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Background Estimated glomerular filtration rate (eGFR) is a key determinant of eligibility for many life-saving therapies in HFrEF. Recently, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) provided new equations based on creatinine (CKD-EPIcr), cystatin C (CKD-EPIcys) or both (CKD-EPIcyscr) that do not include race. These new equations may reclassify individuals, irrespective of race, from one eGFR category to another, with implications for eligibility for HFrEF treatments. Purpose To assess the difference between eGFR estimation using the 2021 CKD-EPIcyscr equation and the 2009 CKD-EPIcr and Modification of Diet in Renal Disease Study (MDRD)-4 equations which are still standard in many European laboratories. Methods We included patients from PARADIGM-HF with cystatin C and creatinine values available at the time of randomization. For each patient, baseline eGFRs were calculated using the 3 equations described. Our focus was on patients with chronic kidney disease (CKD) stages III–V. Results Overall, 1910 patients were eligible. Mean age was 67.3 (10.1) year and 385 (18.7%) were female. Using 2009 CKD-EPIcr, 779 patients were in CKD stages 3–5, of which 233 (30%) were reclassified to a better CKD stage (higher eGFR) with the 2021 CKD-EPIcyscr equation (Table 1). Similar reclassification was seen when comparing MDRD-4 with the 2021 CKD-EPIcyscr equation: 277 (33%) of 831 patients in CKD stages 3–5 were reclassified to a better CKD stage (Figure 1). Conclusions The 2021 CKD-EPIcyscr equation favourably reclassified CKD stage in a large percentage of patients with HFrEF and a low eGFR, potentially increasing the proportion of these patients considered eligible for guideline-recommended therapies. Funding Acknowledgement Type of funding sources: None.

Introduction Bilirubin is a recognized predictor of adverse outcomes in patients with heart failure and reduced ejection fraction (HFrEF), possibly because it is a marker of congestion. Alkaline phosphatase (ALP) is an enzyme produced in many tissues including the biliary ducts and elevated levels are also associated with congestion. Purpose To examine the prognostic value of ALP alone and in combination with bilirubin in patients with HFrEF. Methods The study population was ambulatory patients with HFrEF enrolled in 2 recent clinical trials with similar inclusion and exclusion criteria: ATMOSPHERE (derivation cohort) and PARADIGM-HF (validation). Cut points to define elevated bilirubin and alkaline phosphatase were >17mg/dL and >120 U/L respectively. The composite of cardiovascular death or HF hospitalization, its components, and all-cause death related to elevation of one, other or both of bilirubin and ALP was examined using Cox regression. Univariable and multivariable models with adjustment for other recognized prognostic variables including NT-proBNP were analyzed. Results Of 7016 patients with HFrEF enrolled in ATMOSPHERE, 6870 had a measurement of both bilirubin and ALP at baseline: mean age 63 years, 22% women, mean LVEF 28% and proportion NYHA class III/IV 37%. Bilirubin and ALP were both normal in 4810 (70.0%) patients, bilirubin was elevated in 1393 (20.3%), ALP was elevated in 360 (5.2%) and both were elevated in 307 (4.5%) patients. Patients with elevation of both ALP and bilirubin were older, had lower systolic blood pressure, higher heart rate, higher NT-pro BNP, more clinical features of congestion, more atrial fibrillation and a greater proportion were treated with diuretics and digoxin. The primary endpoint rates (per 100 person-years) were 10.4 (95% CI 9.9–11.0) when both markers were normal, 15.1 (13.9–16.4) when bilirubin was elevated, 12.4 (10.4–14.9) when alkaline phosphatase was elevated, and 25.6 (22.0–29.9) when both markers were elevated (Figure 1). The adjusted hazard ratios (95% CI) were (both biomarkers normal = reference): elevated bilirubin 1.19 (1.07–1.31), P=0.001; elevated ALP 1.03 (0.84–1.26), P=0.81; both elevated 1.45 (1.21–1.73), P Conclusions Elevation of ALP in combination with elevated bilirubin identifies a small group of patients at very high risk of adverse outcomes. This may reflect more significant congestion. ALP and bilirubin, inexpensive and routinely measured biochemical tests, are useful prognostic markers in patients with HFrEF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship.

Background Although multiple novel biomarkers have individually been shown to predict outcomes in patients with HFrEF, the value of these over and above conventional clinical and laboratory variables, plus natriuretic peptides, is uncertain. Purpose To test the incremental predictive value of 11 novel biomarkers added to a recent prognostic model 1 (PREDICT-HF) derived in PARADIGM-HF and validated in ATMOSPHERE and the Swedish heart failure registry. The PREDICT-HF model includes clinical variables, standard laboratory variables, and BNP or NT-proBNP. Methods 1559 participants enrolled in PARADIGM-HF had all 11 biomarkers of interest measured. These reflected different pathophysiological pathways: (i) myocyte injury (high sensitivity cardiac troponin T), (ii) cardiac remodelling and inflammation (growth stimulation expressed gene 2, growth differentiation factor-15 and galectin-3), (iii) extracellular matrix remodelling (matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1), (iv) neurohormonal pathways (aldosterone) and (v) renal dysfunction and injury (cystatin C, kidney injury molecule-1 and urinary albumin to creatinine ratio). The incremental prognostic value of these biomarkers was evaluated using Harrell's C statistic. Results The mean age of participants studied was 67.3 (SD 9.9) years, 1254 (80%) were men and 1103 (71%) were in NYHA class II. During a median follow-up of 31 months, 197 patients died and 300 experienced the primary composite outcome (cardiovascular death or heart failure hospitalization). When each candidate biomarker (log unit) was added individually to the PREDICT-HF base model, GDF-15, ST2, TIMP1, cystatin C, hsTnT and UACR were independent predictors of all-cause mortality (Table 1). GDF-15, TIMP1, hs-TnT and cystatin C consistently increased the risk of both all-cause mortality and the primary outcome. Individuals who had all 4 biomarkers elevated (compared to none elevated) had the highest risk: HR for all-cause mortality 3.65 (2.01–6.64), p Conclusion Several novel biomarkers provide meaningful additional prognostic information in patients with HFrEF. A multimarker approach incorporating biomarkers reflecting different pathophysiological pathways added most information. This approach may be useful in refining risk and targeting treatment. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The PARADIGM-HF trial was funded by Novartis.J.J.V.M is supported by a British Heart Foundation Centre of Excellence Grant

