Nonadherence Is Common in Patients With Apparent Resistant Hypertension: A Systematic Review and Meta-analysis.

BACKGROUND: The prevalence of medication nonadherence in the setting of resistant hypertension (RH) varies from 5% to 80% in the published literature. The aim of this systematic review was to establish the overall prevalence of nonadherence and evaluate the effect of the method of assessment on this estimate. METHODS: MEDLINE, EMBASE, Cochrane, CINAHL, and Web of Science (database inception to November 2020) were searched for relevant articles. We included studies including adults with a diagnosis of RH, with some measure of adherence. Details about the method of adherence assessment were independently extracted by 2 reviewers. Pooled analysis was performed using the random effects model and heterogeneity was explored with metaregression and subgroup analyses. The main outcome measured was the pooled prevalence of nonadherence and the prevalence using direct and indirect methods of assessment. RESULTS: Forty-two studies comprising 71,353 patients were included. The pooled prevalence of nonadherence was 37% (95% confidence interval [CI] 27%-47%) and lower for indirect methods (20%, 95% CI 11%-35%), than for direct methods (46%, 95% CI 40%-52%). The study-level metaregression suggested younger age and recent publication year as potential factors contributing to the heterogeneity. CONCLUSIONS: Indirect methods (pill counts or questionnaires) are insufficient for diagnosis of nonadherence, and report less than half the rates as direct methods (direct observed therapy or urine assays). The overall prevalence of nonadherence in apparent treatment RH is extremely high and necessitates a thorough evaluation of nonadherence in this setting.

Meta-analytic Techniques to Assess the Association Between N-acetylcysteine and Acute Kidney Injury After Contrast Administration: A Systematic Review and Meta-analysis.

Importance: The most suitable analytic method to systematically analyze numerous trials with contradictory results is unclear. Multiple trials assessing the use of N-acetylcysteine (NAC) for prevention of contrast-induced acute kidney injury (CI-AKI) have had contradictory results with recent trials confirming a lack of benefit. Objective: To systematically review the literature on NAC for the prevention of CI-AKI, and to explore the heterogeneity, publication bias, and small-study effect to determine the most suitable analytic method in a setting where the literature is contradictory. Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials databases were used to find randomized clinical trials (RCTs) comparing NAC with any other prophylactic agent or placebo in adults. Study Selection: The search included studies published in English from database inception to January 2020. Two independent reviewers screened the studies, extracted data, and performed the risk of bias assessment. Data Extraction and Synthesis: A meta-analysis was conducted about the effect of NAC on CI-AKI, the need for dialysis, and mortality. Fixed and random effects analyses were also performed. Funnel plots and the trim and fill method were used for assessment of publication bias. Metaregression was performed to explore the heterogeneity and subgroup analysis to examine the association between NAC and CI-AKI when studies were categorized according to sample size and number of events. Results: A total of 101 trials were included in this meta-analysis. The median sample size was 112 (range, 20 to 4993). Twenty-nine trials had a sample size of 200 or more, and only 3 trials had a sample size of 500 or more. Forty-five trials reported the need for kidney replacement therapy, and 41 trials reported mortality as an outcome. NAC seemed to show a benefit, with a pooled OR of 0.72 (95% CI, 0.63-0.82) using random effects model and a pooled OR of 0.82 (95% CI 0.76-0.90) using a fixed effects model. However, there was significant heterogeneity (I2 = 37.6; P < .001) and significant publication bias, which was reduced only when restricting to large RCTs (N ≥ 500). The clinical outcomes (ie, the need for kidney replacement therapy and mortality) revealed little heterogeneity and no publication bias, and each provided a robust neutral summary result. Conclusions and Relevance: In this meta-analysis, NAC was associated with a benefit in the prevention of CI-AKI. However, because of substantial publication bias and other biases, standard meta-analytic techniques resulted in significant heterogeneity and a spurious, or factitious, association, even when using a random effects model. When the analysis was restricted to RCTs with a large sample size to account for publication bias or restricted to trials with clinical outcomes, this issue was reduced and resulted in more robust and neutral effect sizes.

