Genetic polymorphisms and laboratory variables as predictors of blood pressure response to antihypertensive drugs

Hypertension is one of the major risk factors for cardiovascular morbidity. The advantages of antihypertensive therapy have been clearly demonstrated, but only about 30% of hypertensive patients have their blood pressure (BP) controlled by such treatment. One of the reasons for this poor BP control may lie in the difficulty in predicting BP response to antihypertensive treatment. The average BP reduction achieved is similar for each drug in the main classes of antihypertensive agents, but there is a marked individual variation in BP responses to any given drug. The purpose of the present study was to examine BP response to four different antihypertensive monotherapies with regard to demographic characteristics, laboratory test results and common genetic polymorphisms. The subjects of the present study are participants in the pharmacogenetic GENRES Study. A total of 208 subjects completed the whole study protocol including four drug treatment periods of four weeks, separated by four-week placebo periods. The study drugs were amlodipine, bisoprolol, hydrochlorothiazide and losartan. Both office (OBP) and 24-hour ambulatory blood pressure (ABP) measurements were carried out. BP response to study drugs were related to basic clinical characteristics, pretreatment laboratory test results and common polymorphisms in genes coding for components of the renin-angiotensin system, alpha-adducin (ADD1), beta1-adrenergic receptor (ADRB1) and beta2-adrenergic receptor (ADRB2). Age was positively correlated with BP responses to amlodipine and with OBP and systolic ABP responses to hydrochlorothiazide, while body mass index was negatively correlated with ABP responses to amlodipine. Of the laboratory test results, plasma renin activity (PRA) correlated positively with BP responses to losartan, with ABP responses to bisoprolol, and negatively with ABP responses to hydrochlorothiazide. Uniquely to this study, it was found that serum total calcium level was negatively correlated with BP responses to amlodipine, whilst serum total cholesterol level was negatively correlated with ABP responses to amlodipine. There were no significant associations of angiotensin II type I receptor 1166A/C, angiotensin converting enzyme I/D, angiotensinogen Met235Thr, ADD1 Gly460Trp, ADRB1 Ser49Gly and Gly389Arg and ADRB2 Arg16Gly and Gln27Glu polymorphisms with BP responses to the study drugs. In conclusion, this study confirmed the relationship between pretreatment PRA levels and response to three classes of antihypertensive drugs. This study is the first to note a significant inverse relation between serum calcium level and responsiveness to a calcium channel blocker. However, this study could not replicate the observations that common polymorphisms in angiotensin II type I receptor, angiotensin converting enzyme, angiotensinogen, ADD1, ADRB1, or ADRB2 genes can predict BP response to antihypertensive drugs.Kohonnut verenpaine on yksi merkittävimmistä sydän- ja verisuonisairauksien riskitekijöistä. Verenpainelääkityksen hyödyt on hyvin osoitettu, mutta vain noin 30 % verenpainetautia sairastavista potilaista saavuttaa asetut hoidon tavoitteet. Vaikka keskimääräinen verenpainetta alentava teho eri verenpainelääkeryhmien välillä on samankaltainen, niiden tehossa on merkittävää yksilöllistä vaihtelua, mikä saattaa olla yksi syy huonoon verenpainetaudin hoitotulokseen. Tämän tutkimuksen tavoitteena oli selvittää yksilöllisten ominaisuuksien, laboratoriotestitulosten ja yleisesti esiintyvän geneettisen vaihtelun vaikutusta neljän eri verenpainelääkkeen verenpainetta alentavaan tehoon. Tutkimusaineisto koostuu verenpainetautia sairastavista miehistä, jotka ottivat osaa farmakogeneettiseen GENRES-tutkimukseen. 208 tutkimuspotilasta kävi läpi kahdeksan kuukauden mittaisen tutkimusprotokollan sisältäen neljä neljän viikon lääkejaksoa erotettuna neljän viikon lumelääkejaksoilla. Tutkimuslääkkeet olivat amlodipiini, bisoprololi, hydroklooritiatsidi ja losartaani. Verenpainelääkkeiden vasteita tutkittiin suhteessa yksilöllisiin ominaisuuksiin, laboratoriotestituloksiin ja tunnettuun vaihteluun reniini-angiotensiini-aldosteronijärjestelmän osien, alfa-addusiinin ja beeta-adrenergisten reseptoreiden geeneissä. Tutkimuksessa havaittiin, että amlodipiini ja hydroklooritiatsidi laskivat verenpainetta tehokkaammin iäkkäämmillä kuin nuoremmilla potilailla ja että korkeampi painoindeksi ennusti heikompaa vastetta amlodipiinille. Laboratoriokokeista havaittiin, että losartaani ja bisoprololi tehosivat parhaiten potilailla, joilla oli korkea plasman reniinin aktiivisuus ja hydroklooritiatsidi tehosi parhaiten potilailla, joilla oli matala reniinin aktiivisuus. Lisäksi uutena löydöksenä havaittiin, että korkea seerumin kalsiumin ja kolesterolin taso heikensivät amlodipiinin verenpainetta laskevaa vaikutusta. Vaihtelu reniini-angiotensiini-aldosteronijärjestelmän osien, alfa-addusiinin ja beeta-adrenergisten reseptoreiden geeneissä ei merkittävällä tavalla vaikuttanut verenpainelääkevasteisiin. Yhteenvetona väitöskirjatyön tuloksista voidaan todeta, että tutkimus vahvisti aiemmat havainnot plasman reniinin aktiivisuuden suhteesta kolmen verenpainelääkkeen verenpainetta alentavaan tehoon. Uutena löydöksenä havaittiin käänteinen suhde seerumin kalsiumin tason ja amlodipiinin verenpainetta alentavan tehon välillä. Tutkimuksen perusteella tunnetut reniini-angiotensiini-aldosteronijärjestelmän osien, alfa-addusiinin ja beeta-adrenergisten reseptoreiden geenien vaihtelut eivät ennusta verenpainevastetta neljälle yleisesti käytetylle verenpainelääkkeelle