Background Anaemia is common in patients with HFrEF and is associated with poor clinical outcomes. Although they reduce rates of mortality and heart failure hospitalization, renin-angiotensin (RAS) blockers lower haemoglobin and may induce anaemia. Concomitant neprilysin inhibition might ameliorate this effect of RAS blockers. Purpose We investigated the effect of sacubitril/valsartan compared with enalapril on clinical outcomes, according to anaemia status, and on haemoglobin levels in PARADIGM-HF. Methods Patient characteristics and clinical outcomes were compared between patients with and without anaemia (defined as haemoglobin Results Of 8239 participants with a baseline haemoglobin measurement, 1677 (20.4%) were anaemic. Compared to those without anaemia, patients with anaemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement and worse clinical outcomes. Sacubitril/valsartan, compared to enalapril, reduced the risk of the primary endpoint similarly in patients with anaemia (HR 0.84, 95% CI 0.71–1.00) and without anaemia (HR 0.78, 95% CI 0.71–0.87), p-value for interaction=0.478. Between baseline and 12 months, haemoglobin decreased by 1.5 (95% CI 1.7 to 1.2) g/L with sacubitril/valsartan compared with 2.3 (2.6 to 2.0) g/L with enalapril group: mean difference 0.8 (95% CI 0.5 to 1.2) g/L, p Conclusions Compared to enalapril, sacubitril/valsartan reduced mortality and hospitalization in HFrEF patients with and without anaemia. Haemoglobin decreased less with sacubitril/valsartan and the incidence of new anaemia was lower in the sacubitril/valsartan group compared with the enalapril group. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): PARADIGM-HF was funded by Novartis.

Despite improvements in therapy, long-term mortality remains high in patients with heart failure and thus there remains a need for new treatment strategies to reduce the burden of mortality and morbidity associated with this condition. AT(1)-receptor blockers represent a rational approach to the management of heart failure, and have been shown to have beneficial effects on heart failure symptoms and exercise tolerance. However, the two outcome trials reported to date have not shown conclusive evidence of improvements in mortality. The potential benefits of AT(1)-receptor blockers in heart failure are currently being investigated in several trials. The CHARM programme (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) is the largest heart failure trial so far. This comprises three trials: CHARM Alternative, in patients with left ventricular dysfunction who are intolerant to ACE inhibitors; CHARM Added, in patients with left ventricular dysfunction who are also receiving ACE inhibitors; CHARM Preserved, in patients with preserved left ventricular systolic function (ejection fraction >40%). The primary end point will be a composite of cardiovascular mortality and hospitalisation for the treatment of heart failure. Other trials are currently investigating the effects of AT(1)-receptor blockers when used as an alternative or in addition to ACE inhibitors. The CHARM programme, together with other studies, should clarify the role of these agents in the management of heart failure.

This prospective cohort study measured the effect of implementing a person-centered approach to assessment and care planning on quality of life and incontinence care at three residential care facilities for older persons (N=79) in Sweden. Based on the Gothenburg University Center for Person-Centered Care model (Ekman et al 2015), the 10 week behavioral intervention engaged all staff and management. Resident outcomes of quality of life and continence care were measured at base-line, immediately after, and post-six months; staff outcomes included strain. Resident narratives of needs, preferences and earlier habits were recorded in care plans; nursing notes throughout the intervention were examined in relation to these foundational narratives for congruence. Results indicated a significant increase in tailored, individualized assessments for continence care (p

