Jan Östergren

Use of ramipril in preventing stroke: double blind randomised trial

Abstract Objective: To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke. Design: Randomised controlled trial with 2×2 factorial design. Setting: 267 hospitals in 19 countries. Participants: 9297 patients with vascular disease or diabetes plus an additional risk factor, followed for 4.5 years as part of the HOPE study. Outcome measures: Stroke (confirmed by computed tomography or magnetic resonance imaging when available), transient ischaemic attack, and cognitive function. Blood pressure was recorded at entry to the study, after 2 years, and at the end of the study. Results: Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment. Conclusion: Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure. What is already known on this topic Treatment with aspirin and lowering blood pressure reduce the incidence of stroke What this study adds Ramipril, an angiotensin converting enzyme inhibitor, reduces strokes in patients at high risk whose blood pressure is not elevated, despite only a modest lowering of blood pressure The benefits are observed even when patients receive aspirin and other blood pressure lowering treatments

Mortality and Morbidity Reduction With Candesartan in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction Results of the CHARM Low-Left Ventricular Ejection Fraction Trials

Background—Patients with symptomatic chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) have a high risk of death and hospitalization for CHF deterioration despite therapies with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and even an aldosterone antagonist. To determine whether the angiotensin-receptor blocker (ARB) candesartan decreases cardiovascular mortality, morbidity, and all-cause mortality in patients with CHF and depressed LVEF, a prespecified analysis of the combined Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) low LVEF trials was performed. CHARM is a randomized, double-blind, placebo-controlled, multicenter, international trial program. Methods and Results—New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of ≤40% were randomized to candesartan or placebo in 2 complementary parallel trials (CHARM-Alternative, for patients who cannot tolerate ACE inhibitors, and CHARM-Added, for patients who were receiving ACE inhibitors). Mortality and morbidity were determined in 4576 low LVEF patients (2289 candesartan and 2287 placebo), titrated as tolerated to a target dose of 32 mg once daily, and observed for 2 to 4 years (median, 40 months). The primary outcome (time to first event by intention to treat) was cardiovascular death or CHF hospitalization for each trial, with all-cause mortality a secondary end point in the pooled analysis of the low LVEF trials. Of the patients in the candesartan group, 817 (35.7%) experienced cardiovascular death or a CHF hospitalization as compared with 944 (41.3%) in the placebo group (HR 0.82; 95% CI 0.74 to 0.90; P<0.001) with reduced risk for both cardiovascular deaths (521 [22.8%] versus 599 [26.2%]; HR 0.84 [95% CI 0.75 to 0.95]; P=0.005) and CHF hospitalizations (516 [22.5%] versus 642 [28.1%]; HR 0.76 [95% CI 0.68 to 0.85]; P<0.001). It is important to note that all-cause mortality also was significantly reduced by candesartan (642 [28.0%] versus 708 [31.0%]; HR 0.88 [95% CI 0.79 to 0.98]; P=0.018). No significant heterogeneity for the beneficial effects of candesartan was found across prespecified and subsequently identified subgroups including treatment with ACE inhibitors, β-blockers, an aldosterone antagonist, or their combinations. The study drug was discontinued because of adverse effects by 23.1% of patients in the candesartan group and 18.8% in the placebo group; the reasons included increased creatinine (7.1% versus 3.5%), hypotension (4.2% versus 2.1%), and hyperkalemia (2.8% versus 0.5%), respectively (all P<0.001). Conclusion—Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF ≤40% when added to standard therapies including ACE inhibitors, β-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.

Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program.

Background— We wished to determine the prevalence of, potential mechanistic associations of, and clinical outcomes related to anemia in patients with heart failure and a broad spectrum of left ventricular ejection fraction (LVEF). Methods and Results— In multivariable analyses, we examined the associations between hemoglobin and baseline characteristics, laboratory variables, and outcomes in 2653 patients randomized in the CHARM Program in the United States and Canada. Anemia was equally common in patients with preserved (27%) and reduced (25%) LVEF but was more common in black and older patients. Anemia was associated with ethnicity, diabetes, low body mass index, higher systolic and lower diastolic blood pressure, and recent heart failure hospitalization. More than 50% of anemic patients had a glomerular filtration rate <60 mL · min−1 · 1.73 m−2 compared with <30% of nonanemic patients. Despite an inverse relationship between hemoglobin and LVEF, anemia was associated with an increased risk of death and hospitalization, a relationship observed in patients with both reduced and preserved LVEF. There were 133 versus 69 deaths and 527 versus 352 hospitalizations per 1000 patient-years of follow-up in anemic versus nonanemic patients (both P<0.001). The effect of candesartan in reducing outcomes was independent of hemoglobin. Conclusions— Anemia was common in heart failure, regardless of LVEF. Lower hemoglobin was associated with higher LVEF yet was an independent predictor of adverse mortality and morbidity outcomes. In heart failure, the causes of anemia and the associations between anemia and outcomes are probably multiple and complex.

