Showing papers by "Sverre E. Kjeldsen published in 2022"

Individualized Beta-Blocker Treatment for High Blood Pressure Dictated by Medical Comorbidities: Indications Beyond the 2018 European Society of Cardiology/European Society of Hypertension Guidelines.

Abstract: Several hypertension guidelines have removed beta-blockers from their previous position as first-choice drugs for the treatment of hypertension. However, this downgrading may not be justified by available evidence because beta-blockers lower blood pressure as effectively as other major antihypertensive drugs and have solid documentation in preventing cardiovascular complications. Suspected inconveniences of beta-blockers such as increased risk of depression or erectile dysfunction may have been overemphasized, while patients with chronic obstructive pulmonary disease or peripheral artery disease, that is, conditions in which their use was previously restricted, will benefit from beta-blocker therapy. Besides, evidence that from early to late phases, hypertension is accompanied by activation of the sympathetic nervous system makes beta-blockers pathophysiologically an appropriate treatment in hypertension. Beta-blockers have favorable effects on a variety of clinical conditions that may coexist with hypertension, making their use either as specific treatment or as co-treatment potentially common in clinical practice. Guidelines typically limit recommendations on specific beta-blocker use to cardiac conditions including angina pectoris, postmyocardial infarction, or heart failure, with little or no mention of the additional cardiovascular or noncardiovascular conditions in which these drugs may be needed or preferred. In the present narrative review, we focus on multiple additional diseases and conditions that may occur and affect patients with hypertension, often more frequently than people without hypertension, and that may favor the choice of beta-blocker. Notwithstanding, beta-blockers represent an in-homogenous group of drugs and choosing beta-blockers with documented effect in prevention and treatment of disease is important for first choice in guidelines.

Single-pill combinations, hypertension control and clinical outcomes: potential, pitfalls and solutions

Abstract: Hypertension is the most prevalent cardiovascular risk factor and carries the greatest population attributable risk for cardiovascular disease [1]. Better hypertension control is among the most effective public health and population healthcare levers for reducing years of life lost and disability adjusted life years [2]. Unfortunately, the global burden of hypertension and related cardiovascular and renal diseases continues to grow. Hypertension control rates remain low globally [3]. One relatively simple and potentially scalable approach to improving hypertension control is greater use of singlepill combinations (SPC) containing two or more different classes of antihypertensive medications as initial and add-in therapy [4–12]. In this editorial, the literature is selectively reviewed and summarised on SPC, especially as initial therapy, compared with monotherapy and multiple pill regimens on adherence, hypertension control, clinical outcomes, population impact and adverse effects. An attempt is made to quantify the relative use of SPC versus monotherapy and free-dose combinations in hypertension management. Barriers and potential pathways to greater use of SPC in managing hypertension are explored.

Diverse pharmacological properties, trial results, comorbidity prescribing and neural pathophysiology suggest European hypertension guideline downgrading of beta-blockers is not justified

