Chiara Fulcheri

Drugs and Orthostatic Hypotension: Evidence from Literature

Orthostatic hypotension is defined as the reduction of systolic blood pressure of at least 20 mmHg or the dropping of diastolic blood pressure of at least 10 mmHg within 3 minutes of standing compared to baseline values. It can be divided into neurogenic and non neurogenic forms. Neurogenic forms are caused by a primitive damage to autonomic nervous system, while drugs are the most common cause of non neurogenic orthostatic hypotension; they may also complicate or aggravate neurogenic forms. Many drugs can determine orthostatic hypotension, including both cardiovascular drugs and therapies used for neurological and psychiatric disorders. This effect is furthermore enhanced by multiple pharmacological treatments. It is important for the clinician to know the potential hazard of orthostatic hypotension, in order to avoid syncope, falls, hypoperfusion symptoms, excess of mortality and loss of compliance to treatment.

Adherence to antihypertensive therapy and therapeutic dosage of antihypertensive drugs

Adherence to antihypertensive therapy is critical to achieving adequate blood pressure control. About half of hypertensive patients do not take their drugs as directed and the physicians often underestimate this issue. Non-adherence has important public health economic implications (numbers of visits, diagnostic procedures, prescribed drugs) and, moreover, it results in increased morbidity and mortality rates. Poor adherence can have several patients and therapy related causes. Currently, multiple different direct and indirect methods to measure therapeutic adherence are available, but, in clinical practice, there is no cost-effective and simple one. Therapeutic drug monitoring (TDM), characterized by drug (or metabolites) concentration measurement in body fluids (blood or urine), is a cost-effective direct method to assess therapeutic adherence. Despite some limitations, TDM may decrease health costs, by reducing the number of visits and by identifying those patients who would undergo unnecessary invasive procedures. Moreover, TDM can be a new alternative method to identify patients with true resistant hypertension, improving the achievement of blood pressure control In this minor revision, we would assess poor therapeutic adherence in hypertensive population, analyzing the different direct and direct available methods, with emphasis on TDM.

Comparison among Different Screening Tests for Diagnosis of Adolescent Hypertension

The diagnosis of childhood hypertension based upon percentile tables proposed by the international guidelines is complex and often a cause of underdiagnosis, particularly among physicians who have not had specific training in the field of adolescent hypertension. The use of a simple and accurate screening test may improve hypertension diagnosis in adolescents. The aim of our study is to compare the different screening methods currently used in the literature to improve the diagnosis of childhood hypertension. We have conducted a cross-sectional population-based study of 1412 Caucasian adolescents among students of public junior high schools of Turin, Italy. In this population we have defined the hypertensive status with four different screening tests: BPHR, Somus equations, Ardissino, and Kaelber methods. Finally, we compared the diagnostic accuracy of the 4 screening tests with the gold standard. Our analysis identifies in BPHR the test which combines ease of use and diagnostic accuracy.

Appropriateness of Referral to a European Society of Hypertension Center of Excellence

In the European health care system, the general practitioner is a patient’s primary medical contact and point of referral to specialist care. Although current guidelines strongly recommend the pharmacologic treatment of hypertension in patients, adequate blood pressure (BP) control is achieved in only <30% of patients. To improve the care of the hypertensive patient, the ‘‘Hypertension Specialist’’ was introduced by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7). Referral to a specialist is recommended for patients with resistant hypertension, severely complicated hypertension, and if a secondary form of hypertension is suspected. The aim of our study was to determine the appropriateness, in terms of efficiency and effectiveness, of referrals to specialized centers by general practitioners. We reviewed the computer-stored data of 9874 Caucasian hypertensive patients (aged 3–101 years, 4794 men, 5080 women) consecutively referred by general practitioners to our hypertension clinic from 1989 to 2008. The first visit and the 5 follow-up visits were considered for each patient to assess and compare the patient’s management by the general practitioner and the specialist. BP values were classified and resistant hypertension was defined according to 2007 European Society of Hypertension (ESH) ⁄ European Society of Cardiology (ESC) guidelines. Both pediatric hypertension and patients with comorbidities were included in the study. We subdivided the analysis into 3 different periods (1989–1994, 1995–2001, and 2002–2008), chosen on the basis of the publication years of the main hypertension guidelines. The time spent by doctors and patients for inappropriate referral was calculated. Means and standard deviations for descriptive variables and proportions for categoric variables were calculated. One-way analysis of variance (continuous variables) and chi-square test (categorical variables) were used to analyze data. The mean age was significantly increased between the first and the last periods but the body mass index was unchanged. With regards to lifestyle, a significant decrease in smoking was observed with time although a lack of physical activity persisted. BP values (161 ⁄ 99– 150 ⁄ 90 mm Hg, P<.0001) and the average number of antihypertensive drugs taken at the baseline visit (1.32 in the first period and 1.18 in the last, P<.0001) decreased with time. At the baseline visit, 16% of referred patients had controlled BP at the baseline visit and this significantly increased over the 3 periods (5.8% and 23.8% in the first and last periods, respectively) (Table I). Regarding pharmacologic treatment, in the last period only 57.6% of patients were already treated with one drug when referred to our unit, compared with 74.7% in the first period. Overall, 51.63% of patients met at least one of the criteria for referral, with a higher percentage during the mid-period but with a marked reduction over the last period (41.54%). Of patients who were incorrectly referred, 40% were untreated, 31% were taking monotherapy, and only 29% took >1 antihypertensive drug. The most common reasons for referral were complicated hypertension and comorbidities, followed by resistant hypertension. The referral process has impli-