Treatment with angiotensin converting enzyme (ACE) inhibitors delays deterioration and improves survival in chronic congestive heart failure and left ventricular dysfunction. In two large placebo-controlled trials with survivors of acute myocardial infarction, but with left ventricular dysfunction, mortality was significantly lower in the ACE inhibitor arms, with risk reductions of 19% (with captopril) and 27% (with ramipril). A study of left ventricular dysfunction in more than 4000 patients resulted in significantly fewer myocardial infarctions among patients given enalapril than in those receiving placebo; the risk reduction was 24%. Knowledge of the degree of neurohormonal activation in patients with congestive heart failure (New York Heart Association [NYHA] Functional Class II-III) appears to be of major importance in determining the efficacy of ACE inhibition. Patients with plasma concentrations above normal show the greatest increase in survival when treated with ACE inhibitors compared to similarly treated patients with low or normal neurohormonal plasma levels as well as those treated with placebo or direct-acting vasodilators. In a study of 239 patients with NYHA Class IV heart failure, randomized to receive enalapril or placebo, mortality was significantly reduced in patients receiving enalapril who had plasma noradrenaline, adrenaline, angiotensin II, aldosterone, or atrial natriuretic peptide levels above median values. No significant differences in survival between groups were found in patients with hormone levels below the median. A study in 804 men with congestive heart failure who received either enalapril or hydralazine plus isosorbide dinitrate showed the greatest reduction in mortality after 2 years in enalapril treated patients with plasma noradrenaline levels > 900 pg.ml-1 or plasma renin levels > 16 ng.ml-1.h-1. These results indicate that the main rationale for ACE inhibition in chronic congestive heart failure, in left ventricular dysfunction, and after myocardial infarction is the modulation of prolonged neurohormonal activation. Knowledge of this effect may provide the means to forestall disease progression and thus offer long-term treatment benefits.

Static measurements of plasma neurohormones at rest may not be adequate to detect alterations in cardiovascular control mechanisms in congestive heart failure (CHF). Therefore, it is of interest to study neurohormonal activation during different physiological conditions. Plasma neurohormones were measured in 54 patients on diuretic therapy for mild or moderate CHF. Samples were taken at rest and immediately after maximal bicycle exercise, before and after 12 weeks of treatment with ramipril or placebo. There was a strong correlation between the plasma levels of each hormone before and after exercise. An inverse correlation existed at baseline between exercise duration and angiotensin II levels after maximal exercise (r = -0.30, P = 0.03), but not at rest. Plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide (ANP) and noradrenaline were increased after maximal exercise compared to rest. Plasma angiotensin converting enzyme activity and ANP were reduced by ramipril compared to placebo, both at rest and after exercise, but levels of angiotensin II, aldosterone and nordrenaline were not significantly affected. Thus, exercise consistently activates neurohormonal systems in patients with CHF. Patients with the lowest exercise duration had the highest angiotensin II levels after exercise. Measurements of plasma neurohormones after maximal exercise provide limited additional value to measurements at rest.

The objectives of exercise testing in congestive heart failure (CHF) may be summarized as follows: (a) detect impaired cardiac performance, (b) grade severity of cardiac failure and classify functional capability, and (c) assess effects of interventions. Several different methods are available to make these assessments, and we have to ask ourselves how well exercise testing achieves these objectives. It has to be kept in mind that the power generated by the exercising muscles is dependent on the oxygen delivery to the skeletal muscles. Oxygen uptake is the result of an integrated performance of the lungs, heart, and peripheral circulation. In patients, as well as in normal subjects, oxygen uptake is related to hemodynamic indices such as cardiac output, stroke volume, or exercise duration when a stepwise regulated maximal exercise protocol is used. However, there are major differences in the concept of a true maximum in normal subjects versus heart failure patients. Fit-normal subjects will achieve a real maximal oxygen uptake, whereas patients may stop testing before a maximum is reached because of symptoms such as dyspnea or leg fatigue. Therefore, it is better if the actual oxygen uptake can be measured. "Peak" rather than true maximal oxygen uptake has been suggested for the classification of the severity of heart failure. Peripheral factors modify the cardiac output through such factors as vascular resistance, organ function, and hormonal release. Maximal exercise will stress the cardiovascular system to a point where the weakest chain will impose a limiting effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Unstable angina pectoris is a common clinical problem, and the diagnosis is based on clinical symptoms. However, these symptoms cannot identify high-risk patients. Holter monitoring can identify patients at high risk, but analysis of a large number of patients is time- and resource-consuming, as is angiographic examination. We determined whether creatine kinase MB isoenzyme mass concentration could predict the prognosis for patients with unstable angina pectoris. A total of 101 consecutive patients were studied, and blood samples were collected three times a day for 48 h after admission. Patients with unstable angina and elevated CKMB (but still within the normal range) had a significantly higher risk of developing acute myocardial infarction or requiring revascularization during 6 months of follow-up than patients without elevated CKMB. We conclude that CKMB analysis is a valuable tool that may be of use in selecting high-risk patients with unstable angina pectoris. This finding needs to be confirmed by more extensive studies.

To assess the pharmacodynamics of moxonidine in patients with functional NYHA Class II-III congestive heart failure (CHF).A parallel population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed to assess the effect of moxonidine (0.1, 0.2, 0.3 mg twice daily) and placebo treatment on plasma noradrenaline (NA) levels, standing systolic blood pressure (SBP), and heart rate (HR) over 12 weeks in 97 patients with CHF using a parallel group design with dose escalation. A sequential analysis was also developed, where the relative changes in NA concentration were related to both SBP and HR.In the parallel PD analysis, an effect delay was shown for all three end points (NA, SBP, and HR). An inhibitory Emax model was used to characterize the concentration-effect relationships. For SBP and HR, the EC50 value increased over time. For NA, there was a positive baseline drift over the 12 weeks; this was interpreted as disease progression. Moxonidine delayed this increase by 9.8 weeks. For SBP, there was a circadian pattern at baseline. In the sequential PD analysis, the relationship between the drug response (NA) and SBP or HR was best described by an inhibitory Emax model. No effect delays between the response and effects were found.Effects of moxonidine on NA, SBP, and HR could be quantified by an effect compartment model in the presence of disease progression and circadian variations. Disease progression, as judged by increasing NA levels with time, was delayed by moxonidine. A direct relationship was found between NA and SBP/HR.