Abstract: Abstract Beta-blockers have solid documentation in preventing cardiovascular complications in the treatment of hypertension; atenolol, metoprolol, oxprenolol and propranolol demonstrate proven cardiovascular prevention in hypertension mega-trials. Hypertension is characterised by activation of the sympathetic nervous system from early to late phases, which makes beta-blockers an appropriate treatment seen from a pathophysiological viewpoint, especially in patients with an elevated heart rate. Beta-blockers represent a heterogenous class of drugs with regard to both pharmacodynamic and pharmacokinetic properties. This position is manifest by reference to another clinical context, beta-blocker treatment of heart failure, where unequivocally there is no class effect (no similar benefit from all beta-blockers); there are good and less good beta-blockers for heart failure. Analogous differences in beta-blocker efficacy is also likely in hypertension. Beta-blockers are widely used for the treatment of diseases comorbid with hypertension, in approximately 50 different concomitant medical conditions that are frequent in patients with hypertension, leading to many de facto beta-blocker first choices in clinical practice. Thus, beta-blockers should be regarded as relevant first choices for hypertension in clinical practice, particularly if characterised by a long half-life, highly selective beta-1 blocking activity and no intrinsic agonist properties. SUMMARY Beta-blockers have solid documentation in preventing cardiovascular complications in the treatment of hypertension; atenolol, metoprolol, oxprenolol and propranolol demonstrate proven cardiovascular prevention in hypertension mega-trials Hypertension is characterised by activation of the sympathetic nervous system from early to late phases, which makes beta-blockers an appropriate treatment seen from a pathophysiological viewpoint, especially in patients with an elevated heart rate Beta-blockers represent a heterogenous class of drugs with regard to both pharmacodynamic and pharmacokinetic properties This position is manifest by reference to another clinical context, beta-blocker treatment of heart failure, where unequivocally there is no class effect (no similar benefit from all beta-blockers); there are good and less good beta-blockers for heart failure Analogous differences in beta-blocker efficacy is also likely in hypertension Beta-blockers are widely used for the treatment of diseases comorbid with hypertension, in approximately 50 different concomitant medical conditions that are frequent in patients with hypertension, leading to many de facto beta-blockers first choices in clinical practice These observations, in totality, inform our opinion that beta-blockers are relevant first choices for hypertension in clinical practice and this fact needs highlighting Further, these arguments suggest European hypertension guideline downgrading of beta-blockers is not justified

Aortic Root Dilatation in Hypertensive Patients with Left Ventricular Hypertrophy-Application of A New Multivariate Predictive Model. The Life Study.

Abstract: BACKGROUND Available nomograms to predict aortic root (AoR) diameter for body surface area have limitations. The purpose of this study was to evaluate the use of a new multivariate predictive model to identify AoR dilatation in hypertensive patients with left ventricular hypertrophy. METHODS 943 of 961 patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic sub-study had the necessary baseline characteristics and echocardiographic 2D measurements of AoR size to be included. RESULTS Predicted AoR (Sinus of Valsalva) diameter was 1.519 + (age [years] × 0.010) + (height [cm] × 0.010) - (gender [1 = M, 2 = F] × 0.247), and a measured AoR diameter exceeding the 97.5-percentile of this estimate was considered dilated. Measured AoR diameter was larger in men than in women (3.75 vs. 3.48 cm, p < 0.001) and AoR diameter predicted by the model was larger than predicted by nomogram (3.52 vs. 3.28 cm, p < 0.001). Using the multivariate model to identify patients with AoR dilatation, the prevalence was 13.7% in men and 12.3% in women (p = 0.537). There was consensus of AoR phenotype (normal/dilated) between model and nomogram in 92.8% of the patients. In multivariate logistic regression, AoR dilatation by model definition was predicted by presence of aortic regurgitation (OR 2.67, p < 0.001) and SD increase in age (OR 0.75, p = 0.023), pulse pressure (OR 0.64, p < 0.001), left ventricular mass index (OR 1.36, p = 0.08) and stroke volume (OR 1.45, p = 0.002), but not by body weight. CONCLUSIONS Using the proposed model the prevalence of AoR dilatation was equal in men and women and the model seems to address the effects of gender, age and body size on AoR size. CLINICAL TRIAL REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT00338260.

Development of systolic dysfunction unrelated to myocardial infarction in treated hypertensive patients with left ventricular hypertrophy. The LIFE Study

