Improved Persistence to Medication, Decreased Cardiovascular Events and Reduced All-Cause Mortality in Hypertensive Patients With Use of Single-Pill Combinations: Results From the START-Study.

BACKGROUND: Single-pill combination improves adherence and persistence to medication in hypertension. It remains unclear whether this also reduces cardiovascular outcomes and all-cause mortality. We analyzed whether single-pill combinations are superior to identical multiple pills on persistence to medication, cardiovascular outcomes, and all-cause mortality. METHODS: This was a retrospective claims data (German AOK PLUS) analysis. Data from hypertensive patients ≥18 years treated with renin-angiotensin system combinations given as single pill or identical multipills covering the years 2012 to 2018 were analyzed and followed up to at least 1 year. After 1:1 propensity score matching, persistence to medication, cardiovascular events, and all-cause mortality were compared using non-parametric tests. Results were reported as incidence rate ratios and hazard ratios. RESULTS: After propensity score matching data from 57 998 patients were analyzed: 10 801 patients received valsartan/amlodipine, 1026 candesartan/amlodipine, 15 349 ramipril/amlodipine, and 1823 amlodipine/valsartan/hydrochlorothiazide as single pill or identical multipill. No relevant differences in patient characteristics were observed within the 4 groups. In all groups, a significant lower all-cause mortality, a significant a higher persistence to medication, a significant lower event rate in 15 out of 20 comparisons, and a tendency in the remaining 5 comparisons was observed under single pills compared with multipill combinations. CONCLUSIONS: Antihypertensive combination therapy reduces all-cause mortality and cardiovascular events when provided as single pill compared to identical drugs as multipills. This strongly supports the European Society of Cardiology/European Society of Hypertension and International Society of Hypertension guidelines recommending the use of a single-pill combination and thus should be more rigorously implemented into daily clinical practice.

Current practice of blood pressure measurement in Germany: a nationwide questionnaire-based survey in medical practices.

PURPOSE: Discrepancies exist between guideline recommendations and real-world practice of blood pressure (BP) measurements. The aim of this study was to assess, with a nationwide, questionnaire-based survey, the current practice of BP measurement and associated BP values in German medical practices. MATERIAL AND METHODS: A nationwide survey in German medical practices was performed in the period from 10 May 2021 to 15 August 2021. The questionnaire was divided into five sections. The current office BP (OBP) values as well as the current drug therapy were recorded. In addition, the implementation of office BP (OBP) and home BP monitoring (HBPM) was queried. For analysis, questionnaires were scanned and automatically digitised. RESULTS: A total of 7049 questionnaires were analysed, the majority of which came from general practitioners (66%) and internal medicine practices (34%). The average OBP (SD) was 140.0 (18)/82.7 (11) mmHg. 40.8% of treated patients had OBP in the controlled range, with monotherapy (34.7%) or dual combination therapy (38.2%) prescribed in most cases. OBP was taken from a single measurement in 66.3% of cases, and in 21.8% from 23 measurements. OBP was mostly measured after a rest period (87.1%) and in a separate room (80.4%). HBPM was performed in 62.3% of patients; however, in 24.9% of the participants HBP measurements were recorded once a week or less. CONCLUSION: In this nationwide survey in German medical practices, BP control remains at below 50%, while monotherapy is prescribed in around one third of patients. Moreover, office measurements and HBPM are often not performed according to current guideline recommendations.

What is the context?Elevated blood pressure (hypertension) is an important risk factor for diseases such as stroke or heart attack. However, sufficient drug therapy can significantly reduce the risk of complications such as a stroke. An adequate blood pressure measurement is the basis for diagnostics and successful therapy. In order to measure blood pressure as accurately as possible, recommendations for performing blood pressure measurements (at home as well as in the office) have been published by medical societies.Research suggests that blood pressure is not always measured according to these recommendations. However, there are no current studies for Germany.What is new?In this study, we analysed the results of a survey in which medical practices and pharmacies throughout Germany were asked about blood pressure measurement and blood pressure therapy. The key results of our study suggest that:• The blood pressure of many participants with known hypertension is not within the desired target range.• Office blood pressure measurements are often not performed as suggested by guidelines. This mainly affects time-consuming work steps such as repeating the measurement several times.• Home blood pressure is not recorded in a structured form, as suggested, but rather according to a random pattern by the patient. What is important?This study suggests that blood pressure control is not sufficient in the study participants. Furthermore, blood pressure measurement as an important tool for hypertension management is frequently not performed as proposed by guidelines.

Effects of Single Pill Combinations Compared to Identical Multi Pill Therapy on Outcomes in Hypertension, Dyslipidemia and Secondary Cardiovascular Prevention: The START-Study.

