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00004872-201206000-0002600004872_2012_30_1225_trimarco_antihypertensive_6article< 125_0_20_6 >Journal of Hypertension© 2012 Lippincott Williams & Wilkins, Inc.Volume 30(6)June 2012p 1225–1232Persistence and adherence to antihypertensive treatment in relation to initial prescription: diuretics versus other classes of antihypertensive drugs[ORIGINAL PAPERS: Therapeutic aspects]Trimarco, Valentinaa; de Simone, Giovannic; Izzo, Raffaeleb; De Luca, Nicolab; Giudice, Renatab; Marino, Marinab; Damiano, Silviac; Rozza, Francescob; Trimarco, Brunob; Di Renzo, GianfrancoaaDepartment of NeurosciencesbDepartment of Clinical Medicine, Cardiovascular and Immunological SciencescDepartment of Clinical and Experimental Medicine, Federico II University, Naples, ItalyCorrespondence to Bruno Trimarco, MD, Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Federico II University, Naples, Italy (Via Sergio Pansini 5, bld 2 – 80131 Naples). Tel: +39 081 7462250; fax: +39 081 7462256; e-mail: trimarco@unina.itAbbreviations: BP, blood pressure; CRF, Case Report Form; CSN, Campania Salute Network; GP, general practitioner; HR, heart rate; Meds, medicinesReceived 20 October, 2011Revised 18 January, 2012Accepted 2 March, 2012AbstractBackground: The use of thiazide diuretics in the treatment of hypertension is widely considered as a first-line treatment, given the efficacy and low cost of this class of drugs. This indication is not unanimous, because thiazides can cause metabolic alterations, and other side effects that reduce compliance and persistence on treatment.Objectives: In a multicentre, open-label randomized study we compared adherence and persistence to therapy of chlortalidone versus other treatments, as a first-line antihypertensive therapy.Methods: Ninety-two general practitioners (GPs) recruited 2409 hypertensive patients with indication to antihypertensive therapy, who were randomized in two arms to start treatment with chlortalidone (12.5–25 mg daily) or any other single medications (excluding thiazides). The patients have been followed for at least 2 years.Result: Patients receiving diuretic therapy as first-line antihypertensive treatment, modified antihypertensive treatment regimen more often than the others (79.1 versus 43.9%; χ2 < 0.0001). Patients starting with diuretics received greater number of drugs, compared to patients starting with different antihypertensive therapy (1.55 versus 1.4 antihypertensive drugs; P < 0.0001), but achieved the same blood pressure (BP) control during the follow-up. No differences were observed in persistence and adherence to treatment between the two groups.Conclusion: Our results demonstrate that the recommendation to start antihypertensive therapy with diuretics, when no compelling indications are present, is not supported by the evidence that this strategy produces more rapid and better control of BP.INTRODUCTIONMany comments have been issued about similarities and differences between American and European guidelines for the management of arterial hypertension [1,2], especially as the consequence of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [3].The difference between the Seventh Joint National Committee (USA) on Prevention, Diagnosis and Management of Hypertension (JNC VII) and the European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines, often presented as substantial, is mainly in the priority given to diuretics as first line of antihypertensive therapy, in the absence of other compelling indications, consistent with the most waited results of the ALLHAT [3].Several clinical trials, however, agree that the majority of hypertensive patients require more than one medication to achieve optimal blood pressure (BP) control [4–7]. What is now clear is that BP must be optimally controlled to reduce risk of cardiovascular mortality and morbidity in population, no matter what combination of medications is used. Comparison between single medications is substantially academic and conceals the reality: in all trials, comparison is between combinations, more than between single medications. In the Losartan Intervention for Endpoint Reduction Study (LIFE study) [8], for instance, there has been a comparison between the combination of losartan with low-dose hydrochlorothiazide versus the combination of atenolol with the same diuretic, given in more than 50% of participants.One concern about the use of diuretics is the risk of low therapeutic compliance, due to the occurrence of side effects [9,10]. Whether the reported low therapeutic compliance with diuretics is related to spontaneous withdrawal or to change of strategy of doctors, due to appearance of side effects, is unclear. Accordingly, this study was designed to assess whether a follow-up strategy based on a strict cooperation between