Sex Differences in Clinical Characteristics and Prognosis in a Broad Spectrum of Patients With Heart Failure Results of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Program

Background— We wished to test previous hypotheses that sex-related differences in mortality and morbidity may be due to differences in the cause of heart failure or in left ventricular ejection fraction (LVEF) by comparing fatal and nonfatal outcomes in women and men with heart failure and a broad spectrum of left ventricular ejection fraction. Methods and Results— We compared outcomes in 2400 women and 5199 men randomized in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program using multivariable regression analyses. A total of 1188 women (50%) had a low LVEF (≤0.40), and 1212 had a preserved LVEF (>0.40). Among the men, 3388 (65%) had a low LVEF, and 1811 had a preserved LVEF. A total of 1216 women (51%) and 3465 men (67%) had an ischemic cause of their heart failure. All-cause mortality was 21.5% in women and 25.3% in men (adjusted hazard ratio [HR], 0.77; 95% CI, 0.69 to 0.86; P<0.001). Fewer women (30.4%) than men (33.3%) experienced cardiovascular death or heart failure hospitalization (adjusted HR, 0.83; 95% CI, 0.76 to 0.91; P<0.001). The risks of sudden death (HR, 0.70; 95% CI, 0.58 to 0.85) and death due to worsening heart failure (HR, 0.72; 95% CI, 0.58 to 0.89) were reduced to a comparable extent. The adjusted risk of cardiovascular hospitalization was also lower in women (HR, 0.88; 95% CI, 0.82 to 0.95), mainly because of a reduced risk of heart failure hospitalization (HR, 0.87; 95% CI, 0.78 to 0.97). Women had a lower risk of death irrespective of cause of heart failure or LVEF. Conclusions— Among patients with heart failure, women have lower risks of most fatal and nonfatal outcomes that are not explained, as previously suggested, by LVEF or origin of the heart failure.

Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure—Assessment of Reduction in Mortality and morbidity (CHARM) programme

To describe the clinical characteristics and contemporary treatment of a broad spectrum of patients with chronic heart failure (CHF) randomised in the Candesartan in Heart failure—Assessment of Reduction in Mortality and morbidity (CHARM) programme, consisting of three component studies comparing placebo to candesartan.

Interruptions in emergency department work: an observational and interview study

Objective Frequent interruptions are assumed to have a negative effect on healthcare clinicians’ working memory that could result in risk for errors and hence threatening patient safety. The aim of this study was to explore interruptions occurring during common activities of clinicians working in emergency departments. Method Totally 18 clinicians, licensed practical nurses, registered nurses and medical doctors, at two Swedish emergency departments were observed during clinical work for 2 h each. A semistructured interview was conducted directly after the observation to explore their perceptions of interruptions. Data were analysed using non-parametric statistics, and by quantitative and qualitative content analysis. Results The interruption rate was 5.1 interruptions per hour. Most often the clinicians were exposed to interruptions during activities involving information exchange. Calculated as percentages of categorised performed activities, preparation of medication was the most interrupted activity (28.6%). Face-to-face interaction with a colleague was the most common way to be interrupted (51%). Most common places for interruptions to occur were the nurses’ and doctors’ stations (68%). Medical doctors were the profession interrupted most often and were more often recipients of interruptions induced by others than causing self-interruptions. Most (87%) of the interrupted activities were resumed. Clinicians often did not regard interruptions negatively. Negative perceptions were more likely when the interruptions were considered unnecessary or when they disturbed the work processes. Conclusions Clinicians were exposed to interruptions most often during information exchange. Relative to its occurrence, preparation of medication was the most common activity to be interrupted, which might increase risk for errors. Interruptions seemed to be perceived as something negative when related to disturbed work processes.