Antihypertensive Bridge Therapy by Continuous Drug Infusion With an Elastomeric Pump in Device-Resistant Hypertension

Over recent years, invasive hypertension treatments have led to a new clinical condition, called device-resistant hypertension (DRH).1 DRH is defined as blood pressure (BP) >140/90 mm Hg, with at least 3 antihypertensives at maximal doses, including a diuretic,2 without BP decrease after the invasive treatments. These patients are not infrequent and are obliged to visit several hypertension units for managing their BP. We have observed a significant BP decrease only by using intravenous drugs recommended for emergencies.2,3 Thus, we refined a protocol to perform a chronic intravenous antihypertensive infusion in patients with DRH via an elastomeric pump and a peripherally inserted central catheter (PICC). After exclusion of several intravenous drugs for contraindications, urapidil was selected as the drug of choice. Here, we present the case of the first treated patient with DRH. The patient is a 45-year-old male. He was hypertensive and undergoing treatment since 2009. He was overweight (body mass index, 29.6), a smoker and dyslipidaemic. In 2012, he underwent percutaneous transluminal coronary angioplasty plus stenting for unstable angina and underwent a further new percutaneous transluminal coronary angioplasty in 2013. The same year, he was admitted to the Hypertension Unit of the University of Pisa for uncontrolled hypertension (office BP, 240/150 mm Hg and day-time ambulatory BP monitoring 200/102 mm Hg). Secondary causes of hypertension were ruled out. After several drug changes, the patient was treated with furosemide 50 mg/d, metoprolol 100 mg/d, spironolactone 50 mg/d, ramipril 10 mg/d, and amlodipine 10 mg/d without BP control. In March 2014, he underwent radiofrequency renal denervation without complications, but no significant BP reduction. Seven months …

NURSE-OBP: A NURSING STANDARDISED METHOD FOR MEASURING BLOOD PRESSURE

Objective: Objective. The role of the nurse in both diagnostic and therapeutic management of hypertensive patient is becoming more and more important; nevertheless until now there is not a nursing standardised method of blood pressure (BP) measurement. The aim of this study was to standardise a nursing method for measuring blood pressure (Nurse-OBP) and to compare it with the Ambulatory Office Blood Pressure. Figure. No caption available. Design and method: Design and Method. 118 treated non-diabetic hypertensive adults afferent to our Hypertension Unit were included in the study. All underwent an AOBP measurement with Omron HEM-907XL and the Nurse-OBP measurement, designed to be methodologically identical to the classical AOBP proposed by Meyers and colleagues but which takes place with the nurse staying in the same patients room during the BP measurement. All subjects were randomized into two groups, different according to the order in which the two method of measurement were performed to avoid eventual reduction of white coat effect mostly deriving from changes in patient behaviour, and finally, during the medical examination all underwent a traditional OBP measurement. All patients signed an informed consent and the study was approved by local ethical committee (CEI 652). Pearsons correlation coefficient was used to evaluate agreement between AOBP and Nurse-OBP measurements Results: Results. Mean Nurse-OBP values (132 ± 19.4/73.3 ± 12.9) were significantly lower than OBP ones (141.3 ± 18.8/84.7 ± 10.7). When AOBP and Nurse-OBP were compared, no statistically significant differences between the two methods were found. The Bland - Altman analysis showed how the presence of the nurse could cause a minimum rise of BP values, (mean SBP and DBP difference respectively of 3.57 ± 12.23 mmHg and 2.25 ± 7.26 mmHg), but clinically non significant; therefore the two modalities, AOBP and Nurse-OBP, can be considered as comparable. Furthermore no differences in terms of Nurse-OBP values were found when the two groups were compared. Conclusions: Conclusions. Our study proposes a standardised nursing method for measuring BP absolutely comparable to AOBP technique, that could have practical implications mostly when it is not possible to have a dedicated room where performing AOBP.