To evaluate the dose response relationship of moxonidine on plasma concentration of norepinephrine during acute and chronic administration in patients with congestive heart failure (CHF).Sympathetic activation is increased in heart failure. Moxonidine is an imidazoline ligand acting on the central nervous system (CNS) receptors to decrease sympathetic activation.Ninety-seven patients with heart failure and New York Heart Association class II-III symptoms and ejection fraction40% were randomized to placebo or one of three target doses of moxonidine, 0.1, 0.2 or 0.3 mg administered twice daily. An initial dose of moxonidine 0.1 mg twice a day (b.i.d.) was followed by weekly increments of 0.1 mg b.i.d. until target dose. The second and third study days occurred after four weeks (at target dose) and after 12 weeks, respectively. At each study day, repeated blood samples were drawn.There was a significant dose-related decrease of systolic blood pressure across all three study days. Heart rate decreased significantly on study day 3 in a dose-related manner. The acute 2 h decrease in plasma norepinephrine in response to all three doses of moxonidine was significantly different compared with placebo after four and 12 weeks. There was a significant linear relation between dose and plasma norepinephrine after four and 12 weeks in both 2 h peak and the time averaged effect (8 h). The number of adverse events was similar in the moxonidine and placebo groups.The increased sympathetic activation in CHF can be reduced by moxonidine through CNS inhibition.

To assess the efficacy of the Ikr-blocker almokalant attempting to convert chronic atrial tachyarrhythmias, and to find predictors of conversion, to sinus rhythm.The electrophysiological effects of a 6-hour infusion of almokalant, to a total dose of 25 +/- 4 mg, were assessed by ECG and transesophageal atrial electrograms (TAE) in 100 consecutive patients with atrial fibrillation/flutter (n = 95/5) of 8 +/- 12 months' duration (range 1 to 99 months).The conversion rate was 32%. The time to conversion was 3.5 +/- 2.2 hours. During infusion increases in QTtop (292 +/- 35 to 335 +/- 44 ms, p0.001, after 30 minutes), QT (387 +/- 40 to 446 +/- 60 ms, p0.001), corrected QT (425 +/- 30 to 487 +/- 44 ms, p0.001), and QT dispersion (21 +/- 12 to 29 +/- 31 ms, p = 0.02), were paralleled by decreases in T wave amplitude (0.31 +/- 0.19 to 0.23 +/- 0.16 mV, p0.001), and atrial rate (425 +/- 78 to 284 +/- 44 beats per minute (bpm) on ECG, and 396 +/- 72 to 309 +/- 44 bpm on TAE), with no differences between converters to sinus rhythm and non-converters. Patients with aberrantly conducted beats, and T wave variation, also increased. Calcium antagonists were more common among converters. A decreasing T wave amplitude predicted conversion. Four patients developed torsades de pointes.This study demonstrates class III action of almokalant, with a conversion rate of 32% of long-standing, chronic atrial tachyarrhytmias. An early decrease in T wave amplitude was associated with conversion to sinus rhythm.

Chronic heart failure (CHF) is an increasing burden to health care. Pharmacological treatment with angiotensin-converting enzyme (ACE) inhibitors and beta blockers improve survival and reduce hospitalizations in patients with low left ventricular ejection fraction (LVEF). Despite these therapies, morbidity and mortality remains problematic. Furthermore, 30% to 50% of patients with CHF have a preserved LVEF. It is not known if treatments are of benefit in this group.Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) is a program designed to investigate the clinical usefulness of the long-acting angiotensin II type 1 receptor blocker, candesartan cilexetil, in a broad spectrum of patients with symptomatic heart failure. Patients with systolic dysfunction, tolerant or intolerant to an ACE-inhibitor, and patients with preserved systolic function are included. Specifically, the CHARM program consists of 3 independent, parallel, placebo-controlled studies in patients with (1) LVEF less than or equal to 40%, ACE-inhibitor treated (n = 2,300); (2) LVEF less than or equal to 40%, ACE-inhibitor intolerant (n = 1,700); (3) LVEF greater than 40%, not treated with ACE inhibitors (n = 2,500). The 3 studies will be combined to evaluate the effect of candesartan cilexetil on all-cause mortality in the broad spectrum of symptomatic heart failure. The primary objective in each trial is to evaluate the effects on the combined endpoint of cardiovascular mortality or CHF hospitalization. Other endpoints include the effects on myocardial infarction, all-cause hospitalization, and resource utilization. CHARM is intended to randomize 6,500 patients with symptomatic heart failure from 26 countries in Europe, the United States, Canada, South Africa, and Australia. The CHARM program started to enroll patients in March 1999. The follow-up period is a minimum of 2 years. The study is expected to end in the third quarter of 2002.

