| 1. |
|
|
| 2. |
- Lumbers, R. T., et al.
(författare)
-
The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
-
Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
-
Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
|
|
| 3. |
- Dunham, I, et al.
(författare)
-
The DNA sequence of human chromosome 22
- 1999
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 402:6761, s. 489-495
-
Tidskriftsartikel (refereegranskat)
|
|
| 4. |
- Shah, S, et al.
(författare)
-
Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
-
Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
|
|
| 5. |
- Ariti, C. A., et al.
(författare)
-
Days alive and out of hospital and the patient journey in patients with heart failure: Insights from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program
- 2011
-
Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 162:5, s. 900-6
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Conventional composite outcomes in heart failure (HF) trials, for example, time to cardiovascular death or first HF hospitalization, have recognized limitations. We propose an alternative outcome, days alive and out of hospital (DAOH), which incorporates mortality and all hospitalizations into a single measure. A refinement, the patient journey, also uses functional status (New York Heart Association [NYHA] class) measured during follow-up. The CHARM program is used to illustrate the methodology. METHODS: CHARM randomized 7,599 patients with symptomatic HF to placebo or candesartan, with median follow-up of 38 months. We related DAOH and percent DAOH (ie, percentage of time spent alive and out of hospital) to treatment using linear regression adjusting for follow-up time. RESULTS: Mean increase in DAOH for patients on candesartan versus placebo was 24.1 days (95% CI 9.8-38.3 days, P < .001). The corresponding mean increase in percent DAOH was 2.0% (95% CI 0.8%-3.1%, P < .001). These findings were dominated by reduced mortality (23 days) but enhanced by reduced time in hospital (1 day). Percent time spent in hospital because of HF was reduced by 0.10% (95% CI 0.04%-0.14%, P < .001). The patient journey analysis showed that patients in the candesartan group spent more follow-up time in NYHA classes I and II and less in NYHA class IV. CONCLUSIONS: Days alive and out of hospital, especially percent DAOH, provide a valuable tool for summarizing the overall absolute treatment effect on mortality and morbidity. In future HF trials, percent DAOH can provide a useful alternative perspective on the effects of treatment.
|
|
| 6. |
- McMurray, J. J., et al.
(författare)
-
Relationship of dose of background angiotensin-converting enzyme inhibitor to the benefits of candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial
- 2006
-
Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 151:5, s. 985-91
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Whether an angiotensin receptor blocker is of benefit when added to a full dose of angiotensin-converting enzyme (ACE) inhibitor in heart failure (HF) is uncertain. METHODS: The effect of candesartan, compared with placebo, in 2548 patients randomized in the CHARM-Added trial was analyzed according to (i) ACE inhibitor dose at baseline, (ii) ACE inhibitor dose during follow-up, and (iii) combination treatment with ACE inhibitor and beta-blocker at baseline. The main outcome was the composite of cardiovascular death or HF hospitalization. RESULTS: The benefit of candesartan was not modified by the dose of ACE inhibitor. In all patients (n = 2548), the candesartan/placebo hazard ratio (HR) for the primary outcome was 0.85 (95% CI 0.75-0.96). In patients taking a guideline recommended dose of ACE inhibitor at baseline (n = 1291), this HR was 0.79 (95% CI 0.67-0.95; interaction P value .26). In patients taking a Food and Drug Administration-designated maximum dose of ACE inhibitor (n = 529), this HR was 0.75 (95% CI 0.57-0.98; interaction P value .29). The benefit of candesartan was preserved in patients taking beta-blockers in addition to a higher dose of ACE inhibitor and in patients maintaining a high dose of ACE inhibitor throughout follow-up. CONCLUSIONS: These clinical findings support the pharmacologic evidence that ACE inhibitors and angiotensin receptor blockers have distinct mechanisms of action and show that their combined use improves outcomes in patients with HF more than an evidence-based dose of ACE inhibitor alone.
|
|
| 7. |
- McMurray, J. J., et al.
(författare)
-
Resource utilization and costs in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme
- 2006
-
Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 27:12, s. 1447-58
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: More treatments are needed to improve clinical outcomes in chronic heart failure (HF). It is, however, important that treatments for a condition as common as HF are affordable. We have carried out a prospective economic analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. METHODS AND RESULTS: Patients with NYHA class II-IV HF and LVEF < or =0.40 were randomized to CHARM-Alternative if intolerant of an ACE-inhibitor or to CHARM-Added if taking an ACE-inhibitor. Patients with a LVEF >0.40 were randomized in CHARM-Preserved. Each trial compared the effect of candesartan to placebo on the primary outcome of cardiovascular death or HF hospitalization. Detailed information was prospectively collected on hospital admissions, procedures/operations and drugs. A cost-consequence analysis was performed for France, Germany and the UK for CHARM-Overall and a cost-effectiveness analysis for the low LVEF trials. The cost of candesartan was substantially offset by a reduction in hospital admissions, especially for HF. In the cost-consequence analysis, candesartan was cost-saving in most scenarios for CHARM-Alternative and Added but the marginal annual net cost per patient was upto 372 euros per year in CHARM-Preserved, in which candesartan did not reduce the primary outcome significantly. In the cost-effectiveness analysis of patients with a LVEF < or = 0.40, candesartan was cost-saving in some scenarios and in the others the maximum cost per life year gained was 3881 euros. CONCLUSION: Candesartan improves functional class, reduces the risk of hospital admission, and increases survival in patients with a HF and a LVEF < or =0.40 at an acceptable cost.
|
|
| 8. |
- O'Meara, E., et al.