AIM: Current guidelines for the treatment of arterial hypertension (AH) or cardiovascular (CV) prevention recommend combination drug treatments with single pill combinations (SPC) to improve adherence to treatment. We aimed to assess whether the SPC concept is clinically superior to multi pill combination (MPC) with identical drugs. METHODS AND RESULTS: In an explorative study, we analyzed anonymized claims data sets of patients treated with CV drugs for hypertension and/or CV disorders who were insured by the German AOK PLUS statutory health fund covering 01/07/2012-30/06/2018. Patients at age ≥18 years who received either a SPC or MPC with identical drugs were followed for up to one year. A one to one propensity score matching (PSM) was applied within patient groups who started identical drug combinations, and results were reported as incidence rate ratios (IRRs) as well as hazard ratios (HRs). After PSM, data from 59,336 patients were analyzed. In 30 out of 56 IRR analyses, superiority of SPC over MPC was shown. In 5 out of 7 comparisons, the HR for the composite outcome of all-cause death and all-cause hospitalizations was in favor of the SPC regimen (SPC versus MPC): valsartan/amlodipine: HR=0.87 (95% CI: 0.84-0.91, p ≤ 0.001); candesartan/amlodipine: 0.77 (95% CI: 0.65-0.90, p = 0.001); valsartan/amlodipine/hydrochlorothiazide: HR=0.68 (95% CI: 0.61-0.74, p ≤ 0.001); ramipril/amlodipine: HR=0.80 (95% CI: 0.77-0.83, p ≤ 0.001); acetylsalicylic acid (ASA)/atorvastatin/ramipril: HR=0.64 (95% CI: 0.47-0.88, p = 0.005). CONCLUSION: SPC regimens are associated with a lower incidence of CV events and lower all-cause mortality in clinical practice. SPC regimens should generally be preferred to improve patient's prognosis.

Effects of cardiovascular single pill combinations compared with identical multi-pill therapies on healthcare cost and utilization in Germany.

Aim: This study assessed whether a single pill combination (SPC) is associated with lower direct healthcare costs. Materials & methods: Anonymized claims data of patients ≥18 years treated with drugs for cardiovascular (CV)-related diseases either as a single pill combination or multi-pill combination (follow-up to 1 year) were evaluated. After propensity score matching, 59,336 out of 1,369,840 patients were analyzed. Results: In all cohorts, patients receiving a single pill combination had a lower frequency of general practitioner and specialist visits. The patients also had a significantly lower ratio of all-cause hospitalization days and number of CV-related prescriptions as well as all-cause prescriptions (with one exception) compared with those receiving a multi-pill combination. Conclusion: Direct CV-related costs were significantly lower in four out of seven comparisons, with a trend toward lower costs in the other three comparisons.

Safety of Candesartan, Amlodipine, and Atorvastatin in Combination: Interaction Study in Healthy Subjects.

For efficient cardiovascular risk protection antihypertensive treatment is often combined with cholesterol-lowering treatment, although solid data of interaction and side effects are missing. This is a prospective, single-center interaction study conducted in a fixed sequence design at steady state of candesartan, amlodipine, and atorvastatin. Five-day monotherapy of candesartan 8 mg was followed by 5-day atorvastatin 40 mg monotherapy and subsequently 9-day amlodipine 5 mg monotherapy; each treatment separated by washout phases. Immediately after amlodipine monotherapy, all 3 drugs were administered concomitantly for 5 days. Pharmacokinetic parameters as well as safety were assessed. Eighteen healthy subjects enrolled and completed the study. No significant difference in the maximum concentration (Cmax ) and the area the under plasma concentration-time curve (AUC) for amlodipine and AUC of atorvastatin was detected following combination versus monotherapy. Cmax of atorvastatin decreased slightly but clinically not relevantly when given in combination. A statistically significant but not below 0.80-fold decrease between candesartan following combination vs monotherapy was detected for Cmax and AUC. In general, all treatments were well tolerated. Concluding, systemic exposure of candesartan, amlodipine, and atorvastatin is not clinically significantly changed upon coadministration. These data support a fixed-dose combination of the 3 components for dual cardiovascular risk prevention.

Management of arterial hypertension: Transfer from clinical guidelines into daily practice - Results of a survey in German practitioners offices.