[PP.25.08] THERAPEUTIC DRUG MONITORING IN RESISTANT HYPERTENSIVES PREVIOUSLY TREATED WITH INVASIVE APPROACHES

Objective: Renal denervation (RDN) and baroreflex activation therapy (BAT) are invasive therapeutic approaches for resistant hypertension (RH), indicated when antihypertensive drug therapy is inefficacious. Several reports have found an unsatisfactory response to these approaches; one of the factors called upon to account for the failure of these devices is the lack of therapeutic adherence. The aim of this study was to retrospectively evaluate the therapeutic adherence, using an objective assessment as the therapeutic drug monitoring (TDM), in a group of patients who have undergone invasive approach in previous years, either RDN or BAT, and correlate it with the answer to the invasive procedure. Design and method: We retrospectively analysed 12 patients with RH (9 females). Before performing invasive procedure, all patients were considered adherent according to the physician intuition and the answers given to the Morisky questionnaire. Serum TDM, by Ultra High Performance Liquid Cromatography (UHPLC) method, was done during a routine follow up visit, after at least one year from the last invasive approach. A clinical response to invasive approaches was considered as a reduction in 24 h Ambulatory Blood Pressure Monitoring (ABPM) systolic blood pressure (SBP) of at least 10 mmHg at 12 months from the procedure. Patients were considered adherents (AD) if all the prescribed drugs were found or only one was not found; patients were considered non-adherents (NAD) if none of the prescribed drugs were found. Results: 4 patients were AD and 8 NAD. In the whole sample a clinical response was found in 41% of the patients. Among AD the clinical response rate was 75%, whilst among NAD the clinical response rate dropped to 25%. No significant clinical and social differences were found between NAD and AD, but NAD had significant higher office SBP and 24 h ABPM SBP than AD (p < 0.05). Conclusions: Lack of therapeutic adherence is associated to a limited clinical efficacy of invasive approaches in apparent RH. Our data underlines the importance of adherence therapeutic evaluation before and after performing invasive procedures, whose effectiveness can be undermined by poor therapeutic adherence.

[OP.2B.04] DEVELOPMENT OF AN INNOVATIVE, HIGH THROUGHPUT AND COST-EFFECTIVE UHPLC-MS/MS METHOD FOR THE ASSESSMENT OF THERAPEUTIC ADHERENCE IN PATIENTS WITH “RESISTANT” HYPERTENSION

Objective: Nowadays hypertension affects a large fraction of global population. Moreover, 15–30% of patients show drug-resistance, needing the addition of more drugs; meanwhile, polytherapy often results in poor therapeutic adherence, classified as “pseudo-resistant” hypertension. In this context, Therapeutic Drug Monitoring (TDM) of antihypertensive drugs, which consists in the measurement of drug concentration in biological matrices, may help to discern problems in drug pharmacokinetics/pharmacodynamics from cases of poor therapeutic adherence, also considering that not-pharmacological alternative consists in invasive surgery. It has been hence validated an UHPLC-MS/MS method for simultaneous TDM on plasma samples of ten antihypertensive drugs: amlodipine, atenolol, clonidine, chlortalidone, doxazosin, hydrochlorothiazide, nifedipine, olmesartan, ramipril and telmisartan. Design and method: This method has been validated according to FDA guidelines. 200 &mgr;l of sample, standard and quality control, added with 40 &mgr;l of internal standard working solution, undergo a simple protein precipitation protocol, followed by drying step, and resulting extracts are resuspended in water:acetonitrile 90:10 (v:v; +0.05% formic acid) and then analyzed through a Shimadzu NexeraX2® UHPLC system coupled with a LCMS-8050® tandem mass detector. The validated method was tested on real samples from patients with RH/pseudo-RH, all giving informed consent. Results: All analytical parameters of the method fitted FDA guidelines for all the analytes. 42 patients have been enrolled (SEAL study). TDM revealed that 55% of patients (n = 23) had detectable concentration of all prescribed drugs (considered fully adherent), 26% (n = 11) resulted partially non-adherent (only part of the prescribed drugs was detectable) and 19% (n = 8) were totally not-adherent (no drugs were detected). Through univariate/multivariate logistic regression, the diastolic pressure and the “white-coat” increase in heart rate resulted the best predictors of poor adherence. Through ROC curve analysis a diastolic pressure over 124 mmHg resulted predictive of total inadherence. Conclusions: TDM can be a gold-standard for evaluating therapeutic adherence and this method results eligible for a clinical routine use. We managed to discern cases of inadherence, preserving some patients from an invasive and expensive surgery. Figure. No caption available.