Abstract: Aim: While it is commonly thought that left ventricular (LV) systolic function may insidiously deteriorate in hypertensive patients, few prospective data are available to support this notion. Methods: We evaluated 680 hypertensive patients (66 ± 7 years; 45% women) with electrocardiographic (ECG)-LV hypertrophy (ECG-LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echo-sub-study free of prevalent cardiovascular disease and with baseline ejection fraction (EF) ≥ 55%. Echocardiographic examinations were performed annually for 5 years during anti-hypertensive treatment. Development of reduced systolic function was defined as incident EF < 50%. Results: During a mean follow-up of 4.8 ± 1 years, 37 patients developed reduced EF without an inter-current myocardial infarction (5.4%). In analysis of covariance, patients who developed reduced EF were more often men, had greater baseline LV diameter and LV mass, lower mean EF (all P < 0.05), and similar diastolic function indices. At the last available examination before EF reduction, independently of covariates, patients with reduced EF showed a significant increase in left atrium (LA) size, LV diameter, end-systolic stress and mitral E/A ratio, as compared to those who did not develop reduced EF (all P < 0.05). In time-varying Cox regression analysis, also controlling for baseline EF, predictors of developing reduced EF were higher in-treatment LV diameter [hazard ratio (HR) = 5.19 per cm; 95% confidence interval (CI): 2.58–10.41] and higher in-treatment mitral E/A ratio (HR = 2.37 per unit; 95% CI: 1.58–3.56; both P < 0.0001). Conclusions: In treated hypertensive patients with ECG-LVH at baseline, incident reduced EF is associated with the development of dilated LV chamber and signs of increased LV filling pressure (ClinicalTrials.gov identifier: NCT00338260).

Incident atrial fibrillation and heart failure in treated hypertensive patients with left ventricular hypertrophy. The LIFE Study

Abstract: Aim: The present study investigated the appearance and severity of atrial fibrillation (AF) and heart failure (HF) in 8,702 hypertensive patients with left ventricular hypertrophy (LVH) receiving antihypertensive treatment in a prospective trial. Methods: Patients who had a history of AF or HF were not included, and the participants had sinus rhythm when they were randomly allocated to blinded study medication. Endpoints were adjudicated. Results: Incident AF occurred in 679 patients (7.8%) and HF in 246 patients (2.8%) during 4.7 ± 1.1 years mean follow-up. Incident AF was associated with a > 4-fold increased risk of developing subsequent HF [hazards ratios (HRs) = 4.7; 95% confidence intervals (CIs), 3.1–7.0; P < 0.001] in multivariable Cox analyses adjusting for age, sex, race, randomized treatment, standard cardiovascular risk factors and incident myocardial infarction. The development of HF as a time-dependent variable was associated with a multivariable-adjusted 3-fold increase of the primary study endpoint (HRs = 3.11; 95% CIs, 1.52–6.39; P < 0.001) which was a composite of myocardial infarction, stroke or cardiovascular death. Incident HF was associated with a > 3-fold increased risk of developing subsequent AF (HRs = 3.3; 95% CIs, 2.3–4.9; P < 0.001). This development of AF was associated with a > 2-fold increase of the composite primary study endpoint in multivariable Cox analysis (HRs = 2.26; 95% CIs, 1.09–4.67; P = 0.028). Conclusions: Incident atrial fibrillation and heart failure are associated with increased risk of the other in treated hypertensive patients with left ventricular hypertrophy. Such high-risk hypertensive patients who subsequently develop both atrial fibrillation and heart failure have particular high risk of composite myocardial infarction, stroke or cardiovascular death (ClinicalTrials.gov identifier: NCT00338260).

Time-varying serum uric acid predicts new-onset atrial fibrillation in treated hypertensive patients

