Examinando por Autor "Jansky, Petr"
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- PublicaciónAcceso abiertoBlood-pressure and cholesterol lowering in persons without cardiovascular disease(2016-04-02) Yusuf, Salim; Lonn, Eva; Pais, Prem; Bosch, Jackie; Lopez-Jaramillo, Patricio; Zhu, Jun; Xavier, Denis; Avezum, Alvaro; Leiter, Lawrence A.; Piegas, Leopoldo S.; Parkhomenko, Alexander; Keltai, Matyas; Keltai, Katalin; Sliwa, Karen; Chazova, Irina; Peters, Ron J.G.; Held, Claes; Yusoff, Khalid; Lewis, Basil S.; Jansky, Petr; Khunti, Kamlesh; Toff, William D.; Reid, Christopher M.; Varigos, John; Accini, Jose Luis; McKelvie, Robert; Pogue, Janice; Jung, Hyejung; Liu, Lisheng; Diaz, Rafael; Dans, Antonio; Dagenais, Gilles; HOPE-3 InvestigatorsBACKGROUND Elevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol increase the risk of cardiovascular disease. Lowering both should reduce the risk of cardiovascular events substantially. METHODS In a trial with 2-by-2 factorial design, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to rosuvastatin (10 mg perday) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. In the analyses reported here, we compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included heart failure, cardiac arrest, or revascularization. The median follow-up was 5.6 years. RESULTS The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P=0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P=0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of discontinuation of the trial regimen was similar in the two groups. CONCLUSIONS The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.)
- PublicaciónAcceso abiertoBlood-pressure lowering in intermediate-risk persons without cardiovascular disease(2016-04-26) Lonn, Eva; Bosch, Jackie; Lopez-Jaramillo, Patricio; Zhu, Jun; Liu, Lisheng; Pais, Prem; Diaz, Rafael; Xavier, Denis; Sliwa, Karen; Dans, Antonio; Avezum, Alvaro; Leopoldo S., Piegas; Keltai, Katalin; Keltai, Matyas; Chazova, Irina; Peters, Ron J.G.; Held, Claes; Yusoff, Khalid; Lewis, Basil S.; Jansky, Petr; Parkhomenko, Alexander; Khunti, Kamlesh; Toff, William D.; Reid, Christopher M.; Varigos, John; Leiter, Lawrence A.; Molina, Dora I.; McKelvie, Robert; Pogue, Janice; Wilkinson, Joanne; Jung, Hyejung; Dagenais, Gilles; Yusuf, Salim; HOPE-3 InvestigatorsBACKGROUND Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear. METHODS In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years. RESULTS The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P=0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P=0.02 and P=0.009, respectively, for trend in the two outcomes). CONCLUSIONS Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.)
- PublicaciónAcceso abiertoCholesterol lowering in intermediate-risk persons without cardiovascular disease(2016-05-26) Yusuf, Salim; Bosch, Jackie; Dagenais, Gilles; Zhu, Jun; Xavier, Denis; Liu, Lisheng; Pais, Prem; Lopez-Jaramillo, Patricio; Leiter, Lawrence A.; Dans, Antonio; Avezum, Alvaro; Piegas, Leopoldo S.; Parkhomenko, Alexander; Keltai, Katalin; Keltai, Matyas; Sliwa, Karen; Peters, Ron J.G.; Held, Claes; Chazova, Irina; Yusoff, Khalid; Lewis, Basil S.; Jansky, Petr; Khunti, Kamlesh; Toff, William D.; Reid, Christopher M.; Varigos, John; Sánchez Vallejo, Gregorio; McKelvie, Robert; Pogue, Janice; Jung, Hyejung; Gao, Peggy; Diaz, Rafael; Lonn, Eva; The HOPE-3 InvestigatorsBACKGROUND Previous trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease. Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons. It is unclear whether the benefits of statins can be extended to an intermediate-risk, ethnically diverse population without cardiovascular disease. METHODS In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk to receive rosuvastatin at a dose of 10 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included revascularization, heart failure, and resuscitated cardiac arrest. The median follow-up was 5.6 years. RESULTS The overall mean low-density lipoprotein cholesterol level was 26.5% lower in the rosuvastatin group than in the placebo group. The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P=0.002). The results for the second coprimary outcome were consistent with the results for the first (occurring in 277 participants [4.4%] in the rosuvastatin group and in 363 participants [5.7%] in the placebo group; hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P<0.001). The results were also consistent in subgroups defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group. In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of cataract surgery (in 3.8% of the participants, vs. 3.1% in the placebo group; P=0.02) and muscle symptoms (in 5.8% of the participants, vs. 4.7% in the placebo group; P=0.005). CONCLUSIONS Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; HOPE-3 ClinicalTrials.gov number, NCT00468923.