Background: Previous reports suggest that patients with suspected heart failure are inadequately investigated and that patients who do have heart failure are sub-optimally treated. Guidelines on the diagnosis and treatment of heart failure have been published by the European Society of Cardiology and provide a framework for the management of heart failure against which to judge current medical practice. Both primary care and hospital physicians are responsible for ensuring appropriate management of patients with heart failure. This programme concentrates on management of heart failure in primary care and is complementary to a similar exercise that will be conducted in 50 European regions (EUROHEART-CHF). Aims: The IMPROVEMENT of HF initiative investigates, in Europe, how primary care physicians perceive heart failure should be diagnosed and treated and whether they perceive that they are provided with adequate support to implement best medical practice. Subsequently, their perceptions are compared to their actual practice by reviewing relevant case notes. The results will be used to recommend changes in practice. A future study is planned to analyse the impact of the initiative. Methods: The initiative comprises a research phase and an educational phase. For the research phase, 10 regional centres (to include both urban and rural areas) from each of 14 participating countries have been identified and each region has randomly selected 10 primary healthcare physicians. The primary healthcare physicians are participating in two surveys: a 'perception' survey and an 'actual practice' survey. For the 'actual practice' survey, the physicians are supplying case notes of nine patients who have or are at high risk of having heart failure. The results of these surveys will be used to organise an educational programme. Conclusion: This study is expected to provide valuable data on the perceptions of primary care physicians about heart failure, possible deficiencies in the current provision of care and how any deficiencies may be corrected. (C) 1999 Published by European Society of Cardiology. All rights reserved.

Analysis of plasma natriuretic peptides and related propeptide fragments may be a cost-effective aid to diagnostic evaluation and treatment follow-up in cases of heart failure. In diagnostic potential such variables may constitute first-line measures of high negative predictive value, allowing further examination, e.g. by echocardiography, in cases where values are above the respective cut-off levels. However, in many cases evaluation of published reports is rendered difficult by their omission of information on such pre-analytical variables as blood sampling and storage, and drug therapy. Moreover, different analytical methods may yield widely divergent results. Thus, before such assays are introduced in general use, their long-term validity needs to be ensured, for instance by consistency in calibration, and measurements need to be made in representative series of unselected patients for the determination of appropriate cut-off levels.

Quality of life in heart failure patients is receiving increased attention as a reflection of a treatment's potential secondary benefit of general well-being and daily functioning. The Metoprolol in Dilated Cardiomyopathy (MDC) trial was conducted as a large, multicenter trial to establish the effects of metoprolol on mortality and need for heart transplantation in patients with symptomatic idiopathic cardiomyopathy. It was found that metoprolol was well tolerated, improved symptoms and cardiac function, and prevented clinical deterioration in patients with symptomatic idiopathic dilated cardiomyopathy. Quality of life was evaluated as a secondary endpoint in 345 out of 383 randomized patients using a disease-specific questionnaire, the Quality of Life in Heart Failure Questionnaire, depicting physical activity, somatic symptoms, emotions, and life satisfaction. In a comparison of patients treated with metoprolol or placebo, patients treated with metoprolol noted a significantly more favorable response than those treated with placebo in terms of the overall treatment evaluation (p0.05). Additionally, an analysis of the changes from baseline to 18 months, using 95% confidence intervals, revealed that patients treated with metoprolol showed a significant improvement from baseline to 18 months in life satisfaction, physical activity, and the total score, while patients treated with placebo did not change at all. The improvement in quality of life was supported by the correlations with improvement in traditional clinical parameters.

The assessment of quality of life (QoL) has become recognized as an important tool for evaluating heart failure therapy. The angiotensin-converting enzyme inhibitor ramipril (mean dose 8 mg) was evaluated in 223 patients with moderate chronic congestive heart failure at 24 centers in 4 Nordic countries following a randomized, double-blind, placebo-controlled, parallel group design. The follow-up period was 12 weeks. QoL was evaluated using a questionnaire with 47 items, including the disease-specific Severe Heart Failure Questionnaire, the Sleep Dysfunction Scale, and the Psychological General Well-Being Index. In both treatment groups the total score increased from baseline to 12 weeks for both the Severe Heart Failure Questionnaire and for the Psychological Well-Being Index, reflecting relief of symptoms and improved well-being. However, no significant differences between the placebo and ramipril groups could be detected. Only a trend toward improvement in sleep on ramipril compared with placebo therapy was observed. In conclusion, in this placebo-controlled trial no significant effects of 12-week ramipril treatment of QoL could be demonstrated in patients with moderate congestive heart failure.

Studies in patients with moderate heart failure have shown a positive relation between atrial size and plasma atrial natriuretic peptide (ANP)(99-126) concentrations; however, the relation of the hormone level and left atrial size and left ventricular function in patients with severe chronic heart failure has not been determined. Fifty-three patients from the Cooperative North Scandinavian Enalapril Survival Study with severe chronic heart failure were evaluated with M-mode echocardiography and determination of plasma concentrations of ANP(99-126). In 35 patients, the plasma level of N-terminal ANP(1-98) was also measured. A significant negative relation was found between ANP(1-98), ANP(99-126), and left atrial diameter (r = -.28, P = .05 and r = -.41, P.005, respectively). Plasma concentrations of both ANP(1-98) and ANP(99-126) were related to left ventricular systolic function as determined by the systolic time interval index (r = .4, P.05 and r = .29, P.05, respectively). A significant improvement of left ventricular systolic function was found in the enalapril group but not in the placebo group. After 6 weeks of therapy, no correlation was found between changes in left atrial size or systolic function or changes in either the ANP(1-98) or ANP(99-126) concentration. The results indicate that high ANP(1-98) or ANP(99-126) plasma concentration is determined by the depressed left ventricular function rather than increased left atrial size in patients with chronic severe heart failure. The findings suggest that the ANP release relation to atrial pressure/atrial size is distorted in severe heart failure.