[PP.01.15] ACCURACY OF HOME BLOOD PRESSURE MONITORING IN ARTERIAL HYPERTENSION DIAGNOSIS

Objective: The arterial hypertension diagnosis is based on office blood pressure measurement, and current guidelines suggest the use of out-of-office blood pressure measurement techniques in specific cases, as suspected white-coat or masked hypertension. Home Blood Pressure Monitoring (HBPM) is recommended as a complementary method to Ambulatory Blood Pressure Monitoring (ABPM). However usually HBPM is only used for implementing blood pressure control in treated patients. We tried to identify the accuracy between HBPM and ABPM in untreated patients. (We tried to identify HBPM accuracy between to ABPM in untreated patients.) Design and method: We enrolled 83 consecutive untreated patients who performed ABPM in our Hypertension Unit and completed a short HBPM schedule (two measurements, twice daily, for four days) between November 2011 and June 2015. Patients were instructed about HBPM in accord to current hypertension guidelines and they used validated automated arm devices. We compared the accuracy between the two techniques and the HBPM ability to identify arterial hypertension in comparison with ABPM. Results: Pearsons correlation coefficient between HBPM 4-day average and day-time ABPM values was 0.59 for systolic blood pressure (SBP) and 0.77 for diastolic blood pressure (DBP). Bland-Altman analysis revealed a mean difference of -5.68 mmHg, SD 8.82 mmHg for SBP, and -4.64, SD 6.33 mmHg for DBP. ROC curves described AUC for SBP of 0.75 and for DBP of 0.877. The ABPM identify as hypertensive 54 subjects on 83 (65.1%), the HBPM 29 subjects (34.9%), p-value 0.01609. Conclusions: HBPM has a moderate correlation and a moderate accuracy in the identification of arterial hypertension compared with ABPM. Although HBPM is recommended as alternative method respect to ABPM, in untreated patients it is not reliable for arterial hypertension diagnosis and probably it is not able to identify specific hypertension patterns, in contrast with current guidelines.

[PP.23.13] ANALYSIS OF ELIGIBILITY CRITERIA FOR RENAL SYMPATHETIC DENERVATION

Objective: Resistant hypertension (RH) is a rare condition that affects approximately 10% of hypertensive population, its defined as blood pressure (BP) > 140/90 mmHg despite three full doses antihypertensive drugs including a diuretic. True RH is confirmed when pseudo-hypertension, secondary hypertension or poor adherence are excluded. Percutaneous radio-frequency catheter-based renal sympathetic denervation (DRN) is one of the most used invasive treatments for these patients. The goal of the study is to assess the percentage of eligibility to DRN and analyze the exclusion criteria in a group of resistant hypertensive patients. Design and method: We retrospectively analyzed data of 35 patients (63% female) referred to our Hypertension Unit between June 2011 and June 2014. We considered eligible for DRN subjects with office systolic blood pressure > = 160 mmHg and patients with severe hypertension treated with fewer drugs for poly-intolerances/allergies. Secondary hypertension form and white coat hypertension were excluded. Patients with confirmed true resistant hypertension underwent CT angiography in order to check the renal anatomic criteria of eligibility to the DRN. Results: 35 caucasian patients (63% female) referred to our Hypertension Unit between June 2011 and June 2014 for DRN assessment. At the first evaluation median systolic and diastolic office BP were 179 ± 25 mmHg and 105 ± 20 mmHg; six month later, after appropriate changes in lifestyle and drug therapy, systolic/diastolic office BP was reduced of 18/8 mmHg (p < 0.05). In the most of cases, patients had to BP control with introduction of antialdosteronic (35%). In our sample, 27 patients were considered unsuitable for the DRN for many reason: blood pressure control with optimization of drug therapy (52%), evidence of white coat effect (22%), secondary hypertension (22%), lack of true resistant hypertension (18%), absence of consent to the procedure (29%). Conclusions: A carreful patients selection in Specialistic Center is necessary before DRN; indeed frequently a good BP control is obtained with appropriate drug therapy changes and exclusion of secondary forms.