Abstract: Objective: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was the first clinical outcome trial to suggest that lowering of serum uric acid by a uricosuric drug such as losartan has a beneficial effect on cardiovascular outcome independently of changes in renal function or blood pressure. LIFE also showed less new-onset atrial fibrillation in hypertensive patients receiving losartan vs. atenolol based treatment. Because losartan reduces serum uric acid levels, we investigated relations of serum uric acid with new-onset atrial fibrillation in the study. Design and method: Hypertensive patients with electrocardiographic left ventricular hypertrophy and no prior atrial fibrillation (n = 8243) were treated for 5.0 ± 0.4 years with losartan or atenolol based therapy. Associations of serum uric acid with new-onset atrial fibrillation documented by Minnesota coding were assessed by Cox models using serum uric acid and systolic blood pressure as time-varying covariates to take into account changes of serum uric acid related to losartan or diuretic treatment, changes in renal function, and aging. Results: Time-varying serum uric acid was associated with new atrial fibrillation defined by Minnesota code (HR = 1.19 per 16.8 umol/L [1 mg/dL] [95% CIs, 1.12–1.26], P < 0.0001), independent of losartan treatment (HR = 0.75 [95% CIs, 0.61–0.93], P = 0.007), older age (HR = 1.95 per 7.0 years [95% CIs, 1.73–2.20], P < 0.0001), male sex (HR = 1.46 [95% CIs, 1.09–1.94], P = 0.010) and higher Cornell voltage duration product (HR = 1.10 per 1023 msec x mm [95% CIs, 1.01–1.21], P = 0.034). Similar results were obtained in Cox models with serum uric acid levels partitioned according to baseline quartiles and in which atrial fibrillation was defined by physician reports or by both Minnesota coding and physician reports. Conclusions: Thus, we found a strong relationship between time-varying serum uric acid levels during antihypertensive treatment and new-onset atrial fibrillation in elderly patients with left ventricular hypertrophy. Our data suggest that in-treatment serum uric acid is a strong predictor for new onset atrial fibrillation in hypertensive patients, independent of effects of antihypertensive treatment, age, sex, and electrocardiographic left ventricular hypertrophy. Further research is needed to clarify how serum uric acid may provoke atrial fibrillation.

Renal denervation in the antihypertensive arsenal – knowns and known unknowns

Abstract: Even though it has been more than a decade since renal denervation (RDN) was first used to treat hypertension and an intense effort on researching this therapy has been made, it is still not clear how RDN fits into the antihypertensive arsenal. There is no question that RDN lowers blood pressure (BP), it does so to an extent at best corresponding to one antihypertensive drug. The procedure has an excellent safety record. However, it remains clinically impossible to predict whose BP responds to RDN and whose does not. Long-term efficacy data on BP reduction are still unconvincing despite the recent results in the SPYRAL HTN-ON MED trial; experimental studies indicate that reinnervation is occurring after RDN. Although BP is an acceptable surrogate endpoint, there is complete lack of outcome data with RDN. Clear indications for RDN are lacking although patients with resistant hypertension, those with documented increase in activity of the sympathetic system and perhaps those who desire to take fewest medication may be considered.

Nonadherence by Serum Drug Analyses in Resistant Hypertension: 7‐Year Follow‐Up of Patients Considered Adherent by Directly Observed Therapy

Abstract: Background Measurement of serum concentrations of drugs is a novelty found useful in detecting poor drug adherence in patients taking ≥2 antihypertensive agents. Regarding patients with treatment‐resistant hypertension, we previously based our assessment on directly observed therapy. The present study aimed to investigate whether serum drug measurements in patients with resistant hypertension offer additional information regarding drug adherence, beyond that of initial assessment with directly observed therapy. Methods and Results Nineteen patients assumed to have true treatment‐resistant hypertension and adherence to antihypertensive drugs based on directly observed therapy were investigated repeatedly through 7 years. Serum concentrations of antihypertensive drugs were measured by ultra‐high‐performance liquid chromatography–tandem mass spectrometry from blood samples taken at baseline, 6‐month, 3‐year, and 7‐year visits. Cytochrome P450 polymorphisms, self‐reported adherence and beliefs about medicine were performed as supplement investigations. Seven patients (37%) were redefined as nonadherent based on their serum concentrations during follow‐up. All patients reported high adherence to medications. Nonadherent patients expressed lower necessity and higher concerns regarding intake of antihypertensive medication (P=0.003). Cytochrome P450 polymorphisms affecting metabolism of antihypertensive drugs were found in 16 patients (84%), 21% were poor metabolizers, and none were ultra‐rapid metabolizers. Six of 7 patients redefined as nonadherent had cytochrome P450 polymorphisms, however, not explaining the low serum drug concentrations measured in these patients. Conclusions Our data suggest that repeated measurements of serum concentrations of antihypertensive drugs revealed nonadherence in one‐third of patients previously evaluated as adherent and treatment resistant by directly observed therapy, thereby improving the accuracy of adherence evaluation. Registration URL: https://www.clinicaltrials.gov; unique identifier: NCT01673516.

