| 1. |
- Young, J. B., et al.
(författare)
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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
- 2004
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Ingår i: Circulation. - 1524-4539. ; 110:17, s. 2618-26
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Tidskriftsartikel (refereegranskat)abstract
- 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, beta-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 < or =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, beta-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). CONCLUSIONS: Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF < or =40% when added to standard therapies including ACE inhibitors, beta-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.
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| 2. |
- Thune, J. J., et al.
(författare)
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Predictors and prognostic impact of recurrent myocardial infarction in patients with left ventricular dysfunction, heart failure, or both following a first myocardial infarction
- 2011
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Ingår i: European Journal of Heart Failure. - 1388-9842. ; 13:2, s. 148-153
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Recurrent myocardial infarction (MI) is common after a first MI and is associated with increased morbidity and mortality. Predictors and prognosis of a recurrent MI with contemporary management are not well known. METHODS AND RESULTS: We assessed the predictors and prognostic impact of a first recurrent MI in 10 599 patients with left ventricular dysfunction, heart failure, or both following a first MI from the Valsartan in Acute Myocardial Infarction Trial (VALIANT) cohort. During a median follow-up of 27.4 months, 861 patients (9.6%) had a recurrent MI. The median time to recurrence was 136 days (quartiles 35-361 days), with a declining rate of recurrent MI within the first 3 months. The strongest predictors of recurrent MI were reduced estimated glomerular filtration rate, unstable angina, diabetes, and age. Mortality was markedly elevated (20.5%) within the first 7 days of a recurrent MI. Patients who survived 7 days after a recurrent MI continued to be at increased risk of death compared with patients without a recurrent MI and the risk of death remained elevated more than two-fold a year after the recurrent MI (adjusted hazards ratio 2.4, 95% confidence interval 1.7-3.2). One-year mortality for the entire VALIANT cohort was 10.3%, whereas 38.3% of the patients were dead 1 year after recurrent MI. Early reinfarctions (within 1 month) was associated with significantly higher 30-day mortality than later reinfarctions. CONCLUSION: Even in the context of contemporary treatment, a recurrent MI confers a significantly increased risk of death in patients following a high-risk first MI. Strategies aimed at reducing recurrent MI will thus likely prolong survival in post-MI survivors.
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| 3. |
- Ariti, C. A., et al.
(författare)
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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
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Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 162:5, s. 900-6
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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.
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| 4. |
- Cunningham, J. W., et al.
(författare)
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Myocardial Infarction in Heart Failure With Preserved Ejection Fraction Pooled Analysis of 3 Clinical Trials
- 2020
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Ingår i: Jacc-Heart Failure. - : Elsevier BV. - 2213-1779. ; 8:8, s. 618-626
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES The authors investigated the relationship between past or incident myocardial infarction (MI) and car-diovascular (CV) events in heart failure with preserved ejection fraction (HFpEF). BACKGROUND MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain. METHODS The authors pooled data from 3 trials-CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N 1/4 8,916)-and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization. RESULTS At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p < 0.001). Excess sudden death drove this difference (1.9 vs. 1.2 events/100 py, adjusted HR: 1.55 [95% CI: 1.23 to 1.97]; p < 0.001). There was no difference in HF hospitalization (5.9 vs. 5.5 events/100 py, adjusted HR: 1.05, 95% CI: 0.92 to 1.19) or HF death by prior MI. During follow-up, MI occurred in 336 patients (3.8%). Risk of CV death increased 31-fold in the first 30 days after first post-enrollment MI, and remained 58% higher beyond 1 year after MI. Risk of first or recurrent HF hospitalization increased 2.4-fold after MI. CONCLUSIONS Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302) (J Am Coll Cardiol HF 2020;8:618-26) (c) 2020 by the American College of Cardiology Foundation.
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| 5. |
- Hillege, H. L., et al.