- PublicaciónAcceso abiertoDesign and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide(Diabetes, Obesity and Metabolism, 2018-01-05) Gerstein, Hertzel C.; Colhoun, Helen M.; Dagenais, Gilles R.; Diaz, Rafael; Lakshmanan, Mark; Pais, Prem; Probstfield, Jeffrey; Riddle, Matthew C.; Ryden, Lars; Xavier, Denis; Atisso, Charles M.; Avezum, Alvaro; Basile, Jan; Chung, Namsik; Conget, Ignacio; Cushman, William C.; Franek, Edward; Hancu, Nicolae; Hanefeld, Markolf; Holt, Shaun; Jansky, Petr; Keltai, Matyas; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Cardona-Munoz, Ernesto G.; Pirags, Valdis; Pogosova, Nana; Raubenheimer, Peter J.; Shaw, Jonathan; Sheu, Wayne H-H.; Temelkova-Kurktschiev, Theodora; The REWIND Trial Investigators; MasiraThe aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.
- PublicaciónAcceso abiertoDulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial(ELSEVIER, 2019-07-13) Gerstein, Hertzel C.; Colhoun, Helen M.; Dagenais, Gilles R.; Diaz, Rafael; Lakshmanan, Mark; Pais, Prem; Probstfield, Jeffrey; Riesmeyer, Jeffrey S.; Riddle, Matthew C.; Rydén, Lars; Xavier, Denis; Messan Atisso, Charles; Dyal, Leanne; Hall, Stephanie; Rao-Melacini, Purnima; Wong, Gloria; Avezum, Alvaro; Basile, Jan; Chung, Namsik; Conget, Ignacio; Cushman, William C.; Franek, Edward; Hancu, Nicolae; Hanefeld, Markolf; Holt, Shaun; Jansky, Petr; Keltai, Matyas Matyas; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Cardona-Munoz, Ernesto German; Pirags, Valdis; Pogosova, Nana; Raubenheimer, Peter J.; Shaw, Jonathan E.; Sheu, Wayne H-H.; Temelkova-Kurktschiev, Theodora; The REWIND Investigators; EverestBackground Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. Methods This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). Interpretation Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.
- PublicaciónAcceso abiertoDulaglutide and incident atrial fibrillation or flutter in patients with type 2 diabetes. A post hoc analysis from the REWIND randomized tria(2022-01-04) Raubenheimer, Peter J.; Cushman, William C.; Avezum, Alvaro; Basile, Jan; Conget, Ignacio; Dagenais, Gilles; Hoover, Anastasia; Jansky, Petr; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Pogosova, Nana; Probstfield, Jeffrey; Rao-Melacini, Purnima; Rydén, Lars; Sheu, Wayne H.-H; Temelkova-Kurktschiev, Theodora; Gerstein, Hertzel C.; MasiraAim To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once-weekly subcutaneous dulaglutide versus placebo. Materials and Methods Patients without electrocardiographic (ECG)-confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure. Results Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow-up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person-years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person-years (P = .59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure. Conclusion This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at-risk group of patients with type 2 diabetes.