Incident left bundle branch block predicts cardiovascular events and death in hypertensive patients with left ventricular hypertrophy. The LIFE Study

Abstract: Aim: Whether incident left bundle branch block (LBBB) is associated with increased cardiovascular (CV) morbidity and mortality in treated hypertensive patients with left ventricular hypertrophy (LVH) is unknown. Thus, the present study aimed to examine CV outcomes of incident LBBB in treated hypertensive patients with LVH. Methods: In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, 9,193 hypertensive patients with LVH on screening electrocardiogram (ECG) were randomized to losartan or atenolol based treatment. Participants (n = 8,567) did not have LBBB (Minnesota code 7.1) on baseline ECG. Cox regression models controlling for significant covariates assessed independent associations of incident LBBB with CV events and all-cause mortality during 4.8 years mean follow-up. Results: Annual follow-up ECGs identified 295 patients (3.4%) with incident LBBB associated with male gender (P < 0.05), older age, higher Cornell voltage (both P < 0.005) and history of diabetes, isolated systolic hypertension and prevalent CV disease. When adjusted for the history of previous CV disease, diabetes, isolated systolic hypertension, the Framingham risk score, ECG-LVH and randomized study treatment, Cox regression models showed that incident LBBB predicted higher risk of the composite endpoint CV death, myocardial infarction and stroke [hazard ratio (HR) 1.9, 95% confidence intervals (CIs) 1.3–2.9, P < 0.001], CV death (HR 3.0, 95% CIs 1.84–5.0, P < 0.001), heart failure (HR 3.6, 95% CIs 1.9–6.6, P < 0.001) and all-cause mortality (HR 3.0, 95% CIs 2.0–4.3, P < 0.001). Conclusions: These data suggest that among hypertensive patients with ECG-LVH receiving aggressive antihypertensive therapy, incident LBBB independently predicts increased risk of subsequent CV events including congestive heart failure and CV and all-cause mortality (ClinicalTrials.gov identifier: NCT00338260).

Patient perspectives on treatment adherence in hypertension: preliminary results of an esh survey in five countries

Abstract: Objective: The ESH Working group on Lifestyle, Cardiovascular Therapy and Adherence, in partnership with Servier, has developed a web-based questionnaire in different languages to investigate patients’ perspectives on hypertension and treatment adherence. The objective of this survey was to decipher patients’ perception, motivations and barriers to drug treatment adherence in hypertension. Design and method: Eligible participants were men and women aged > 18 years, living in France, Germany, Italy, Spain and UK, with a diagnosis of hypertension made by a physician and internet access. Data were collected through patients’ websites and organizations from January to March 2022. Results: We included 595 participants (329 women, 55.3%, mean age 65 y); 72% were hypertensive for > 5 years, 93% were treated with antihypertensive medications for > 3 months and 50% had uncontrolled (140/90 mmHg) office BP at 3 months. The median number of all medications taken every day was 4 of which 2 were antihypertensive drugs. On a 10-point Likert scale, participants reported a modest impact of hypertension on their quality of life (3) or social and family life (3.1). The median level of stress was 5.2. In 76.6% of participants home BP was measured several times weekly (25%) or monthly (31%) or more. Antihypertensive medications were stopped unintentionally by 40% or taken irregularly by 44% of patients. The reasons for non-adherence to medications were forgetfulness (45%), side effects (17%) and running out of medications (15%). In 50% of cases, patients do not inform their physicians when stopping medications. The most useful approaches to support adherence reported by participants were single-pill combinations and smaller and cheaper pills. Information on hypertension and its treatment were considered sufficient for 33% of patients. Conclusions: In patients with internet access and willing to participate, our survey shows that despite having an uncontrolled office 3 month BP in 50% of them, participants report: 1) a modest impact of hypertension on their quality of life and a moderate level of anxiety, 2) frequent and usually non intentional non-adherence to prescribed antihypertensive medications, and 3) the necessity to improve the information provided to them.

