Impact of Geographic Region on the COMMANDER-HF Trial

Ferreira, João Pedro; Cleland, John G.F.; Lam, Carolyn S.P.; Veldhuisen, Dirk J. van; Byra, William M.; Police, David A. La; Anker, Stefan D.; Mehra, Mandeep R.; Leroy, Céline; Eschwège, Valérie; Toussaint-Hacquard, M.; Rossignol, Patrick; Greenberg, Barry; Zannad, Faı̈ez

doi:10.1016/j.jchf.2020.11.007

Cited by 7 publications

(16 citation statements)

References 24 publications

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“…In HF patients, stroke risk inversely correlates with LV function even in the absence of atrial fibrillation; however, annual stroke risks are lower in contemporary trials than Fig. 4 Calculated event rates for stroke and ISTH-major bleedings in patients with cardiovascular disease and heart failure in sinus rhythm in the Western European subgroup of the COMMANDER-HF trial comparing the factor Xa-inhibitor rivaroxaban at a dose of 2.5 mg twice daily to placebo; ER event rate of both treatments per region in COMMANDER-HF [43], E Plac calculated event rate on placebo, E Riva calculated event rate on rivaroxaban, ISTH-major bleeding major bleeding as defined according to the International society on Thrombosis and Haemostasis [29], RR relative risk on treatment per region as reported for COMMANDER-HF [43] initially predicted. Routine anticoagulation with VKA did not provide a clinical benefit owing to the increased rate of major bleedings and lower than expected stroke rates.…”

Section: Discussionmentioning

confidence: 99%

“…During the 1990s, large heart failure trials such as Survival and Ventricular Enlargement (SAVE) and Studies of Left Ventricular Dysfunction (SOLVD) indicated an increased risk of thromboembolism with decreasing LV-EF postulating an inverse relation of 18% relative increase in stroke per 5% absolute reduction in LV-EF [1][2][3]. In a nationwide Danish cohort study including almost 43.000 patients, of whom only 22% had atrial fibrillation, HF patients had a high ischemic stroke risk, the CHA 2 DS 2 -VASc score modestly predicted the risk, and patients with HF in the absence of atrial fibrillation and CHA 2 DS 2 -VASc scores ≥ 4 had a high absolute risk of ischemic stroke. HF patients without atrial fibrillation and high risk scores had a similar rate of thromboembolism as patients with atrial fibrillation [4].…”

Section: Increased Stroke Risk In Patients With Chronic Heart Failure and Sinus Rhythmmentioning

confidence: 99%

“…Patients in Western Europe (combined with South Africa) were on average 71-years old, 21% female, had a median NT-proBNP of 2752 pg/mL, and a median LV-EF of 30% with 77% having a LV-EF < 35%. In Western Europe (plus South Africa), the event rates for stroke and for ISTH-major bleeding were reported to be 1.9 per 100 patient-years for both endpoints and the treatment effect of rivaroxaban was reported to be 0.16 for stroke and 1.81 for ISTH-major bleeding, respectively [ 43 ]. Based on these data, rivaroxaban reduced stroke rate from 3.3 to 0.5 per 100 patient-years (HR 0.16 (0.04–0.72) while increasing ISTH-major bleeding from 1.4 to 2.4 per 100 patient-years (HR 1.81 (0.61–5.39) (Fig.…”

Section: Evidence For Noac To Reduce Stroke Risk In Hf With Sinus Rhythmmentioning

confidence: 99%

“…

Fig. 4 Calculated event rates for stroke and ISTH-major bleedings in patients with cardiovascular disease and heart failure in sinus rhythm in the Western European subgroup of the COMMANDER-HF trial comparing the factor Xa-inhibitor rivaroxaban at a dose of 2.5 mg twice daily to placebo; ER event rate of both treatments per region in COMMANDER-HF [ 43 ], E Plac calculated event rate on placebo, E Riva calculated event rate on rivaroxaban, ISTH-major bleeding major bleeding as defined according to the International society on Thrombosis and Haemostasis [ 29 ], RR relative risk on treatment per region as reported for COMMANDER-HF [ 43 ] …”

Section: Evidence For Noac To Reduce Stroke Risk In Hf With Sinus Rhythmmentioning

confidence: 99%

“…In the absence of AF, there are some data for ischemic HFrEF patients for low-dose rivaroxaban plus ASA primarily from the COMMANDER-HF trial [ 39 ]. While the risk–benefit-balance both for the composite efficacy endpoint or stroke alone compared to major bleeding was neutral in the overall trial, the net-benefit appears to be in favour of intensified antithrombotic treatment in the Western European subgroup [ 43 ]. For patients with non-ischemic HFrEF as in our initial case scenario, we have no trial data available and the overall guideline recommendations are against anticoagulation.…”