Plasma NT‐proBNP concentration is related to ambulatory pulse pressure in peripheral arterial disease

Background. Increased levels of N‐terminal prohormone brain natriuretic peptide (NT‐proBNP) are associated with left ventricular dysfunction (LVD) and left ventricular hypertrophy (LVH), but the relation of NT‐proBNP to ambulatory blood pressure (ABP) and hypertensive target organ damage in high‐risk patients with peripheral arterial disease (PAD) has not been studied. We hypothesized that NT‐proBNP levels were increased in patients with PAD in comparison to a matched control group and that levels of NT‐proBNP were related to ABP. Methods. Blood samples were analysed for NT‐proBNP in 103 males with PAD and 96 age‐ and sex‐matched controls. Ninety‐eight PAD patients performed ABP monitoring and 99 underwent Tc‐99m Sestamibi myocardial perfusion SPECT. Results. NT‐proBNP was significantly increased in PAD patients compared with controls [median (interquartiles)] 167(76, 418) vs 68(38, 142) pg/ml, p<0.001. Plasma levels of NT‐proBNP correlated positively to systolic blood pressure (SBP), pulse pressure (PP), night–day ratio of SBP and showed the strongest correlation to average night PP (r = 0.42, p<0.001). In multiple regression analysis, night PP remained independently related to NT‐proBNP. Conclusion. NT‐proBNP levels are markedly increased in PAD patients compared to age‐matched controls. Night PP is related to NT‐proBNP levels independently of other variables highlighting the importance of ambulatory PP as a cardiovascular risk factor. Measurement of NT‐proBNP could be indicated in PAD patients for further risk stratification.

Episodes of ST‐segment depression is related to changes in ambulatory blood pressure and heart rate in intermittent claudication

Abstract. Svensson P, Niklasson U, Östergren J (Karolinska Hospital, Stockholm, Sweden). Episodes of ST‐segment depression is related to changes in ambulatory blood pressure and heart rate in intermittent claudication. J Intern Med 2001; 250: 398–405.

Comparison of CNS-related subjective symptoms in hypertensive patients treated with either a new controlled release (CR/ZOK) formulation of metoprolol or atenolol

The present study evaluated and compared subjective symptoms in hypertensive patients (N = 83) at therapeutically comparable dosages of a new controlled release (CR/ZOK) formulation of metoprolol (100 mg od) and atenolol (50 mg od). The trial was a 4‐week randomized double‐blind study preceded by a placebo run‐in period. Blood pressure (BP) was recorded 24 hours after intake of last dose. In subpopulations, 24‐hour ambulatory BP was recorded and exercise tests performed. Subjective symptoms were evaluated with a previously documented questionnaire (MSE‐profile) which has been shown to be sensitive in detecting CNS‐related symptoms caused by beta blockers. The MSE‐profile includes three dimensions: Contentment, Vitality and Sleep.

Contributing factors to errors in Swedish emergency departments

OBJECTIVE The Emergency Department (ED) is a complex and dynamic environment, often resulting in a somewhat uncontrolled and unpredictable workload. Contributing factors to errors in health care and in the ED are largely related to communication breakdowns. Moreover, the ED work environment is predisposed to multitasking, overcrowding and interruptions. These factors are assumed to have a negative impact on patient safety. Reported errors from care providers are mainly related to diagnostic procedures in Swedish EDs. However, there is a lack of knowledge and national oversight regarding contributing factors. The aim of this study was therefore to describe contributing factors in regards to errors occurring in Swedish EDs. METHOD Descriptive design based on registry data from the Lex Maria database of the Swedish National Board of Health and Welfare. RESULTS The results indicate that factors contributing to errors in Swedish EDs are multifactorial in nature. The most common contributing factor was human error followed by factors in the local ED environment and teamwork failure. CONCLUSION Factors contributing to ED errors were multifactorial and included both organizational and teamwork failure in which human error was implicated. To reduce errors, further research is needed to develop methods that disclose latent working conditions such as high workload and interruptions. Patient safety research needs to include understanding of human behaviour in complex organizational systems and the impact of working conditions on patient safety and quality of care.