The Prevalence of Nonadherence in Patients With Resistant Hypertension: A Systematic Review Protocol.

BACKGROUND: Resistant hypertension, usually defined as blood pressure remaining above goal despite the concurrent use of 3 or more antihypertensive agents of different classes, is common (about 10% prevalence) and known to be a risk factor for cardiovascular events. These patients also undergo more screening intensity for secondary hypertension. However, not all patients with apparent treatment-resistant hypertension have true resistant hypertension, with some of them being nonadherent to prescribed pharmacotherapy. The prevalence of nonadherence varies from about 5% to 80% in the published literature. However, the relative contributions of intentional and nonintentional nonadherence are not well described. Nonintentional nonadherence refers to occasional forgetfulness and/or carelessness and can sometimes be related to an inability to follow instructions, because of either cognitive or physical limitations. Intentional nonadherence refers to an active process in which a patient may choose to alter the prescribed medication regimen by discontinuing medications, skipping doses, or modifying doses or dosing intervals. OBJECTIVE: Our objective is to establish the overall prevalence of nonadherence in the apparent treatment-resistant hypertension population and evaluate the relative contributions of nonintentional and intentional nonadherence subtypes. DESIGN: We will conduct a systematic review and meta-analysis. SETTING: We will include observational studies and randomized controlled trials where adherence to antihypertensive medications is measured using a test of adherence, either direct or indirect. PATIENTS: We will include adult human participants aged 18 years or older with a diagnosis of resistant hypertension. MEASUREMENTS: Data extracted from individual studies will include title, first author, design, country, publication year, funding body, method of assessing adherence to antihypertensive medication, prevalence of medication nonadherence, definition of resistant hypertension, sample size, sex, mean age, and coexistent comorbidities. METHODS: A librarian will search the databases Medline, EMBASE, Cochrane, CINAHL, and Web of Science for studies meeting criteria for inclusion. Two reviewers will independently screen the titles and abstracts retrieved and assess the methodological quality of eligible full-text articles using the Cochrane Risk of Bias tool for clinical trials and the Newcastle-Ottawa Scale for observational studies. Summary estimates of prevalence will be generated using pooled analysis using the random-effects method. Subgroup analyses, sensitivity analyses, and evaluation of publication bias will also be performed. RESULTS: The outcomes of interest are the pooled prevalence of nonadherence to antihypertensive medication in apparent treatment-resistant hypertension and the prevalence of nonadherence based on different methods of assessing nonadherence (indirect vs direct), which will allow us to estimate the relative proportion of unintentional and intentional nonadherence subtypes in the overall phenomenon of medication nonadherence. LIMITATIONS: Possible limitations of this study include the finding of severe heterogeneity, the limitations of the literature search, publication bias, and the lack of granular data in the published studies for a study-level meta-analysis. CONCLUSIONS: This systematic review will provide a synthesis of current evidence on the prevalence of medication nonadherence in apparent treatment-resistant hypertension and on the relative contributions of nonintentional and intentional nonadherence subtypes. These findings will provide clinicians with a better understanding of the factors underlying treatment-resistant hypertension and will serve as a strong research base to guide future research on interventions to address medication nonadherence as well as the nonintentional and intentional subtypes. TRIAL REGISTRATION: This protocol has been registered with PROSPERO. We will add registration details once available.

