for non-adherence to treatment in Portuguese patients.</p><p id="par0110" class="elsevierStylePara elsevierViewall">The available evidence does not identify which drug classes are more prone to non-adherence<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>; this review only included clinical trials on drugs designed to reduce the cardiovascular risk associated with hypertension and dyslipidemia (although the UMPIRE trial included antiplatelet use, the outcomes were concerned with changes in serum lipids and BP profile).<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> A large number of recent trials have studied antithrombotic and antiarrhythmic drugs, but most of them had double-blind and/or double-dummy designs and many were placebo-controlled, and hence could not assess the impact of dosing frequency on medication adherence, since all study arms used the same dosing frequency, including for placebo. The few open-label studies that we identified did not report data on adherence to therapy.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Due to the aims and scope of this review, we did not include clinical trials with short follow-up or observational studies, since the inclusion of such heterogeneous material without unifying factors would have raised various methodological issues and hindered interpretation of the results. However, Coleman et al. recently published a systematic review that included 29 studies (68% short-term clinical trials, some of them placebo-controlled, and 32% observational studies) of chronic CVD and assessed the impact of dosing frequency on medication adherence.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> These authors, analyzing different types of studies from the present review, also concluded that a single daily dose was associated with better adherence to treatment.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Limitations</span><p id="par0120" class="elsevierStylePara elsevierViewall">The present study is a systematic review and meta-analysis of clinical trials, not an analysis of data on individual patients. The inclusion in a quantitative assessment (meta-analysis) of studies with different populations (with dyslipidemia, hypertension, and/or high cardiovascular risk), interventions and definitions of adherence could lead to bias and heterogeneity, which would affect the conclusions. However, the low degree of heterogeneity between the results of the studies, and the consistent results of the sensitivity analysis, suggest that the methodology adopted is coherent.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusions</span><p id="par0125" class="elsevierStylePara elsevierViewall">Few clinical trials have assessed the long-term impact of dosing frequency on medication adherence and clinical outcomes in chronic CVD. The best available evidence suggests that taking medication once daily decreases the risk of non-adherence to treatment by approximately 50%.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethical disclosures</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Protection of human and animal subjects</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Confidentiality of data</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Right to privacy and informed consent</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article.</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflicts of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">D. Caldeira has no conflicts of interest to declare. A. Vaz Carneiro and J. Costa are respectively the Director and Assistant Director of the Center for Evidence-Based Medicine (CEMBE) of the Faculty of Medicine of Lisbon University, which in recent years has provided consulting services in the field of emerging health technologies. None of the firms with whom CEMBE has worked had any direct or indirect input to any stage of this study.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres381497" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction and Objective" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec360308" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres381496" "titulo" => array:5 [ 0 => "Resumo" 1 => "Introdução e objetivos" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusões" ] ] 3 => array:2 [ "identificador" => "xpalclavsec360307" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Risk of non-adherence to therapy" ] ] ] 7 => array:3 [ "identificador" => "sec0025" "titulo" => "Discussion" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Limitations" ] ] ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 9 => array:3 [ "identificador" => "sec0040" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 11 => array:2 [ "identificador" => "xack101623" "titulo" => "Acknowledgments" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-01-10" "fechaAceptado" => "2014-01-27" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec360308" "palabras" => array:5 [ 0 => "Medication adherence" 1 => "Patient compliance" 2 => "Cardiovascular disease" 3 => "Chronic disease" 4 => "Drug administration regimen" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec360307" "palabras" => array:5 [ 0 => "Adesão terapêutica" 1 => "Compliance do doente" 2 => "Doenças cardiovasculares" 3 => "Doença crónica" 4 => "Posologia de administração diária" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction and Objective</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Non-adherence to drug treatment is a major health problem. In Europe, it has been estimated that 9% of cardiovascular events can be attributed to non-adherence. The complexity of dosing regimens is one of the factors identified as contributing to non-adherence. In this systematic review we aimed to assess the impact of dosing frequency on adherence to drug treatment in patients with chronic cardiovascular disease.</p> <span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">MEDLINE and the Cochrane Library (November 2013) were searched for randomized controlled trials (RCTs) comparing different dosing regimens (once-daily administration vs. two or more daily administrations) and assessing adherence to therapy in patients with chronic cardiovascular disease. Only trials with at least five months of follow-up were included. The results of the studies were pooled through a random effects meta-analysis. Relative risk (RR) and 95% confidence interval (CI) were derived. Statistical heterogeneity was calculated using the I<span class="elsevierStyleSup">2</span> test.</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Four RCTs (a total of 2557 patients) were included. Dosing regimens with once-daily administration were associated with a significant 56% reduction in risk of non-adherence to drug therapy (RR: 0.44; 95% CI: 0.35–0.54, I<span class="elsevierStyleSup">2</span>=25%).</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Few clinical trials have assessed the long-term impact of dosing frequency on medication adherence in chronic cardiovascular disease. The best available evidence suggests that taking medication once daily decreases the risk of non-adherence to treatment by approximately 50%. The impact on clinical outcomes remains to be established.</p>" ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introdução e objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A não-adesão à terapêutica constitui um problema de saúde importante. Na Europa, foi estimado que 9% dos eventos cardiovasculares podem ser atribuídos à não-adesão terapêutica. A complexidade dos esquemas posológicos é um dos fatores apontados como contribuindo para a não-adesão terapêutica. Nesta revisão sistemática pretendemos avaliar o impacto, em doentes com patologia cardiovascular crónica, da frequência posológica na adesão terapêutica.</p> <span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Pesquisa na MEDLINE e Cochrane Library (novembro 2013) de ensaios clínicos controlados e aleatorizados (RCT) que comparassem, em doentes com patologia cardiovascular crónica, diferentes tipos de regimes posológicos (administração única diária <span class="elsevierStyleItalic">versus</span> duas ou mais administrações) e que avaliassem adesão terapêutica. Foram apenas incluídos ensaios com uma duração de pelo menos cinco meses. Os resultados dos estudos foram agregados através de uma meta-análise (efeitos aleatórios) e calculou-se o risco relativo (RR) e respetivo intervalo de confiança 95% (IC 95%). A heterogeneidade estatística foi calculada com o teste do I<span class="elsevierStyleSup">2</span>.</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Foram incluídos quatro RCT (2.557 doentes). Os regimes posológicos com administração única diária estão associados a uma redução de 56% do risco de um doente ser não aderente à terapêutica (RR: 0,44; IC 95%: 0,35-0,54; I<span class="elsevierStyleSup">2</span>=25%).</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusões</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Poucos ensaios clínicos de longo termo avaliaram o impacto da frequência posológica na adesão terapêutica em doentes com patologia cardiovascular crónica. A melhor evidência disponível sugere que a toma de medicamentos em posologia diária única diminui o risco de não-adesão terapêutica em cerca de 50%. O impacto em termos de <span class="elsevierStyleItalic">outcomes</span> clínicos não está estudado.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Caldeira D, Vaz-Carneiro A, Costa J. Impacto da frequência posológica na adesão terapêutica em doenças cardiovasculares crónicas: revisão sistemática e meta-análise. Rev Port Cardiol. 