A 30th anniversary and a glimpse of the future

Abstract: In 1992, Lennart Hansson, Sverker Jern and Thomas Hedner, three enthusiastic and enterprising clinicians interested in hypertension research decided to create a new journal, which they entitled BLOOD PRESSURE (Figure 1). Their main objective was to ‘facilitate the communication of research findings as effectively as possible in order to stimulate exchange of new ideas and thereby initiate further progress’ [1]. As mentioned in their first editorial, the ambition was also to emphasise on clinical rather than on basic research. Initially, BLOOD PRESSURE was printed by Scandinavian University Press, a publishing company resulting from the merge of a Norwegian and a Swedish publisher, but today, after a consolidation within the scientific publishing sector, Taylor and Francis Ltd. is the official publisher of the journal. While celebrating its 30-year anniversary in 2022, founders of BLOOD PRESSURE could be proud of the development of their journal. Indeed, over the years, BLOOD PRESSURE has witnessed an increasing popularity as a publisher of highimpact clinical research, which is reflected by a steadily rising impact factor, this latter having increased more than two-fold between 2010 and 2020 to reach 2.83. Several factors have contributed to the successful development of the journal. The first was undoubtedly the great contribution of Scandinavian investigators who covered a wide range of important hypertension topics from basic physiology, with world experts like Prof. Bj€ orn Folkow [2], to drug development and large clinical outcome studies with trial experts like Profs. Lennart Hansson, Bj€ orn Dahl€of, Hans Ibsen, Lars Lindholm, Per Lund-Johansen and Sverre E. Kjeldsen. Indeed, the development and the participation in large clinical morbidity and mortality trials in hypertension has become a ‘specialty’ of Nordic countries, which were perfectly organised and experienced to run such large trials. Thus, over the years, numerous outcome studies in hypertension were conducted in Scandinavia. These included for example STOP, STOP-2, CAPPP, NORDIL, HOT, LIFE, VALUE, ASCOT and ACCOMPLISH though with time large fractions of patients were also included in UK, USA and in other countries. Although results of these trials were always published in the Lancet or the New England Journal of Medicine, BLOOD PRESSURE benefitted a lot from these studies. In this respect, one reference article, published in BLOOD PRESSURE in 1992, is the first description of the PROBE (Prospective Randomised Open Blinded Endpoint) design for large clinical outcome trials, a method that became rapidly adopted for use in several large clinical morbidity and mortality outcome studies [3]. Papers describing protocols, including background, randomised populations and progress reports were frequently published in BLOOD PRESSURE. The second major factor is certainly the tight link between the journal and the European Society of Hypertension (ESH). From its introduction, the journal enjoyed the full support and endorsement of the ESH and with time all ESH council members served on the BLOOD PRESSURE editorial board. In addition, several ESH presidents (L. Hansson, S. Kjeldsen, K. Narkiewicz) contributed to the journal as editors in chief or editors. In 2002, the BLOOD PRESSURE 10th anniversary Research Prize was attributed to Prof. Andrzej Januszewicz, current secretary of the ESH council. Thereby, the journal became more European and nowadays international with the support of more than 150 hypertension experts from all over the world. This fruitful collaboration has resulted in the publication of several ESH Newsletters and ESH guidelines [4] or practice guidelines [5] in BLOOD PRESSURE. At last, one should not forget that the successful development of the journal is due in large part to the enthusiasm, the high level of competences and the perseverance of the successive editors and associate editors who succeeded in maintaining the reputation of the journal.