Seventy-nine patients with stable chronic congestive heart failure were randomized into a double-blind, crossover placebo controlled study with 3-month treatment periods, where either 100 mg coenzyme Q10 (CoQ10) or placebo was added to conventional therapy. Mean patient age was 61 +/- 10 years, ejection fraction at rest was 22% +/- 10%, and maximal exercise tolerance was 91 +/- 30 W. The follow-up examinations included ejection fraction (primary objective), exercise test, and quality of life questions. Ejection fraction at rest, during a slight volume load, and during a submaximal supine exercise increased slightly compared with placebo: 24% +/- 12% versus 23% +/- 12% (NS), 25% +/- 13% versus 23% +/- 12% (P.05), and 23% +/- 11% versus 22% +/- 11% (NS). Maximal exercise capacity increased from 94 +/- 31 W during the placebo period to 100 +/- 34 W during the CoQ10 period (P.05). Total score for the quality of life assessment increased significantly from 107 +/- 23 during the placebo period to 113 +/- 22 during the CoQ10 period (P.05). The results indicate that oral long-term treatment with 100 mg CoQ10 in patients with congestive heart failure only slightly improves maximal exercise capacity and the quality of life and that the clinical importance of this needs to be further evaluated.

Pharmacological therapy in cases of chronic congestive heart failure (CHF) is usually evaluated by maximal exercise time. To assess the effect of an angiotensin converting enzyme inhibitor, ramipril, 223 patients with moderate CHF were studied in 24 centres in four Nordic countries in a randomized, double-blind, placebo-controlled, parallel group design. The study drug was titrated from 1.25 mg to a maximum of 10 mg once daily (o.d) over a period of 4 weeks (mean dose 8 mg). A symptom-limited bicycle exercise test, starting at 30 watts and increasing by 10 watts.min-1, was used to evaluate exercise capacity. Reproducible tests were required at baseline, and the test was repeated after 4, 8 and 12 weeks of treatment. Seven deaths were recorded in the placebo group and one death in the ramipril group. A total of 195 patients completed 12 weeks of treatment (placebo group n = 91, ramipril group n = 104). The groups had similar baseline characteristics. Maximal exercise time was increased by mean (SD) 35 s (9) and 41 s (8) in the placebo and ramipril groups, respectively. The adjusted difference between the groups at 12 weeks was 9 s (12) (ns). A significant decrease in blood pressure and rate-pressure product at rest and at end of exercise was obtained by ramipril as compared with placebo. Significantly fewer patients deteriorated in NYHA class from baseline to 12 weeks of ramipril treatment compared to placebo (P = 0.012). Concomitant medication for CHF increased significantly in the placebo group as compared with ramipril-treated patients (P = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of angiotensin converting enzyme (ACE) inhibitors on mortality following acute myocardial infarction (MI) has recently been studied in several clinical trials. The rationale for the use of these drugs following an injury to the myocardium is largely based on their ability to attenuate left ventricular volume expansion and modulate neurohormonal activation. Left ventricular dilatation following MI is due to complex structural changes in the infarcted myocardium as well as alterations in the non-infarcted contractile myocardium. The magnitude of this remodelling is associated with adverse prognosis. Neurohormonal systems are activated in the early phase of acute MI. Prolonged neurohormonal activation mainly occurs among patients with marked left ventricular dysfunction. The CONSENSUS II trial examined the effects on mortality of the ACE inhibitor enalapril, when initiated within 24 h from the onset of the infarct and continued for 6 months. There were 6090 patients randomly assigned to placebo (n = 3046) or enalapril (n = 3044). At the end of the trial, 598 patients had died: 286 (9.4%) in the placebo group and 312 (10.2%) in the enalapril group (P = 0.26). These results are in contrast to some other studies in which mortality was reduced by ACE inhibitor therapy post-MI. It is considered likely that the positive effects of ACE inhibitors following MI are confined mainly to patients with marked left ventricular dysfunction and prolonged neurohormonal activation.

Forty-two patients with congestive heart failure were studied in order to clarify whether the plasma level of neuropeptide Y-like immunoreactivity (NPY-LI) rises in parallel with plasma noradrenaline (NA) during physical exercise in congestive heart failure (CHF). All patients were studied in a randomized placebo-controlled trial with the ACE-inhibitor ramipril during 12 weeks to determine whether ACE-inhibition alters the response of plasma NPY-LI to exercise. The patients were treated with diuretics and had stable congestive heart failure (NYHA classes II-III). Plasma NPY-LI was 50 +/- 5 pmol l-1 (mean +/- standard error of the mean) at rest and 60 +/- 6 pmol l-1 at the end of exercise at baseline (P < 0.01). The corresponding values for plasma NA were 2.8 +/- 0.2 nmol l-1 and 15.3 +/- 1.2 nmol l-1 (P < 0.001). Before ACE-inhibition, there was a correlation between high NPY-LI and NA values after exercise. After treatment with ramipril or placebo for 12 weeks, there was no difference in plasma NPY-LI and NA at rest or after exercise between the two treatment groups. The maximal exercise time was unchanged. It is concluded that plasma NPY-LI and NA were elevated at rest in CHF. The additional rise of plasma NPY-LI and NA after exercise was attenuated in CHF compared to healthy individuals. ACE-inhibition with ramipril did not alter plasma NPY-LI or NA at rest or after exercise compared to placebo.