2014;33:431–437.</p>" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0160" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0070" ] ] ] ] "nomenclatura" => array:1 [ 0 => array:3 [ "identificador" => "nom0005" "titulo" => "<span class="elsevierStyleSectionTitle" id="sect0065">Abbreviations</span>" "listaDefinicion" => array:1 [ 0 => array:1 [ "definicion" => array:9 [ 0 => array:2 [ "termino" => "HCTZ" "descripcion" => "<p id="par0165" class="elsevierStylePara elsevierViewall">hydrochlorothiazide</p>" ] 1 => array:2 [ "termino" => "CVD" "descripcion" => "<p id="par0170" class="elsevierStylePara elsevierViewall">cardiovascular disease</p>" ] 2 => array:2 [ "termino" => "CI" "descripcion" => "<p id="par0175" class="elsevierStylePara elsevierViewall">confidence interval</p>" ] 3 => array:2 [ "termino" => "NNTB" "descripcion" => "<p id="par0180" class="elsevierStylePara elsevierViewall">number needed to treat to benefit</p>" ] 4 => array:2 [ "termino" => "LDL" "descripcion" => "<p id="par0185" class="elsevierStylePara elsevierViewall">low-density lipoprotein</p>" ] 5 => array:2 [ "termino" => "BP" "descripcion" => "<p id="par0190" class="elsevierStylePara elsevierViewall">blood pressure</p>" ] 6 => array:2 [ "termino" => "MBP" "descripcion" => "<p id="par0195" class="elsevierStylePara elsevierViewall">mean blood pressure</p>" ] 7 => array:2 [ "termino" => "RR" "descripcion" => "<p id="par0200" class="elsevierStylePara elsevierViewall">relative risk</p>" ] 8 => array:2 [ "termino" => "UMPIRE" "descripcion" => "<p id="par0205" class="elsevierStylePara elsevierViewall">Use of a Multidrug Pill in Reducing Cardiovascular Events</p>" ] ] ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2236 "Ancho" => 2563 "Tamanyo" => 346943 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart of selection of studies for analysis.</p>" ] ] 1 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 771 "Ancho" => 3333 "Tamanyo" => 255596 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Impact of a single daily dose on risk for non-adherence to therapy. CI: confidence interval.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">BP: blood pressure; CVD: cardiovascular disease; HCTZ: hydrochlorothiazide; LDL: low-density lipoprotein; MAP: mean arterial pressure.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Population \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Interventions and control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Follow-up (months) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Definition of non-adherence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Results \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lee et al.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">313 hypertensive patients with mild renal dysfunction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antihypertensive once daily (target BP <92 mmHg) vs. antihypertensive twice daily (target MAP 102–107 mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Taking <80% of prescribed pills according to pill count and electronic monitoring \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50% of adherent patients in both intervention and control groups, but only 14% of non-adherent patients achieved target BP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leenen et al.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">190 patients with mild hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amlodipine (once daily) vs. slow-release diltiazem (twice daily) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Taking <80% of prescribed pills according to electronic monitoring \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-adherence had a negative impact on BP control in the diltiazem group but not in the amlodipine group \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Andrejak et al.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">133 hypertensive patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trandolapril (once daily) vs. captopril (twice daily) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Taking <90% of prescribed pills according to electronic monitoring \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No difference in proportion of patients requiring addition of a diuretic and with controlled BP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UMPIRE<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1921 patients with high cardiovascular risk or documented CVD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fixed-dose combination of aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and 50 mg atenolol or 12.5 mg HCTZ (polypill) (once daily) vs. these drugs taken individually \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not taking the medication (antiplatelet, statin, and ≥2 antihypertensives) for at least 4 days during the week preceding the end-of-study assessment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Significant reductions in systolic BP (−2.6 mmHg) and LDL cholesterol (−4.2 mg/dl) in the intervention (polypill) group \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab581532.