CONTEXTE: On définit généralement l'hypertension réfractaire comme une valeur de pression artérielle qui demeure au-dessus de la valeur cible, et ce, malgré l'administration concomitante d'au moins trois agents antihypertenseurs de classes différentes. L'hypertension réfractaire est fréquente (prévalence d'environ 10 %) et constitue un facteur de risque d'événements cardiovasculaires. Les patients atteints d'hypertension réfractaire font également l'objet d'un dépistage plus intensif de l'hypertension secondaire. Cependant, tous les cas apparents d'hypertension résistante au traitement ne constituent pas nécessairement des cas d'hypertension réfractaire. Certains résultent plutôt d'une inobservance de la pharmacothérapie prescrite. La littérature rapporte une prévalence d'environ 5 à 80 % de l'inobservance du traitement, mais les contributions relatives de l'inobservance intentionnelle et non intentionnelle ne sont pas clairement établies. L'inobservance non intentionnelle fait référence aux oublis occasionnels ou à la négligence, qui peuvent être liés à l'incapacité de suivre des instructions en raison de limitations physiques ou cognitives. L'inobservance intentionnelle désigne quant à elle un processus actif où le patient choisit consciemment de modifier la posologie de sa médication, soit en interrompant le traitement, en sautant des doses ou en modifiant les doses ou les intervalles posologiques. OBJECTIFS: Nous souhaitons mesurer la prévalence globale de l'inobservance au traitement parmi les cas apparents d'hypertension réfractaire et établir la contribution relative des sous-types intentionnel et non intentionnel d'inobservance. TYPE D'ÉTUDE: Nous procéderons à une revue systématique et à une méta-analyse de la documentation pertinente. CADRE: L'étude inclura les études observationnelles et les essais contrôlés à répartition aléatoire traitant d'une mesure de l'observance du traitement antihypertenseur au moyen d'un test d'observance direct ou indirect. SUJETS: Seront inclus tous les patients adultes ayant reçu un diagnostic d'hypertension réfractaire. MESURES: Les données suivantes seront extraites de chaque étude : le titre de l'article, le nom de l'auteur principal, la méthodologie et le lieu de l'étude, l'année de publication, l'organisme ayant financé les travaux, la méthode employée pour la mesure de l'observance, la prévalence de l'inobservance, la définition d'hypertension réfractaire, la taille de l'échantillon, ainsi que le sexe, l'âge moyen et les comorbidités des patients. MÉTHODOLOGIE: Un bibliothécaire fera une présélection des études répondant aux critères d'inclusion dans les bases de données Medline, EMBASE, Cochrane, CINAHL et Web of Science. Les titres et résumés des articles retenus seront révisés de façon indépendante par deux examinateurs qui évalueront également la qualité méthodologique des articles complets à l'aide de l'outil Cochrane sur le risque de biais (essais cliniques) et de l'échelle de Newcastle-Ottawa (études observationnelles). Des estimations sommaires de la prévalence seront générées par l'analyse de l'ensemble des données par une méthode à effets aléatoires. Nous procéderons également à des analyses de sous-groupes, à des analyses de sensibilité, de même qu'à l'évaluation des biais de publication. RÉSULTATS: Le principal résultat attendu est la combinaison de la prévalence de l'inobservance du traitement antihypertenseur dans les cas d'hypertension réfractaire apparente et de la prévalence de l'inobservance selon la méthode employée pour la mesurer (indirecte ou directe). Ce résultat nous permettra d'estimer la proportion des sous-types (inobservance intentionnelle et non intentionnelle) dans l'ensemble des cas répertoriés d'inobservance au traitement. LIMITES: Les résultats pourraient être limités par une importante hétérogénéité, des facteurs limitant la recherche documentaire, des biais de publication et le manque de données agrégées dans les études publiées pour procéder à une méta-analyse au niveau de l'étude. CONCLUSION: Cette revue systématique constituera une synthèse des données probantes sur la prévalence de l'inobservance au traitement dans les cas apparents d'hypertension réfractaire et sur les contributions relatives des sous-types intentionnel et non intentionnel d'inobservance. Ces résultats permettront aux cliniciens de mieux comprendre les facteurs sous-tendant l'hypertension réfractaire. Ils serviront également de base solide pour orienter les recherches futures sur des interventions visant à aborder l'inobservance au traitement médicamenteux et ses sous-types intentionnel et non intentionnel.