INTRODUCTION: The principal objective of clinical guidelines is to improve the quality of medical care. However, standardized evaluation of the adoption into daily practice is missing. The aim of our study was to investigate the implementation of guideline recommendations on the management of arterial hypertension (AH) in German general practitioner's (GPs) offices. METHODS: A questionnaire focusing on the implementation of the German guidelines for the management of AH was developed and prospectively rolled out in 3.200 GPs and field-based specialists in internal medicine in Germany. Data were interpreted in an explorative way. RESULTS: Data from 689 German physicians that participated in the survey were analyzed. Effectiveness of lifestyle changes in the management of AH was rated as very high or high in 36.6%. When lifestyle changes only will not normalize blood pressure (BP), medical treatment will be initiated after 2-6 months by majority of physicians. Decision for mono- or combination therapy was driven by BP and patient's risk profile. Choice for a specific antihypertensive substance was based on the recommendations of scientific guidelines in the majority of GPs. CONCLUSIONS: Medication treatment algorithms recommended in 2015 by German guidelines are well accepted by GPs. Lifestyle changes are voted by only slightly more than one-third as a reasonable tool for the management of AH in the setting of the medical office. This might reflect a lack of certified medical education regarding this topic. Our study was not designed to register the time from publication of guidelines to practical implementation.

Single Pill Regimen Leads to Better Adherence and Clinical Outcome in Daily Practice in Patients Suffering from Hypertension and/or Dyslipidemia: Results of a Meta-Analysis.

INTRODUCTION: Cardiovascular diseases (CVD) represent the first cause of mortality in western countries. Hypertension and dyslipidemia are strong risk factors for CVD, and are prevalent either alone or in combination. Although effective substances for the treatment of both factors are available, there is space for optimization of treatment regimens due to poor patient's adherence to medication, which is usually a combination of several substances. Adherence decreases with the number of pills a patient needs to take. A combination of substances in one single-pill (single pill combination, SPC), might increase adherence, and lead to a better clinical outcome. AIM: We conducted a meta-analysis to compare the effect of SPC with that of free-combination treatment (FCT) in patients with either hypertension, dyslipidemia or the combination of both diseases under conditions of daily practice. METHODS: Studies were identified by searching in PubMed from November 2014 until February 2015. Search criteria focused on trials in identical hypertension and/or dyslipidemia treatment as FCT therapy or as SPC. Adherence and persistence outcome included proportion-of-days-covered (PDC), medication possession ratio (MPR), time-to treatment gap of 30 and 60 days and no treatment gap of 30 days (y/n). Clinical outcomes were all cause hospitalisation, hypertension-related hospitalisation, all cause emergency room visits, hypertension-related emergency room visits, outpatient visits, hypertension-related outpatient visits, and number of patients reaching blood pressure goal. Randomized clinical studies were excluded because they usually do not reflect daily practice. RESULTS: 11 out of 1.465 studies met the predefined inclusion criteria. PDC ≥ 80% showed an odds ratio (OR) of 1.78 (95% CI: 1.30-2.45; p = 0.004) after 6 months and an OR of 1.85 (95% CI: 1.71; 2.37; p < 0.001) after ≥ 12 months in favour to the SPC. MPR ≥ 80% after 12 months also was in favour to SPC (OR 2.13; 95% CI: 1.30; 3.47; p = 0.003). Persistence was positively affected by SPC after 6, 12, and 18 months. Time to treatment gap of 60 days resulted in a hazard ratio (HR) of 2.03 (95% CI: 1.77; 2.33, p < 0.001). The use of SPC was associated with a significant improvement in systolic blood pressure reduction, leading to a higher number of patients reaching individual blood pressure goals (FCT vs SPC results in OR = 0.77; 95% CI: 0.69; 0.85, p < 0.001). Outpatient visits, emergency room visits and hospitalisations, both overall and hypertension-related were reduced by SPC: all-cause hospitalisation (SPC vs FCT: 15.0% vs 18.2%, OR 0.79, 95% CI 0.67; 0.94, p = 0.009), all-cause emergency room visits (SPC vs FCT: 25.7% vs 31.4%, OR 0.75, 95% CI 0.65; 0.87, p = 0.001) and hypertension related emergency room visits (SPC vs FCT: 9.7% vs 14.1%, OR 0.65, 95% CI 0.54; 0.80, p < 0.001). CONCLUSIONS: SPC improved medication adherence and clinical outcome parameter in patients suffering from hypertension and/or dyslipidemia and led to a better clinical outcome compared to FCT under conditions of daily practice.

Requirements for Parkinson's disease pharmacotherapy from the patients' perspective: a questionnaire-based survey.