general practitioners (GPs) and hypertension specialists allows using diuretics as first-line antihypertensive treatment to obtain adherence to treatment and to achieve comparable BP normalization [i.e. SBP <140 mmHg, and DBP <90 mmHg] equivalent to any other first-line antihypertensive therapy. Assessment of safety and efficacy for reduction of cardiovascular risk has been also performed as the secondary endpoint.METHODSDesignThe study was designed as an open-label randomized trial comparing adherence to and persistence of antihypertensive therapeutic strategies in a group of patients starting antihypertensive therapy with chlortalidone (12.5–25 mg daily) (the diuretic arm, called group D), and a group of patients starting antihypertensive treatment with any other class of medication, except any diuretics (called group A). Addition of other medicines (meds) was left free, including diuretics in the group A, if optimal BP was not achieved. Evaluation was performed by medical staff blinded to treatment.PopulationThe study was conducted in collaboration with the Campania Charters of the Italian Society of General Medicine (Società Italiana di Medicina Generale, SIMG), and of the Italian Society of Hypertension (Società Italiana dell’Ipertensione Arteriosa, SIIA) and was approved by the Bioethic Committee of the Federico II University of Naples and was part of the CampaniaSalute Network (CSN). The CSN [11] is an Italian regional network aimed to improve the management of essential hypertension by integrating the clinical activity of hypertension specialists with Outpatient Hypertensive Clinics allocated in different Community Hospitals in the Campania Region and GPs’ offices, homogeneously allocated in the regional area. Details of the network have been previously reported [11–13].The trial has been registered and ClinicalTrials.gov Identifier is: NCT00408512. Participants were recruited in the offices of 92 GPs with documented previous experience in controlled studies performed according to recommendations of Good Clinical Practice, and availability to access to Internet. Selected GPs were trained to the use of the web-based database on which they stored the required information of patients participating in the study. This training period lasted a week and was supervised by the Coordinating Centre established in the Hypertension Centre of the Federico II University Hospital. The recruitment phase lasted 8 months. Duration of the study was 2 years.Inclusion criteria were: age 18–75 years and stage I or II essential hypertension, previously untreated or poorly controlled. Women in fertile age not using recognized contraceptive methods, or pregnant or nursing, were excluded from the study. Exclusion was established for patients with documented coronary or cerebrovascular events during the previous 6 months, evidence or history of congestive heart failure or ejection fraction less than 45% at the baseline echocardiographic exam, secondary hypertension, cancer disease, chronic renal disease (serum creatinine >2 mg/dl), liver cirrhosis, or any other health problem that may interfere with the projected 2-year follow-up.Hypertension was defined according to 2003 ESH/ESC guidelines [2]. Blood and urine tests were prescribed, according to guidelines for Hypertension Management for GPs of the Campania Region (published on the Bollettino Ufficiale Regione Campania, number 11, 18/02/2002). Briefly, this screening includes complete blood count, serum creatinine, sodium, potassium, uric acid, total cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol, glucose, urine analysis and ECG. Low-density lipoprotein (LDL)-cholesterol was calculated from total cholesterol, triglyceride and HDL-cholesterol by Friedewald equation [14].ProtocolGeneral practitioners were required to record a full medical history, including smoking and drinking habits, based on a predefined clinical record; to collect demographic and anthropometric measures (age, sex, height, weight, waist circumference at the iliac crest); and to perform a complete physical examination. At baseline and at each monthly visit thereafter, seated office BP was measured in triplicate using an aneroid sphygmomanometer according to international guidelines [1]. Measurements were rounded to the closest 2 mmHg interval. At each visit, GPs also recorded drug therapy, including concomitant medications, evaluated persistence of and compliance to assigned antihypertensive regimen, and monitored and recorded adverse events by reporting all data in the Case Report Form (CRF).When BP normalization was obtained, GPs monitored BP at 2-month intervals, at the renewal of the drug prescription.Patients recruited by GPs were referred to the Coordinating Centre for end-organ damage evaluation by ECG, carotid ultrasound and urine dip-stick, at baseline, after 1 