Erfarenheter av idarucizumab, en antidot mot den direkta antikoagulansen dabigatran

English summary

Cardiopulmonary resuscitation in adults over 80 : outcome and the perception of appropriateness by clinicians

OBJECTIVES: To determine the prevalence of clinician perception of inappropriate cardiopulmonary resuscitation (CPR) regarding the last out‐of‐hospital cardiac arrest (OHCA) encountered in an adult 80 years or older and its relationship to patient outcome. DESIGN: Subanalysis of an international multicenter cross‐sectional survey (REAPPROPRIATE). SETTING: Out‐of‐hospital CPR attempts registered in Europe, Israel, Japan, and the United States in adults 80 years or older. PARTICIPANTS: A total of 611 clinicians of whom 176 (28.8%) were doctors, 123 (20.1%) were nurses, and 312 (51.1%) were emergency medical technicians/paramedics. RESULTS AND MEASUREMENTS: The last CPR attempt among patients 80 years or older was perceived as appropriate by 320 (52.4%) of the clinicians; 178 (29.1%) were uncertain about the appropriateness, and 113 (18.5%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the “appropriate” subgroup was 8 of 265 (3.0%), 1 of 164 (.6%) in the “uncertain” subgroup, and 2 of 107 (1.9%) in the “inappropriate” subgroup (P = .23); 503 of 564 (89.2%) CPR attempts involved non‐shockable rhythms. CPR attempts in nursing homes accounted for 124 of 590 (21.0%) of the patients and were perceived as appropriate by 44 (35.5%) of the clinicians; 45 (36.3%) were uncertain about the appropriateness; and 35 (28.2%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the nursing home patients was 0 of 107 (0%); 104 of 111 (93.7%) CPR attempts involved non‐shockable rhythms. Overall, 36 of 543 (6.6%) CPR attempts were undertaken despite a known written do not attempt resuscitation decision; 14 of 36 (38.9%) clinicians considered this appropriate, 9 of 36 (25.0%) were uncertain about its appropriateness, and 13 of 36 (36.1%) considered this inappropriate. CONCLUSION: Our findings show that despite generally poor outcomes for older patients undergoing CPR, many emergency clinicians do not consider these attempts at resuscitation to be inappropriate. A professional and societal debate is urgently needed to ensure that first we do not harm older patients by futile CPR attempts. J Am Geriatr Soc 68:39–45, 201