Implications of cyp2d6 polymorphisms for therapeutic drug monitoring in patients with hypertension

Abstract: Objective: When using therapeutic drug monitoring for evaluating non-adherence, serum concentrations of drugs are related to the actual intake, but also to pharmacokinetic variability. We aimed to map CYP2D6 polymorphisms in treated hypertensive patients and assess implications for a previous classification of adherence. Metoprolol is predominantly metabolized by CYP2D6, and is the most commonly prescribed beta-blocker in our population. Reduced metabolism can lead to increased concentrations of this drug, potentially causing more side effects and erroneous evaluation of adherence. Design and method: In a multicenter study we mapped CYP2D6 polymorphisms retrospectively in 331 patients being prescribed at least 2 antihypertensive agents, already reported as adherent or non-adherent based on serum concentrations of antihypertensive drugs by mass-spectrometry (UPLC-MS/MS). The CYP2D6 panel included the non-functional variants (null) 2D6*3, 2D6*4, 2D6*5, 2D6*6, 2D6*13 and 2D6*68, and the reduced-functional variants (red) 2D6*9, 2D6*10 and 2D6*41. 2D6*2 or absence of the assayed variant alleles was interpreted as 2D6*1 (wild-type). Patients with *null/*null and absent enzyme activity were classified as poor metabolizers, and patients with *null/*wild-type or *null/*red and varied degree of reduced enzyme activity as intermediate metabolizers. Normal metabolizers included homozygote wildtype and *wildtype/*red. Patients with duplications of functional alleles, leading to increased enzyme activity, were classified as ultra-rapid metabolizers. Results: Based on genotype, 117 patients (35.3%) were intermediate-, 21 (6.3%) were poor- and 3 (0.9%) were ultra-rapid metabolizers, comparable to the European reference population. The low frequency of ultra-rapid metabolizers did not affect the classification of non-adherence. Serum concentrations of metoprolol were related to the CYP2D6 genotype. Some (perhaps 5–10%) non-adherent patients with absent or severely reduced enzyme activity may have been misclassified as adherent; with a higher serum concentration of metoprolol due to poor metabolism rather than excellent adherence. onclusions: In 331 hypertensive patients with a normal distribution of CYP2D6 polymorphisms, the genotype seemed to influence the serum concentration of metoprolol, but did not affect the classification of non-adherence. However, perhaps 5–10% of the non-adherent patients with reduced metabolism may have been misclassified as adherent.

Abstract P221: Cardiovascular Outcomes In Hypertensive Patients Who Discontinue Study Medication In A Large Outcome Trial. The Life Study.

Abstract: Objective: Patient discontinuation of study medication during a hypertension outcome trial has implications for study power. We aimed to assess patient characteristics and outcomes in patients with hypertension and left ventricular hypertrophy (LVH) who discontinued the study drug but otherwise remained in the study until the end of follow-up. Methods: In patients who discontinued vs. those continuing, Cox proportional hazards models identified baseline variables that had a significant impact on the occurrence of the primary composite endpoint (cardiovascular death, stroke, and myocardial infarction) in 9,193 hypertensive patients and LVH in the LIFE study. Results: During a mean follow-up of 4.8 years, 3,281 patients (35.7%) discontinued one or more days, not counting death as a reason for discontinuation. The distribution of days to discontinuation was highly skewed towards the first part of the study; the 25 th percentile was at day 161, and the median was at day 669. Reasons for discontinuation were a clinical adverse event (50%), a secondary study endpoint (19%), required study therapy (11%), withdrawal (2%), administrative (18%), and lost to follow-up (0.2%). Those who discontinued were older, more often male, had slightly lower body mass index, higher systolic and lower diastolic pressure, higher Framingham Risk Score (FRS), and more ECG LVH determined by either Cornell product or Sokolow-Lyon criteria. Patients randomized to losartan discontinued less than those randomized to atenolol. Multivariate analyses showed that older age, male gender, FRS, Sokolow-Lyon criteria, atenolol treatment as well as a history of pre-study myocardial infarction, cerebral vascular disease, peripheral vascular disease, and atrial fibrillation as well as lower levels of hemoglobin, higher serum creatinine and lower cholesterol independently predicted discontinuation. Conclusions: Patients discontinued during the first part of the study mainly due to a clinical adverse event. Patients who discontinued the study drug had, on average, more previous and concurrent cardiovascular disease than those who continued until the study ended. Thus, too high risk in an outcome study implies early drug discontinuation and thus reduction in the study power.