year and at the end of trial. At the same gates, blood tests and urine analysis were also controlled.All participants started treatment with one single drug, which was titrated to the highest dose before adding subsequent medications, based on the GP's judgement. Eligible patients were asked to sign informed written consent and therefore randomized to start antihypertensive therapy with chlortalidone (12.5–25 mg daily) in the diuretic arm (called group D), or with any other antihypertensive medication (excluding thiazide diuretic) in the alternative arm (called group A).After randomization, patients were evaluated monthly at the GPs’ office for therapy adjustment, to achieve BP normalization (i.e. SBP <140 mmHg, and DBP <90 mmHg or <130/80 mmHg in diabetic patients). In both arms, if BP normalization was not achieved, it was possible to add any other antihypertensive drug, once the maximal dose of the first drug was achieved: timing and modality of the therapy modification were established according to the GPs’ clinical judgement and appropriately reported in the CRF.When BP normalization was achieved, GPs monitored BP every 2 months, at the renewal of the drug prescription. BP values were stored in the central database. At each visit, GPs recorded drug therapy, including concomitant medications, evaluated the adherence to assigned antihypertensive regimen, and monitored and recorded adverse events by reporting all data in the CRF.Two years after randomization, patients were checked for blood and urine tests and referred to the Hypertension Specialist Centre for final ECG, carotid ultrasounds and urine dip-stick (Fig. 1). These data were all stored in the central database.FIGURE 1. Flow-chart of the study randomization.Adherence to treatment was defined according to the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) [15] as the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen. Adherence to treatment was evaluated at each control visit by the GP, using a combination of record of prescriptions and questionnaire administered to each patient. Adherence was established when the answer to the questionnaire was consistent with the time of prescription. Adherence was scored as 1 to each visit, whereas nonadherence was scored as 0. ‘Adherence score’ was defined as the sum of the scores obtained at each visit divided by the number of visits.Persistence refers to continuing treatment for the prescribed duration [15]. Patients were considered persistent users of an antihypertensive agent at 12 months if they had regularly refilled their prescription. In contrast, patients were considered to have discontinued therapy if they had not refilled their prescription or did not have a series of refills that would indicate persistent use of the drug. There was no way of determining whether refills indicated actual use or whether the prescription was used by someone other than the person for whom it was filled [15].Data managementData were stored in an electronic database located in the Coordinating Centre, to which GPs had access for uploading data on a daily base, using personal, encrypted, login and password [11].OutcomesAdherence to treatment was the primary outcome of the study. Withdrawal or modification of treatment regimen due to adverse side effects was considered as events. The total duration of study was 3 years, including the accrual time. Final main analysis was performed immediately after the conclusion of follow-up of the last recruited patient.Statistical analysisSample size estimateThe main outcome to be tested was that the adherence to therapy of an antihypertensive regimen based on diuretics as first choice is equivalent to that obtained in a free regimen using any other antihypertensive medication as first choice (equivalence study). Sample size has been calculated on the assumption that adherence to treatment will be maintained in 70% of participants in both arms. The margin of equivalence, given in terms of difference, extends symmetrically from of −6 to 6% (from 64 to 76%). Given the symmetry of confidence interval (CI), the actual between-arm difference is 0. A coverage probability of 90% for this CI has been assumed. The sample size is, therefore, calculated to be 1262 both in the treatment group and in the reference group, to achieve 90% power to detect equivalence with a two-tailed α error of 0.05.Distribution analysis was performed to detect deviations from normality and, when needed, log transformation was adopted. Descriptive statistics of the baseline conditions and changes of the two groups have been performed using ANOVA (and ANCOVA) or chi-squared statistics, with computation of the exact two-tailed P value, using MonteCarlo method. Least square linear regression was also used for crude assessment of relevant relations. The equivalence hypothesis of