Women have a higher short-term mortality in acute myocardial infarction (MI) compared with men. This may be partly explained by differences in risk factors such as age and diabetes. However, several reports have focused on the occurrence of a sex bias making women less likely to be subjected to angiography and revascularization as well as aggressive pharmacologic treatment of acute MI. The decision to initiate these procedures is often based on ischemic changes of the electrocardiogram. It was therefore investigated whether differences between men and women in magnitude of electrocardiographic changes during myocardial ischemia could explain some of the differences previously reported. A total of 178 patients with chest pain suggestive of MI (135 men and 43 women) included in a study of thrombolytics were monitored for 24 hours with continuous vectorcardiography. Also, 81 patients with stable angina pectoris undergoing elective angioplasty were monitored during the procedure. In patients admitted with suspicion of MI, the initial summated ST deviation was 178 +/- 146 microV for men as compared with 105 +/- 91 microV for women (P = .002). During angioplasty, men had significantly more pronounced maximum ST deviation during inflation of the balloon (235 +/- 165 vs 156 +/- 89 microV; P = .036). In conclusion, men have more pronounced ST changes than women during myocardial ischemia. When fixed magnitudes of ST deviation are required for initiating therapy such as thrombolytics, this will favor treatment of men. A sex-adjusted limit for administrating thrombolytic drugs may be warranted in the light of the above findings.

Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy. Our large multicentre study aimed to find out whether metoprolol improves overall survival and morbidity in this disorder. 383 subjects with heart failure from idiopathic dilated cardiomyopathy (ejection fraction0.40) were randomly assigned placebo or metoprolol. 94% were in New York Heart Association functional classes II and III, and 80% were receiving background treatment. A test dose of metoprolol (5 mg twice daily) was given for 2-7 days; those tolerating this dose (96%) entered randomisation. Study medication was increased slowly from 10 mg to 100-150 mg daily. There were 34% (95% CI -6 to 62%, p = 0.058) fewer primary endpoints in the metoprolol than the placebo group; 2 and 19 patients, respectively, deteriorated to the point of needing transplantation and 23 and 19 died. The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo (0.13 vs 0.06, p0.0001). Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo (5 vs 2 mm Hg, p = 0.06). Exercise time at 12 months was significantly greater (p = 0.046) in metoprolol-treated than in placebo-treated patients. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol prevented clinical deterioration, improved symptoms and cardiac function, and was well tolerated.

All surviving patients in a double-blind study comparing the effects of enalapril and placebo on survival in severe congestive heart failure were recommended to be treated with active drug after stopping the trial. Two-year follow-up from the end of the blinded trial demonstrated that among 77 survivors of 127 patients originally allocated to the group with enalapril, 38 were still alive. Of 126 patients allocated to the group with placebo 58 survived the blinded study, and after 2-year follow-up 26 were still alive. Thus, the difference between the original treatment groups remained, despite that treatment with enalapril was made available to all surviving patients and that those in the group with enalapril were sicker at baseline than those in the group with placebo. If enalapril was prescribed, the mortality was 47% compared with 75% if it was not. Life-table analysis suggests a marked carry-over effect of treatment in the group with enalapril that lasted for up to 15 months before mortality rates became comparable in the 2 treatment groups. This strongly suggests that enalapril confers structural protection to the failing myocardium.

Changes of the QRS complex are the electrocardiographic expression of irreversible injury of the myocardium. In humans, the process of infarction occurs over several hours. A more rapid development of QRS changes has been reported in patients treated with thrombolytic agents. Patients with strongly suspected acute myocardial infarction (AMI) included in a placebo-controlled trial of 100 mg of recombinant tissue-type plasminogen activator (rt-PA) were monitored for 24 hours with continuous, on-line vectorcardiography. The magnitude of the QRS vector changes correlated with infarct size estimated by the maximal value of lactate dehydrogenase-1 (r = 0.69, p less than 0.001) as well as with left ventricular ejection fraction 30 days after randomization (r = 0.49, p less than 0.001). Treatment with intravenous rt-PA limited total QRS vector change but the QRS vector changes observed occurred more rapidly and reached a plateau 131 minutes earlier in patients treated with rt-PA than in those receiving placebo (p less than 0.01). A certain pattern of highly variable ST vector magnitude was identified and was associated with higher maximal lactate dehydrogenase-1 values (23 +/- 13 vs 14 +/- 10 mu kat/liter, p less than 0.001) and a tendency to higher 1-year mortality (24 vs 9%, p = 0.08) than in patients without this pattern. In patients with this pattern, rt-PA did not affect maximal lactate dehydrogenase-1, time to maximal creatine kinase and final magnitude of QRS vector change.

We randomized 352 patients with suspected acute myocardial infarction (AMI) to treatment with rt-PA (n = 177) or placebo (n = 175). Patients were eligible if evaluated within 2 h and 45 min from onset of chest pain, and if aged less than 75 years. There were no ECG criteria for inclusion. A mobile coronary-care unit with a cardiologist present was used to initiate treatment at home in 29% of cases. During 1 year of follow-up the mortality in patients treated with rt-PA was 10.2%, as compared with 14.3% in patients the initial ECG, the mortality during the first year was 8% in the rt-PA group vs. 18% in the placebo group (P less than 0.05). Among patients without ST-elevation the mortality was 9% for the rt-PA group vs. 12% for the placebo group (NS). Requirement for rehospitalization, symptoms of angina pectoris and congestive heart failure, time of return to work and requirement for various medications did not differ significantly between the two groups, regardless of the initial ECG pattern.