- PublicaciónAcceso abiertoDulaglutide and incident atrial fibrillation or flutter in patients with type 2 diabetes. A post hoc analysis from the REWIND randomized trial(Diabetes, Obesity and Metabolism, 2022-01-04) Raubenheimer, Peter J.; Cushman, William C.; Avezum, Alvaro; Basile, Jan; Conget, Ignacio; Dagenais, Gilles; Hoover, Anastasia; Jansky, Petr; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Pogosova, Nana; Probstfield, Jeffrey; Rao-Melacini, Purnima; Ryden, Lars; Sheu, Wayne H.-H.; Temelkova-Kurktschiev, Theodora; Gerstein, Hertzel C.; MasiraAim To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once-weekly subcutaneous dulaglutide versus placebo. Materials and Methods Patients without electrocardiographic (ECG)-confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure. Results Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow-up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person-years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person-years (P = .59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure. Conclusion This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at-risk group of patients with type 2 diabetes.
- PublicaciónAcceso abiertoDulaglutide and renal outcomes in type 2 diabetes. An exploratory analysis of the REWIND randomised, placebo-controlled trial(The Lancet, 2019-07-13) Gerstein, Hertzel C.; Colhoun, Helen M.; Dagenais, Gilles R.; Diaz, Rafael; Lakshmanan, Mark; Pais, Prem; Probstfield, Jeffrey; Riesmeyer, Jeffrey S.; Riddle, Matthew C.; Rydén, Lars; Xavier, Denis; Messan Atisso, Charles; Dyal, Leanne; Hall, Stephanie; Rao-Melacini, Purnima; Wong, Gloria; Avezum, Alvaro; Basile, Jan; Chung, Namsik; Conget, Ignacio; Cushman, William C.; Franek, Edward; Hancu, Nicolae; Hanefeld, Markolf; Holt, Shaun; Jansky, Petr; Keltai, Matyas; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Cardona-Munoz, Ernesto German; Pirags, Valdis; Pogosova, Nana; Raubenheimer, Peter J.; Shaw, Jonathan E.; Sheu, Wayne H-H.; Temelkova-Kurktschiev, Theodora; The REWIND Investigators; EverestBackground: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. Interpretation: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.
- PublicaciónAcceso abiertoLowering cholesterol, blood pressure, or both to prevent cardiovascular events: Results of 8.7 years of follow-up of Heart Outcomes Evaluation Prevention (HOPE)-3 study participants(Oxford Academic, 2021-08-14) Bosch, Jackie; Lonn, Eva M.; Jung, Hyejung; Zhu, Jun; Liu, Lisheng; Lopez-Jaramillo, Patricio; Pais, Prem; Xavier, Denis; Diaz, Rafael; Dagenais, Gilles; Dans, Antonio; Avezum, Alvaro; Piegas, Leopoldo S.; Parkhomenko, Alexander; Keltai, Kati; Keltai, Matya; Sliwa, Karen; Held, Claus; Peters, Ronald J.G.; Lewis, Basil S.; Jansky, Petr; Yusoff, Khalid; Khunti, Kamlesh; Toff, William D.; Reid, Christopher M.; Varigos, John; Joseph, Philip; Leiter, Lawrence A.; Yusuf, Salim; The Heart Outcomes Prevention Evaluation (HOPE)-3 Investigators; MasiraAims. Rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV) events by 24% in 12 705 participants at intermediate CV risk after 5.6 years. There was no benefit of blood pressure (BP) lowering treatment in the overall group, but a reduction in events in the third of participants with elevated systolic BP. After cessation of all the trial medications, we examined whether the benefits observed during the active treatment phase were sustained, enhanced, or attenuated. Methods and results. After the randomized treatment period (5.6 years), participants were invited to participate in 3.1 further years of observation (total 8.7 years). The first co-primary outcome for the entire length of follow-up was the composite of myocardial infarction, stroke, or CV death [major adverse cardiovascular event (MACE)-1], and the second was MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization (MACE-2). In total, 9326 (78%) of 11 994 surviving Heart Outcomes Prevention Evaluation (HOPE)-3 subjects consented to participate in extended follow-up. During 3.1 years of post-trial observation (total follow-up of 8.7 