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Main characteristics and results of the selected studies.</p>" ] ] 3 => array:7 [ "identificador" => "upi0005" "etiqueta" => "Supplementary Table 1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.docx" "ficheroTamanyo" => 161109 ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Search strategy in the databases.</p>" ] ] 4 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Supplementary Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "mmc2.jpeg" "Alto" => 4244 "Ancho" => 3251 "Tamanyo" => 1084809 ] ] "descripcion" => array:1 [ "en" 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 12 | 5 | 17 |
| 2024 October | 52 | 34 | 86 |
| 2024 September | 58 | 25 | 83 |
| 2024 August | 51 | 41 | 92 |
| 2024 July | 43 | 26 | 69 |
| 2024 June | 62 | 35 | 97 |
| 2024 May | 45 | 24 | 69 |
| 2024 April | 53 | 24 | 77 |
| 2024 March | 53 | 22 | 75 |
| 2024 February | 46 | 31 | 77 |
| 2024 January | 39 | 29 | 68 |
| 2023 December | 39 | 27 | 66 |
| 2023 November | 43 | 27 | 70 |
| 2023 October | 32 | 19 | 51 |
| 2023 September | 32 | 21 | 53 |
| 2023 August | 39 | 8 | 47 |
| 2023 July | 50 | 14 | 64 |
| 2023 June | 44 | 21 | 65 |
| 2023 May | 56 | 24 | 80 |
| 2023 April | 49 | 5 | 54 |
| 2023 March | 44 | 31 | 75 |
| 2023 February | 41 | 18 | 59 |
| 2023 January | 56 | 25 | 81 |
| 2022 December | 84 | 26 | 110 |
| 2022 November | 87 | 33 | 120 |
| 2022 October | 111 | 29 | 140 |
| 2022 September | 101 | 36 | 137 |
| 2022 August | 82 | 33 | 115 |
| 2022 July | 85 | 46 | 131 |
| 2022 June | 93 | 22 | 115 |
| 2022 May | 64 | 29 | 93 |
| 2022 April | 52 | 34 | 86 |
| 2022 March | 70 | 38 | 108 |
| 2022 February | 57 | 34 | 91 |
| 2022 January | 29 | 23 | 52 |
| 2021 December | 37 | 33 | 70 |
| 2021 November | 69 | 32 | 101 |
| 2021 October | 44 | 46 | 90 |
| 2021 September | 33 | 39 | 72 |
| 2021 August | 74 | 36 | 110 |
| 2021 July | 20 | 35 | 55 |
| 2021 June | 50 | 27 | 77 |
| 2021 May | 34 | 33 | 67 |
| 2021 April | 85 | 38 | 123 |
| 2021 March | 57 | 19 | 76 |
| 2021 February | 57 | 20 | 77 |
| 2021 January | 23 | 10 | 33 |
| 2020 December | 35 | 8 | 43 |
| 2020 November | 40 | 11 | 51 |
| 2020 October | 18 | 7 | 25 |
| 2020 September | 51 | 14 | 65 |
| 2020 August | 18 | 6 | 24 |
| 2020 July | 40 | 10 | 50 |
| 2020 June | 30 | 5 | 35 |
| 2020 May | 40 | 7 | 47 |
| 2020 April | 42 | 9 | 51 |
| 2020 March | 40 | 12 | 52 |
| 2020 February | 69 | 31 | 100 |
| 2020 January | 25 | 8 | 33 |
| 2019 December | 30 | 13 | 43 |
| 2019 November | 36 | 3 | 39 |
| 2019 October | 30 | 7 | 37 |
| 2019 September | 31 | 10 | 41 |
| 2019 August | 35 | 3 | 38 |
| 2019 July | 40 | 15 | 55 |
| 2019 June | 25 | 8 | 33 |
| 2019 May | 38 | 14 | 52 |
| 2019 April | 22 | 20 | 42 |
| 2019 March | 73 | 14 | 87 |
| 2019 February | 100 | 12 | 112 |
| 2019 January | 89 | 10 | 99 |
| 2018 December | 104 | 14 | 118 |
| 2018 November | 126 | 12 | 138 |
| 2018 October | 365 | 16 | 381 |
| 2018 September | 100 | 16 | 116 |
| 2018 August | 98 | 16 | 114 |
| 2018 July | 27 | 15 | 42 |
| 2018 June | 37 | 9 | 46 |
| 2018 May | 46 | 3 | 49 |
| 2018 April | 46 | 14 | 60 |
| 2018 March | 62 | 6 | 68 |
| 2018 February | 42 | 3 | 45 |
| 2018 January | 43 | 11 | 54 |
| 2017 December | 59 | 15 | 74 |
| 2017 November | 55 | 14 | 69 |
| 2017 October | 47 | 15 | 62 |
| 2017 September | 41 | 18 | 59 |
| 2017 August | 43 | 25 | 68 |
| 2017 July | 33 | 19 | 52 |
| 2017 June | 59 | 21 | 80 |
| 2017 May | 54 | 27 | 81 |
| 2017 April | 54 | 12 | 66 |
| 2017 March | 42 | 34 | 76 |
| 2017 February | 36 | 10 | 46 |
| 2017 January | 44 | 8 | 52 |
| 2016 December | 44 | 15 | 59 |
| 2016 November | 21 | 8 | 29 |
| 2016 October | 29 | 18 | 47 |
| 2016 September | 30 | 12 | 42 |
| 2016 August | 15 | 3 | 18 |
| 2016 July | 15 | 5 | 20 |
| 2016 June | 8 | 7 | 15 |
| 2016 May | 20 | 8 | 28 |
| 2016 April | 66 | 1 | 67 |
| 2016 March | 85 | 20 | 105 |
| 2016 February | 73 | 28 | 101 |
| 2016 January | 61 | 12 | 73 |
| 2015 December | 64 | 18 | 82 |
| 2015 November | 58 | 15 | 73 |
| 2015 October | 71 | 17 | 88 |
| 2015 September | 75 | 18 | 93 |
| 2015 August | 57 | 15 | 72 |
| 2015 July | 56 | 16 | 72 |
| 2015 June | 45 | 9 | 54 |
| 2015 May | 41 | 13 | 54 |
| 2015 April | 63 | 24 | 87 |
| 2015 March | 41 | 10 | 51 |
| 2015 February | 49 | 14 | 63 |
| 2015 January | 51 | 15 | 66 |
| 2014 December | 61 | 25 | 86 |
| 2014 November | 61 | 22 | 83 |
| 2014 October | 83 | 30 | 113 |
| 2014 September | 94 | 30 | 124 |
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