adherence to therapy was explored using logistic regression analysis, adjusting for relevant confounders that have been identified during descriptive procedures. Variance inflation factor was computed for the group of covariates, based on a linear modelling, and variables with variance inflation greater than 1.3, if present, were step-by-step excluded, according to a backward procedure. If any residual collinearity remained, factor analysis was carried out for extraction of principal components and the regression model re-runned using principal components. Logistic analysis allowed quantification of the probability of adherence to treatment during diuretic-based therapy, as compared to standard alternative treatments, by computation of the exponential of regression coefficient, corresponding to adjusted relative risk and 95% CI. Wald statistics was used to estimate the relative weight of independent variables in the final logistic model.RESULTSAt the end of the enrolment period, among the 2409 patients recruited, 1205 were randomized in group D and 1204 in group A. Among the initial population, 1051 patients in group D (or 87%) and 1026 in group A (or 85%) completed the study. Three hundred and thirty-two patients (14%) were excluded because they were lost to follow-up or because of missing data in the CRF.At baseline patients in group D were more often women. No differences were found in the other clinical or laboratory parameters between the two study groups (Table 1).TABLE 1 Demographic and other baseline characteristicsIn both study groups there was a significant and similar reduction in SBP and DBP values and heart rate (HR) at the end of follow-up (both P < 0.0001; Tables 2 and 3). In contrast, no differences were observed between group D and group A in the modifications of anthropometric parameters, metabolic and renal profile (Table 2). An optimal BP control was achieved in a similar proportion of patients in group D and in group A (Table 2). These results were also confirmed after adjusting for age and sex.TABLE 2 Changes in clinical and laboratory characteristics of the two study arms and the relative confidence intervals at the end of follow-up compared to baselineTABLE 3 Heart rate, SBP and DBP modifications in the two study groups during follow-up periodAdherence to treatment and change of prescriptionFor the entire period of the study, no significant differences were recorded between group D and group A in the adherence to treatment measured as ‘adherence score’ (0.91 ± 0.15 versus 0.91 ± 0.14 in group D and group A, respectively; P = NS).During the follow-up period the GPs modified antihypertensive therapy in the 61.5% of the patient population (79.1% in group D and 43.9% in group A; χ2 < 0.0001). The reported reasons for changing therapy were the following: poor BP control (57.8% in group D, 37.4% in group A; P < 0.0001), side effects (9.7% in group D, 3.2% in group A; P < 0.0001), drug intolerance (6.9% in group D, 1.0% in group A; P < 0.0001). Reasons for therapy modification were not reported in the 5.9% of the group D and in the 5.2% of the group A, respectively (P = NS) (Fig. 2). At the end of the follow-up, the used antihypertensive drugs [β-blockers, AT1-antagonists, angiotensin-converting enzyme inhibitors (ACEIs), calcium-channel blockers (CCBs)] were not statistically different in group D and group A (Table 4). As expected, diuretics were more used in group D than in group A (P < 0.0001; Table 4). Patients in group D received 1.55 antihypertensive drugs compared to 1.4 in group A (P < 0.0001).FIGURE 2. Reasons for therapy modification during the follow-up period in the two study groups.TABLE 4 Distribution of classes of antihypertensive drugs at the end of follow-upDuring follow-up 44 cardiovascular events were recorded: 12 strokes and 32 myocardial infarctions (2.3% in group D and 1.6% in group A; NS). No significant fatal and/or nonfatal serious treatment-related side effect was recorded.DISCUSSIONIn contrast with most trials evaluating single-drug effects, this study compared two strategies of antihypertensive management, based on daily clinical practice prescriptions without specific recommendations, compared to a regimen in which chlortalidone was recommended to be the first line of the antihypertensive therapy, when compelling indications were not present. Whereas our findings do not contrast the large evidence that diuretics are useful to achieve BP control in association with other meds, as also clinical trials focused on drug-to-drug comparison have shown, this is the first time that the recommendation to start antihypertensive therapy with diuretics, when no compelling indications are present, is shown to be unjustified in a real-life setting.Many comments have been issued about similarities and differences between 2003 American and European