years), participants originally randomized to rosuvastatin compared with placebo had a 20% additional reduction in MACE-1 [95% confidence interval (CI), 0.64–0.99] and a 17% additional reduction in MACE-2 (95% CI 0.68–1.01). Therefore, over the 8.7 years of follow-up, there was a 21% reduction in MACE-1 (95% CI 0.69–0.90, P = 0.005) and 21% reduction in MACE-2 (95% CI 0.69–0.89, P = 0.002). There was no benefit of BP lowering in the overall study either during the active or post-trial observation period, however, a 24% reduction in MACE-1 was observed over 8.7 years. Conclusion. The CV benefits of rosuvastatin, and BP lowering in those with elevated systolic BP, compared with placebo continue to accrue for at least 3 years after cessation of randomized treatment in individuals without cardiovascular disease indicating a legacy effect
- PublicaciónAcceso abiertoNovel Approaches in Primary Cardiovascular Disease Prevention : The HOPE-3 Trial Rationale, Design, and Participants' Baseline Characteristics(2016-03) Lonn, Eva; Bosch, Jackie; Pogue, Janice; Avezum, Alvaro; Chazova, Irina; Dans, Antonio; Diaz, Rafael; Fodor, George J.; Held, Claes; Jansky, Petr; Keltai, Matyas; Keltai, Katalin; Kunti, Kamlesh; Kim, Jae Hyung; Leiter, Lawrence A.; Lewis, Basil S.; Liu, Lisheng; Lopez-Jaramillo, Patricio; Pais, Prem; Parkhomenko, Alexander; Peters, Ron J.G.; Piegas, Leopoldo S.; Reid, Christopher M.; Sliwa, Karen; Toff, William D.; Varigos, John; Xavier, Denis; Yusoff, Khalid; Zhu, Jun; Dagenais, Gilles; Yusuf, Salim; The HOPE-3 InvestigatorsRésumé Introduction Il est possible de faire baisser efficacement et en toute sécurité le cholestérol et la pression artérielle (PA) avec les statines et les antihypertenseurs tout en réduisant de 20 à 30 % les manifestations cardiovasculaires majeures en l’espace de cinq ans chez les personnes à risque élevé. Les données obtenues dans les populations exposées à un risque plus faible sont néanmoins limitées. L’essai HOPE-3 (Heart Outcomes Prevention Evaluation-3) tâche de déterminer si l’abaissement du cholestérol à l’aide d’une statine, l’abaissement de la pression artérielle à l’aide de deux agents antihypertenseurs administrés à raison d’une faible dose et leur association permettent de réduire en toute sécurité les manifestations cardiovasculaires majeures chez les personnes exposées à un risque intermédiaire qui n’ont pas d’antécédents d’événements vasculaires et dont le taux de cholestérol et la PA se situent dans la moyenne. Méthodes Au total, 12 705 femmes et hommes, les unes âgées de 65 ans et plus et les autres de 55 ans et plus, qui présentent au moins un facteur de risque cardiovasculaire et qui n’ont pas de maladie cardiovasculaire connue ni aucune indication ou contre-indication claires aux médicaments à l’étude, ont été répartis aléatoirement pour recevoir de la rosuvastatine à raison de 10 mg par jour ou un placebo et l’association candésartan/hydrochlorothiazide à raison de 16/12,5 mg par jour ou un placebo (plan factoriel 2 × 2). Ces patients seront suivis pendant une moyenne de 5,8 ans. Les principaux paramètres d’évaluation de l’étude combinent le décès d’origine cardiovasculaire, l’infarctus du myocarde non mortel et l’AVC non mortel d’une part, et le décès d’origine cardiovasculaire, l’infarctus du myocarde non mortel, l’AVC non mortel, la réanimation après arrêt cardiaque, l’insuffisance cardiaque et la revascularisation artérielle d’autre part. Résultats Les participants ont été recrutés dans 21 pays situés en Amérique du Nord, en Amérique du Sud, en Europe, en Asie et en Australie. L’âge moyen au moment de la répartition aléatoire était de 66 ans, et 46 % des sujets étaient des femmes. Conclusions L’essai HOPE-3 fournira de nouveaux renseignements sur l’abaissement du taux de cholestérol et de la PA dans des populations exposées à un risque intermédiaire dont le taux de cholestérol et la PA se situent dans la moyenne. Il devrait également fournir des données à l’appui des stratégies de prévention primaire mises en place partout dans le monde (HOPE-3 ClinicalTrials.gov NCT00468923).