OBJECTIVE: Knowledge of patients' treatment needs is an important requirement for comprehensive long-term patient care. The objective of this investigation was to assess the requirements of patients with Parkinson's disease (PD) regarding pharmacotherapy. METHODS: A total of 17,500 members of the German Parkinson Association were given the opportunity to anonymously answer a questionnaire about their health-related quality of life, PD pharmacotherapy and their improvement suggestions for new PD medication. RESULTS: Answers from 6351 patients were available for analysis. The majority (87.2%) of patients were older than 60 years; 88.9% had been diagnosed with PD for longer than 3 years and 84.4% selected one of the three most severe categories (categories 1-3 on a 6-point scale) when rating the impact of PD on their quality of life. Symptoms that were regarded as very important for improvement with pharmacotherapy included motor fluctuations (66.3%), early morning akinesia (55.4%) and sleep disturbances (43.5%). Properties of a new PD medication that were rated as very important included continuous drug delivery over 24 hours (66.6%) and 24-hour symptom control (55.8%). The majority of patients used physicians (84.2%) and/or self-help groups (69.4%) to obtain information about PD. Topics of particular interest included comorbid diseases (78.3%), mobility and exercise (77.3%) and research (53%). CONCLUSION: PD has a major impact on patients' quality of life. From the patient's perspective, PD pharmacotherapy needs to address a range of symptoms including not only motor symptoms, but also non-motor symptoms such as sleep disturbances. In selecting the most appropriate treatment regimen, patient preference is an important consideration.

High doses of rotigotine transdermal patch: results of an open-label, dose-escalation trial in patients with advanced-stage, idiopathic Parkinson disease.

OBJECTIVE: The objective of the study was to determine the maximal achievable dose of rotigotine by assessing the tolerability of escalating doses of rotigotine transdermal patch in patients with advanced-stage Parkinson disease. METHODS: Thirty-four patients aged 30 years or older on a stable dose of l-dopa with an off time of at least 2.5 h/d were randomized to 2-titration schemes. The patients started on a dosage of 4 mg/24 h and received an incremental dosage of 4 mg/24 h per week in the fast-titration group and 2 mg/24 h per week in the slow-titration group to the maximal target dosage of 24 mg/24 h (patch size of 120 cm(2)). Thereafter, both groups entered a maintenance period of 42 days or longer for the rapid-titration group and 7 days or longer for the slow titration group followed by a 2-week safety follow-up period with stepwise dosage de-escalation of 4 mg/24 h for 4 days. RESULTS: Twenty-seven patients completed the trial, of whom 24 completed without dose reduction. Twenty-six patients (76%) were titrated to the maximum target dose and thus had a maximal achievable dosage of at least 24 mg/24 h. Adverse events, generally mild or moderate, included application site reaction (12%), nausea, dyskinesia, and visual hallucinations (9% each). The mean time spent off decreased by 2 to 3 h/d. Duration of on without dyskinesia periods increased (2 h/d). The mean total (SD) Unified Parkinson's Disease Rating Score decreased by 18.9 (14.2) in the fast-titration group and 17.8 (14.0) in the slow titration group. A shift from off to on without dyskinesias in status after waking up was observed. CONCLUSIONS: Rotigotine transdermal patch, up to 24 mg/24 h, was effective and well tolerated by patients with advanced-stage Parkinson disease.

Rotigotine transdermal patch enables rapid titration to effective doses in advanced-stage idiopathic Parkinson disease: subanalysis of a parallel group, open-label, dose-escalation study.

OBJECTIVE: Rotigotine (Neupro) is formulated as a transdermal delivery system designed to provide a selective, non-ergot D3/D2/D1 agonist to the systemic blood flow over a 24-hour period. In clinical trials, patches were applied once daily and uptitrated to the individual effective dose in increments of 2 mg/24 h every week. The aim of this analysis was to determine the safety of a more rapid titration of rotigotine by assessing the tolerability of escalating transdermal doses of rotigotine given in 2 different titration schemes. METHODS: We analyzed the safety of rotigotine in 2 groups of patients with advanced stage Parkinson Disease. The starting dose of 4 mg/24 h was increased every week by 2 mg/24 h in the slow-titration group and 4 mg/24 h in the fast-titration group. The primary focus of this subanalysis was the separate tolerability of rotigotine in each randomized treatment arm, during the dose-escalation period. However, the 2 titration schemes were also compared with each other. RESULTS: The dose of first reported nausea and/or vomiting was 8 mg/24 h for the fast-titration group and 4 mg/ 24 h for the slow-titration group. There were no remarkable differences concerning the side-effect profile between the 2 different titration schemes. CONCLUSIONS: The fast-titration regimen had a similar adverse event profile to slower titration, and allowed rotigotine to be introduced quickly. This subanalysis suggests that rotigotine may be uptitrated more rapidly.