Section: Limitation Of Current Trialsmentioning

confidence: 99%

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Anticoagulants for stroke prevention in heart failure with reduced ejection fraction

2021

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Impaired left-ventricular ejection-fraction (LV-EF) is a known risk factor for ischemic stroke and systemic embolism in patients with heart failure (HF) even in the absence of atrial fibrillation. While stroke risk is inversely correlated with LV-EF in HF patients with sinus rhythm, strategies using anticoagulation with Vitamin-K antagonists (VKA) were futile as the increase in major bleedings outweighed the potential benefit in stroke reduction. Non-Vitamin K oral anticoagulants (NOACs) proved to be an effective and in general safer approach for stroke prevention in patients with atrial fibrillation and may also have a favourable risk–benefit profile in HF patients. In HF patients with sinus rhythm, the COMPASS trial suggested a potential benefit for rivaroxaban, whereas the more dedicated COMMANDER-HF trial remained neutral on overall ischemic benefit owed to a higher mortality which was not influenced by anticoagulation. More recent data from subgroups in the COMMANDER-HF trial, however, suggest that there might be a benefit of rivaroxaban regarding stroke prevention under certain circumstances. In this article, we review the existing evidence for NOACs in HF patients with atrial fibrillation, elaborate the rationale for stroke prevention in HF patients with sinus rhythm, summarise the available data from anticoagulation trials in HF with sinus rhythm, and describe the patient who might eventually profit from an individualised strategy aiming to reduce stroke risk. Graphic abstract

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Section: Discussionmentioning

confidence: 99%

Section: Increased Stroke Risk In Patients With Chronic Heart Failure and Sinus Rhythmmentioning

confidence: 99%

Section: Evidence For Noac To Reduce Stroke Risk In Hf With Sinus Rhythmmentioning

confidence: 99%

“…

Section: Evidence For Noac To Reduce Stroke Risk In Hf With Sinus Rhythmmentioning

confidence: 99%

Section: Limitation Of Current Trialsmentioning

confidence: 99%

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Anticoagulants for stroke prevention in heart failure with reduced ejection fraction

2021

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Clinical trials: conventional or pragmatic?

Tavazzi

Maggioni

Rapezzi

et al. 2022

European J of Heart Fail

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Geographic differences in patients with acute myocardial infarction in the PARADISE‐MI trial

Butt

Claggett

Miao

et al. 2023

European J of Heart Fail

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AimThe globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments, and outcomes. We examined these differences in PARADISE‐MI.Methods and resultsOverall, 23.0% were randomized in Eastern Europe/Russia, 17.5% in Western Europe, 12.2% in Southern Europe, 10.1% in Northern Europe, 12.0% in Latin America (LA), 9.3% in North America (NA), 10.0% in East/South‐East Asia and 5.8% in South Asia (SA). Those from Asia, particularly SA, were different from patients enrolled in the other regions, being younger and thinner. They also differed in terms of comorbidities (high prevalence of diabetes and low prevalence of atrial fibrillation), type of myocardial infarction (more often ST‐elevation myocardial infarction), and treatment (low rate of primary percutaneous coronary intervention). By contrast, patients from LA did not differ meaningfully from those randomized in Europe or NA. Use of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers (34.8%) and beta‐blockers (65.5%) was low in SA, whereas mineralocorticoid receptor antagonist use was lowest in NA (22%) and highest in Eastern Europe/Russia (53%). Rates of the primary composite outcome of cardiovascular death or incident heart failure varied two‐fold among regions, with the lowest rate in SA (4.6/100 person‐years) and the highest in LA (9.2/100 person‐years). Rates of incident heart failure varied almost six‐fold among regions, with the lowest rate in SA (1.0/100 person‐years) and the highest in Northern Europe (5.9/100 person‐years). The effect of sacubitril/valsartan was not modified by region.ConclusionIn PARADISE‐MI, there were substantial regional differences in patient characteristics, treatments and outcomes. Although the generalizability of these findings to a ‘real‐world’ unselected population may be limited, these findings underscore the importance of considering both regional and within‐region differences when designing global clinical trials.

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Impact of Geographic Region on the COMMANDER-HF Trial

Cited by 7 publications

References 24 publications

Anticoagulants for stroke prevention in heart failure with reduced ejection fraction

Anticoagulants for stroke prevention in heart failure with reduced ejection fraction

Clinical trials: conventional or pragmatic?

Geographic differences in patients with acute myocardial infarction in the PARADISE‐MI trial

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