The long-term prognosis in severe congestive heart failure is very poor. Therapeutic regimens, in order to improve prognosis, should directly or indirectly influence the compensatory systems that are activated, ACE-inhibitor therapy has emerged as an important regimen in this context. In the CONSENSUS-trial (3), we could demonstrate that the addition of enalapril to conventional therapy in severe CHF significantly improved survival. The experience from this study forms the background for the recommendations in this work. 253 patients with severe heart failure (New York Heart Association (NYHA) Classification functional class IV) were randomized at 35 Scandinavian centers to placebo (n = 126) or enalapril (n = 127), in addition to their conventional therapy. The treatment dose of enalapril varied between 2.5 and 40 mg daily (man 18.3 mg). Blood samples for measurement of serum electrolytes and serum creatinine were taken repeatedly during follow-up. There seems to be about a 10% increase in creatinine within 2 weeks of initiating enalapril therapy. This increase seems to be independent of baseline creatinine level. Adverse experience regarding serum creatinine was reported in 22 placebo-treated patients and in 51 patients in the enalapril group. This reporting was based upon the investigators' feelings of significant importance of the observation and not on symptomatology. This was the main reason for permanent withdrawal in 2 and 7 patients, respectively. During initiation of enalapril therapy the blood pressure response is important after the very first dose, but for renal function the response may not appear until several days later. However, in most patients there are no problems with starting enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

In a randomized, double-blind study, rt-PA vs. placebo treatment in early suspected acute myocardial infarction (AMI) was evaluated in patients both in hospital and prehospitally. The inclusion criteria were as follows: (a) age less than 75 years; and (b) chest pain indicative of AMI, of no longer than 2.75 h duration before first examination. In the prehospital setting a mobile coronary-care unit, accompanied by a cardiologist, was sent out by the ambulance services to 350 patients, of whom 205 (59%) were classified as non-eligible when examined by the cardiologist. Of the 145 patients who fulfilled the inclusion criteria, 44 were excluded due to contraindications to thrombolytic treatment. Thus 101 patients were randomized to blinded treatment outside hospital. The median time interval between onset of pain and treatment was 75 min, 45 min less than for those subjects who were randomized in hospital. The prevalence of confirmed AMI was 42% in the prehospital group, compared to 66% in the hospital group. Bleeding and cardiac complications for prehospital treatment were few, and similar to those for hospital treatment. In conclusion, prehospital thrombolysis was feasible, and delay times prior to treatment were significantly reduced. However, the specificity and diagnostic accuracy were lower than those achieved with in-hospital therapy.

In 319 patients who participated in a double-blind trial to evaluate the effect of early rt-PA administration compared to placebo in suspected acute myocardial infarction, infarct size was assessed from analyses of serum activity of lactate dehydrogenase isoenzyme 1 (LD 1). Treatment was always started less than 3 h after the onset of symptoms, with one-third of the patients' treatment being initiated outside the hospital. The maximum activity of LD 1 was reduced by 32%, from 13.3 mu kat l-1 in placebo to 9.0 mu kat l-1 in rt-PA treated patients (P = 0.001). A reduction in LD-1 activity after rt-PA treatment was restricted to patients with ST-elevation in the initial electrocardiogram, and was more pronounced in patients with previous ischaemic heart disease, above median age, and in those with a shorter delay in initiation of treatment. We conclude that very early intravenous treatment with rt-PA limits indirect signs of infarct size. The effect appears to be restricted to patients with ST-segment elevation in their initial electrocardiogram.

Independent trials of early administration of beta-blockers and thrombolytic agents have shown beneficial effects on both short- and long-term prognoses in acute myocardial infarction (AMI). The effects of a combination of the two strategies have not been thoroughly documented. Three hundred and fifty-two patients, of less than 75 years of age, with chest pain indicative of AMI, and onset less than 2 h and 45 min before first examination, were randomized to treatment with rt-PA or placebo. All patients without contraindication were given intravenous metoprolol 15 mg acutely and then 200 mg orally daily. Treatment was started either at the prehospital stage or in hospital. Thirty-seven per cent of patients had contraindications to beta-blockade, the most frequent of which were heart rate less than 60 beats min-1 and hypotension. The remaining 63% were given intravenous beta-blockade. No side-effects of metoprolol, alone or in combination with rt-PA, were observed during the prehospital phase. Overall, toleration of the treatment was good. Reduction in enzymatically estimated infarct size by rt-PA was more pronounced in patients who were also treated with metoprolol (41%, P less than 0.001) than in those with contraindications to beta-blockade (15%, NS). Patients who were also treated with metoprolol also had a lower incidence of Q-wave infarctions, congestive heart failure and ventricular fibrillation than those who were not given intravenous beta-blockade. In conclusion, toleration of intravenous administration of rt-PA and metoprolol was good, and this was also the case in the prehospital phase.(ABSTRACT TRUNCATED AT 250 WORDS)