(författare)
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Renal function as a predictor of outcome in a broad spectrum of patients with heart failure
- 2006
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Ingår i: Circulation. - 1524-4539 .- 0009-7322. ; 113:5, s. 671-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Decreased renal function has been found to be an independent risk factor for cardiovascular outcomes in patients with chronic heart failure (CHF) with markedly reduced left ventricular ejection fraction (LVEF). The aim of this analysis was to evaluate the prognostic importance of renal function in a broader spectrum of patients with CHF. METHODS AND RESULTS: The Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of three component trials that enrolled patients with symptomatic CHF, based on use of ACE inhibitors and reduced (< or =40%) or preserved LVEF (>40%). Entry baseline creatinine was required to be below 3.0 mg/dL (265 micromol/L). Routine baseline serum creatinine assessments were done in 2680 North American patients. An analysis of the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation and LVEF on risk of cardiovascular death or hospitalization for heart failure, as well as on all-cause mortality, was conducted on these 2680 patients. The proportion of patients with eGFR <60 mL/min per 1.73 m2 was 36.0%; 42.6% for CHARM-Alternative, 33.0% for CHARM-Added, and 34.7% for CHARM-Preserved. During the median follow-up of 34.4 months (total 6493 person-years), the primary outcome of cardiovascular death or hospital admission for worsening CHF occurred in 950 of 2680 subjects. Both reduced eGFR and lower LVEF were found to be significant independent predictors of worse outcome after adjustment for major confounding baseline clinical characteristics. The risk for cardiovascular death or hospitalization for worsening CHF as well as the risk for all-cause mortality increased significantly below an eGFR of 60 mL/min per 1.73 m2 (adjusted hazard ratio, 1.54 for 45 to 60 mL/min per 1.73 m2 and 1.86 for <45 mL/min per 1.73 m2 for the primary outcome, both P<0.001, and hazard ratio of 1.50, P=0.006, and 1.91, P=0.001, respectively, for all-cause mortality). The prognostic value of eGFR was not significantly different among the three component trials. There was no significant interaction between renal function, the effect of candesartan, and clinical outcome. CONCLUSIONS: Impaired renal function is independently associated with heightened risk for death, cardiovascular death, and hospitalization for heart failure in patients with CHF with both preserved as well as reduced LVEF. There was no evidence that the beneficial effect of candesartan was modified by baseline eGFR.
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| 6. |
- Kober, L., et al.
(författare)
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Previously known and newly diagnosed atrial fibrillation: a major risk indicator after a myocardial infarction complicated by heart failure or left ventricular dysfunction
- 2006
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Ingår i: European journal of heart failure. - 1388-9842. ; 8:6, s. 591-8
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To characterize the relationship between known and newly diagnosed atrial fibrillation (AF) and the risk of death and major cardiovascular (CV) events in patients with acute myocardial infarction (MI) complicated by heart failure (HF) and/or left ventricular systolic dysfunction (LVSD). METHODS: The VALIANT trial enrolled 14,703 individuals with acute MI complicated by HF and/or LVSD. AF was assessed at presentation and at randomization (median 4.9 days after symptom onset). Primary outcomes were risk of death and major CV events 3 years following acute MI. RESULTS: A total of 1812 with current AF (AF between presentation and randomization), 339 patients with prior AF (history of AF without current AF), and 12,509 without AF were enrolled. Patients with AF were older; had more prior HF, angina, and MI, and received beta-blockers and thrombolytics less often than those without AF. Three-year mortality estimates were 20% in those without AF, 37% with current AF, and 38% with prior AF. Compared with patients without AF, the multivariable adjusted HR of death was 1.25 (1.03-1.52; p=0.03) for prior AF and 1.32 (1.20-1.45; p<0.0001) for current AF. HR for major CV events was 1.15 (0.98-1.35; p=0.08) and 1.21 (1.12-1.31; p<0.0001). CONCLUSION: AF is associated with greater long-term mortality and adverse CV events with acute MI complicated by HF or LVSD.
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| 7. |
- Lewis, E. F., et al.
(författare)
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Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM
- 2007
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842. ; 9:1, s. 83-91
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Limited comparative studies assessing the health-related quality of life (HRQL) in heart failure (HF) patients with preserved vs. low ejection fraction (LVEF) have been disparate. AIMS: The aims of this study were a) to characterize HRQL in a large population of HF patients with preserved and low LVEF and b) to determine the factors associated with worse HRQL. METHODS: Patients with symptomatic HF (NYHA Class II-IV) enrolled in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) HRQL study completed the Minnesota Living with Heart Failure questionnaire at randomization. Patients were stratified into 2 HF cohorts: preserved LVEF (>40%) and low LVEF (
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| 8. |
- McMurray, J. J., et al.
(författare)
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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
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Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 151:5, s. 985-91
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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.
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| 9. |
- McMurray, J. J., et al.
(författare)
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Resource utilization and costs in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme
- 2006
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 27:12, s. 1447-58
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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.
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| 10. |
- O'Meara, E., et al.
(författare)
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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
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842. ; 7:4, s. 650-6
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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.
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