guidelines for the management of arterial hypertension [16,17], especially after the publication of the ALLHAT [3]. Both guidelines agree that BP must be optimally controlled to reduce risk of cardiovascular mortality and morbidity in a population, independently of which combination of meds is used. However, the JNC VII indicated diuretic therapy as the first line, consistent with results from the ALLHAT [3], a study providing evidence of better control of BP with chlortalidone. In ALLHAT, chlortalidone also exhibited a greater protection for combined fatal and nonfatal coronary heart disease than lisinopril, but this greater protection was less evident than the superiority in controlling BP.Another ALLHAT finding supporting the preference for diuretics was the lower incidence of heart failure compared to both amlodipine and lisonopril arms. A major concern about the use of diuretics in arterial hypertension is the risk of low therapeutic compliance of hypertensive patients, due to the diuretic effect and other hypokalaemia-related side effects [9,10].Indeed, diuretics are known to be the pharmacological class of antihypertensive medications associated with the worst compliance, whereas other classes of medications are associated with a greater proportion of patients continuing initial treatment, a proportion that seems to be particularly high with angiotensin II (A-II) antagonist therapy [18]. However, diuretics are generally recognized to be indispensable to achieve target BP control. In fact, in the Cardio-Sys trial, diuretics and, to a lesser extent, angiotensin-receptor blockers resulted to be more frequently used in order to achieve a tight control of SBP [19].Several clinical trials comparing the effectiveness of thiazides and β-blockers with the newer drug classes have been conducted in the past decade [3,20–25] and the results are now available [3,20–25]. Some of these studies are consistent with ALLHAT conclusions, giving support to the recommendation of thiazides as first line of antihypertensive therapy, because of the documented reduction of cardiovascular risk at least as effective as with other antihypertensive drugs [26,27]. This evidence yielded the assumption that use of thiazides as first-line antihypertensive therapy would have produced a substantial cost savings due to their lower price [28]. This strong belief has never been proved. More recent trials have been changing these paradigms.In the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension study an exceptional BP control was achieved by using an initial combination therapy with ACEI + CCB challenging current diuretic-based first-line suggestion and providing a new option for cardiovascular risk reduction to millions of patients with hypertension [29]. The study is also having an important impact on clinical practice. At present, many patients do not achieve BP targets when treated according to current guidelines, which recommend starting with one drug – often a diuretic – and gradually adding other meds if necessary to achieve recommended BP.Of course, in contrast with the artificial environment of many clinical trials, in real-life clinical practice more than one drug is needed to control hypertension [30]. To optimize cost/benefit ratio of preserving public's health and saving finances, effective and rapid achievement of target BP should be mandatory independent of the classes of meds, keeping side effects as low as possible.Accordingly, similar to the nature of CardioSis, the present study was not designed to contrast two meds, but to compare compliance and persistence of two antihypertensive strategies in which thiazides are a compulsive first-line antihypertensive therapy versus a regimen, more fitting with the real-world prescription in clinical practice, in which doctors were free to make their choice of first-line antihypertensive therapy. Assessment of safety and efficacy for reduction of cardiovascular risk has been also performed as secondary endpoint.In our study we found that patients who received thiazides as first-line antihypertensive treatment changed more often antihypertensive treatment regimen because of poor BP control, side effects and/or intolerance to diuretic therapy, consistent with previous studies reporting greater rate of side effects than with other antihypertensive meds. Our results show that indication to use mono-therapy with thiazides as first-line medication is not supported by direct clinical experience and might paradoxically increase the financial burden, blunting a more rapid control of BP and potentially yielding more medical attention for side effect. The mean number of prescribed medications to achieve an optimal BP control (BP values <140/90 mmHg and/or <130/80 mmHg in diabetic patients) was in fact larger in patients receiving diuretics as first-line