(författare)
-
Patient perception of the effect of treatment with candesartan in heart failure. Results of the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) programme
- 2005
-
Ingår i: European journal of heart failure. - : Wiley. - 1388-9842. ; 7:4, s. 650-6
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: To evaluate the effect of the angiotensin receptor blocker candesartan on patients' perception of symptoms, using the McMaster Overall treatment evaluation (OTE), in a broad spectrum of patients with chronic heart failure (CHF). METHODS AND RESULTS: Patients with symptomatic CHF, randomised in the CHARM Programme in North America (n=2498), were studied. OTE was assessed at baseline, at 6, 14 and 26 months and the patient's final or closing visit. Patient's status was classified as "improved (score +1 to +7)", "unchanged (score 0)" or "deteriorated (score -1 to -7)" at the end of the study compared to baseline. Both a simple "last visit carried forward" (LVCF) analysis and "worst rank carried forward" (WRCF) analysis (where patients who died were allocated the worst OTE score) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (37.7% versus 33.5%) and fewer worsened (10.8% versus 12.0%) in OTE (p=0.017). The WRCF analysis also showed better overall OTE scores with candesartan compared to placebo (p=0.029). There was no heterogeneity in the response to candesartan between the CHARM component trials or across four exploratory sub-groups (age, sex, NYHA class and beta-blocker). CONCLUSIONS: Candesartan was shown to be better than placebo, when using the McMaster OTE to measure patient perception of treatment. More patients treated with candesartan reported improvement and fewer reported deterioration. This benefit was obtained when candesartan was added to extensive background therapy and is consistent with the benefits of candesartan on NYHA class, hospital admission for worsening heart failure and mortality.
|
|
| 9. |
- Pocock, S. J., et al.
(författare)
-
Weight loss and mortality risk in patients with chronic heart failure in the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) programme
- 2008
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 29:21, s. 2641-50
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: The curiosity that leanness is associated with poor survival in patients with chronic heart failure (CHF) needs further insight by investigating the impact of weight loss on prognosis in a large sample of patients across a broad spectrum of both reduced and preserved left ventricular (LV) systolic function. METHODS AND RESULTS: We investigated the change in weight over 6 months in 6933 patients in the Candesartan in Heart failure: Reduction in Mortality and morbidity (CHARM) programme, and its association with subsequent mortality (1435 deaths) over a median 32.9 months follow-up using Cox proportional hazard models to account for the impact of body mass index and other risk predictors. We then used time-updated Cox models to relate each patient's ongoing data on annual weight change to their mortality hazard. The percentage weight loss over 6 months had a highly significant monotonically increasing association with excess mortality, both for cardiovascular and for other causes of death. Patients with 5% or greater weight loss in 6 months had over a 50% increase in hazard compared with those with stable weight. Weight loss carried a particularly high risk in patients who were already lean at study entry. Findings were similar in the presence of dependent oedema, preserved or reduced LV ejection fraction, and treatment with candesartan, although weight loss was significantly less common on candesartan. The time-updated analyses revealed an even stronger link between weight loss and short-term risk of dying, i.e. risk increased more than four-fold for patients whose last recorded annual weight loss exceeded 10%. Weight gain had a more modestly increased short-term mortality risk. Weight loss accelerates in the year prior to death. CONCLUSIONS: Weight loss and leanness are important predictors of poor prognosis in CHF. Being lean and losing weight is particularly bad. The detection of weight change, and particularly weight loss, should be considered as an adverse sign prompting further evaluation.
|
|
| 10. |
- Rogers, J. K., et al.
(författare)
-
Analysing recurrent hospitalizations in heart failure: a review of statistical methodology, with application to CHARM-Preserved
- 2014
-
Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 16:1, s. 33-40
-
Tidskriftsartikel (refereegranskat)abstract
- Aims Heart failure is characterized by recurrent hospitalizations, but often only the first event is considered in clinical trial reports. In chronic diseases, such as heart failure, analysing all events gives a more complete picture of treatment benefit. We describe methods of analysing repeat hospitalizations, and illustrate their value in one major trial. Methods and results The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study compared candesartan with placebo in 3023 patients with heart failure and preserved systolic function. The heart failure hospitalization rates were 12.5 and 8.9 per 100 patient-years in the placebo and candesartan groups, respectively. The repeat hospitalizations were analysed using the Andersen-Gill, Poisson, and negative binomial methods. Death was incorporated into analyses by treating it as an additional event. The win ratio method and a method that jointly models hospitalizations and mortality were also considered. Using repeat events gave larger treatment benefits than time to first event analysis. The negative binomial method for the composite of recurrent heart failure hospitalizations and cardiovascular death gave a rate ratio of 0.75 [95% confidence interval (CI) 0.62-0.91, P = 0.003], whereas the hazard ratio for time to first heart failure hospitalization or cardiovascular death was 0.86 (95% CI 0.74-1.00, P = 0.050). Conclusions In patients with preserved EF, candesartan reduces the rate of admissions for worsening heart failure, to a greater extent than apparent from analysing only first hospitalizations. Recurrent events should be routinely incorporated into the analysis of future clinical trials in heart failure.
|
|