- PublicaciónAcceso abiertoSimilar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin(European Society of Cardiology, 2021-07-07) Ferrannini, Giulia; Gerstein, Hertzel; Colhoun, Helen Martina; Dagenais, Gilles R.; Diaz, Rafael; Dyal, Leanne; Lakshmanan, Mark; Mellbin, Linda; Probstfield, Jeffrey; Riddle, Matthew Casey; Shaw, Jonathan Edward; Avezum, Alvaro; Basile, Jan Neil; Cushman, William C.; Jansky, Petr; Keltai, Mátyás; Lanas, Fernando; Leiter, Lawrence Alan; Lopez-Jaramillo, Patricio; Pais, Prem; Pīrāgs, Valdis; Pogosova, Nana; Raubenheimer, Peter Johann; Huey-Herng Sheu, Wayne; Rydén, Lars; MasiraObjective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. Results Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81–1.05) vs. 0.78 (CI 0.61–0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. Conclusion This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.
- PublicaciónAcceso abiertoThe effect of dulaglutide on stroke(Elsevier, 2020-02-02) Gerstein, Hertzel C.; Hart, Robert; Colhoun, Helen M.; Diaz, Rafael; Lakshmanan, Mark; Botros, Fady T.; Probstfield, Jeffrey; Riddle, Matthew C.; Rydén, Lars; Messan Atisso, Charles; Dyal, Leanne; Hall, Stephanie; Avezum, Alvaro; Basile, Jan; Conget, Ignacio; Cushman, William C.; Hancu, Nicolae; Hanefeld, Markolf; Jansky, Petr; Keltai, Matyas; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Cardona Muñoz, Ernesto Germán; Pogosova, Nana; Raubenheimer, Peter J.; Shaw, Jonathan E.; Sheu, Wayne H-H.; Temelkova-Kurktschiev, Theodora; EverestBackground Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial. Methods REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries. Men and women (aged ≥50 years) with established or newly detected type 2 diabetes whose HbA1c was 9·5% or less (with no lower limit) on stable doses of up to two oral glucose-lowering drugs with or without basal insulin therapy were eligible if their body-mass index was at least 23 kg/m2. Participants were randomly assigned (1:1) to weekly subcutaneous injections of either masked dulaglutide 1·5 mg or the same volume of masked placebo (containing the same excipients but without dulaglutide). Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. Participants, investigators, the trial leadership, and all other personnel were masked to treatment allocation until the trial was completed and the database was locked. During the treatment period, participants in both groups were instructed to inject study drug on the same day at around the same time, each week. Strokes were categorised as fatal or non-fatal, and as either ischaemic, haemorrhagic, or undetermined. Stroke severity was assessed using the modified Rankin scale. Participants were seen at 2 weeks, 3 months, 6 months, and then every 3 months for drug dispensing and every 6 months for detailed assessments, until 1200 confirmed primary outcomes accrued. The primary endpoint was the first occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular or unknown causes. All analyses were done according to an intention-to-treat strategy that included all randomly assigned participants, irrespective of adherence. The trial is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, we screened 12 133 patients, of whom 9901 with type 2 diabetes and additional cardiovascular risk factors were randomly assigned to either dulaglutide (n=4949) or an equal volume of placebo (n=4952). During a median follow-up of 5·4 years, cerebrovascular and other cardiovascular outcomes were ascertained and adjudicated. 158 (3·2%) of 4949 participants assigned to dulaglutide and 205 (4·1%) of 4952 participants assigned to placebo had a stroke during follow-up (hazard ratio [HR] 0·76, 95% CI 0·62–0·94; p=0·010). Dulaglutide reduced ischaemic stroke (0·75, 0·59–0·94, p=0·012) but had no effect on haemorrhagic stroke (1·05, 0·55–1·99; p=0·89). Dulaglutide also reduced the composite of non-fatal stroke or all-cause death (0·88, 0·79–0·98; p=0·017) and disabling stroke (0·74, 0·56–0·99; p=0·042). The degree of disability after stroke did not differ by treatment group. Interpretation Long-term dulaglutide use might reduce clinically relevant ischaemic stroke in people with type 2 diabetes but does not affect stroke severity.