therapy. These findings do not contrast the large evidence that diuretics are extremely useful to achieve BP control in association with other meds, as also clinical trials focused on drug-to-drug comparison have shown.Some effort might be directed to improve adherence and persistence of initial treatment with diuretics, when this first therapy is considered preferable to other options. This objective might be obtained by improving the procedures of follow-up, for instance, as we have recently proposed, by implementing internet-based digital networks, connecting hypertension specialists with GPs [11] and making regular clinical activity closer to the trial environments. This follow-up strategy also allows active pharmacovigilance procedures, with side effects promptly reported to the GPs, thus preventing the occurrence of difference in compliance among the various antihypertensive treatments.LimitationsOne potential limitation of our analysis is that pill count was not performed. However, this study is not a vis-a-vis comparison trial, but a strategy study reflecting what happens in real life. This way of examining data is appreciated [31] and presents advantages [19]. In a real-life context, the procedure of assessing adherence and persistence to therapy in our study seems largely acceptable.In conclusion, this study demonstrates that the recommendation to start antihypertensive therapy with diuretics, when no compelling indications are present, is not supported by evidence and that might produce delay in BP control and, possibly, increased cost/benefit ratio.ACKNOWLEDGEMENTSList of general practitioners who participated in the study: Alano Raffaele, Arpino Giovanni, Avvento Giovanni, Barra Roberto, Bellucci Luisa, Bernardi Giuseppe, Boncompagni Salvatore, Cambri Vittorio, Canciello Elisa, Capezzuto Carmine, Capretti Roberto, Carlino Saverio, Carrano Paolo, Castaldo Gennaro, Celani Serafino, Ceracchio Alessandro, Ciarnelli Bruno, Ciotola Pietro, Colella Claudia, Costantino Angelo, Crispino Mariarosaria, De Camillis Umberto, De Cenzo Bruno, De Rosa Augusto, Della Monica Angeloantonio, Di Guida Giuseppe, Di Martino Pasquale, Di Pasquale Franco, Di Pasquale Pasquale, Ercolino Luigi, Fatigati Domenico, Ferraro Claudio, Ferro Gennaro, Ficco Corrado, Fresa Umberto, Garaffa Elio, Giordano Leonardo, Giovanni Lampitelli, Girardi Vincenzo, Guida Vincenzo, Guillaro Bruno, Iadicicco Daniele Arcangelo, Iaselli Carlo, Indice Elisabetta, Kurtam Shafik, La Torre Angelo, Laringe Matteo, Latte Francesco, Liguori Mario, Lombardo Gianfranco, Marotta Massimo, Marzocchella Antonio, Mazzarella Luigi, Mazzeo Salvatore, Minervino Francesco, Montefusco Silvana, Mundo Francesco, Napoli Luigi, Papulino Francesco, Pelle Guido, Pezzullo Giovanni, Pezzullo Vincenzo, Piccinocchi Gaetano, Polistina Claudio, Ragone Pasquale, Romano Marco, Russo Francesco, Sabini Alfredo, Sammarco Angelo, Santullo Carlo, Sarnataro Michele, Savarese Aniello, Scola Vincenzo, Serrentino Giuseppe, Sessa Pasquale, Sestito Mariarosaria, Sica Gennaro, Simonelli Antonio, Somma Stefano, Sorbo Edgardo, Soverina Patrizio, Spezzano Alfredo, Spina Giovanni, Spinuso Antonio, Stabile Luigi, Tommasielli Giuseppina, Tozzoli Alfonso, Vanacore Liberato, Varriale Antonio, Vignone Leonardo, Viola Dario, Volpe Augusto.Conflicts of interestThere are no conflicts of interest.Reviewers’ Summary Evaluations Reviewer 1The use of thiazide diuretics as first line therapy is still recommended by current guidelines. A number of studies, with a follow-up for up to 10 years, have shown that persistence on these drugs is not as good as the one on other types of antihypertensive agents, in particular blockers of the renin-angiotensin system. These studies consisted generally of retrospective analysis of drug prescriptions. The study of V. Trimarco and colleagues is interesting for 2 main reasons: 1) it was carried-out prospectively; 2) it involved chlortalidone, a non-thiazide diuretic that is considered to have major advantages compared with hydrochlorothiazide, the most popular thiazide diuretic.Reviewer 2The study investigates the persistence on therapy in patients initially treated with two different strategies: a first line strategy based on thiazide diuretics (cholortalidone) as recommended by current American Guidelines, when compelling indications were not present, in comparison with other first line therapeutic strategies based on daily clinical practice. 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and adherence to antihypertensive treatment in relation to initial prescription: diuretics versus other classes of antihypertensive drugsTrimarco, Valentina; de Simone, Giovanni; Izzo, Raffaele; De Luca, Nicola; Giudice, Renata; Marino, Marina; Damiano, Silvia; Rozza, Francesco; Trimarco, Bruno; Di Renzo, GianfrancoORIGINAL PAPERS: Therapeutic aspects630