Examinando por Autor "Toff, William D."
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- PublicaciónAcceso abiertoAntihypertensives and Statin Therapy for Primary Stroke Prevention: A Secondary Analysis of the HOPE-3 Tria(Stroke, 2021-05-14) Bosch, Jackie; Lonn, Eva; Dagenais, Gilles; Gao, Peggy; Lopez-Jaramillo, Patricio; Zhu, Jun; Pais, Prem; Avezum, Alvaro; Sliwa, Karen; Chazova, Irina E.; Peters, Ron; Held, Claes; Yusoff, Khalid; Lewis, Basil S.; Toff, William D.; Khunti, Kamlesh; Reid, Christopher M.; Leiter, Lawrence A.; Yusuf, Salim; Hart, Robert G.; The HOPE-3 Investigators; MasiraBackground and Purpose: The HOPE-3 trial (Heart Outcomes Prevention Evaluation–3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups. Methods: Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed. Results: Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59–1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55–1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34–1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41–2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52–0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37–0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59–2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57–2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36–0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23–0.72]). Conclusions: Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated.
- 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.
- PublicaciónRestringidoEffects of lipid-lowering and antihypertensive treatments in addition to healthy lifestyles in primary prevention : An analysis of the HOPE-3 trial(2018) Lopez-Jaramillo, Patricio; Dagenais, Gilles; Jung, Hyejung; Lonn, Eva; Bogaty, Peter M.; Dehghan, Mahshid; Held, Claes; Avezum, Alvaro; Petr, Jansky; Keltai, Matyas; Lawrence A., Leiter; Toff, William D.; Bosch, Jackie; Yusuf, SalimBackground-—It is not clear whether the effects of lipid-lowering or antihypertensive medications are influenced by adherence to healthy lifestyle factors. We assessed the effects of both drug interventions in subgroups by the number of healthy lifestyle factors in participants in the HOPE-3 (Heart Outcomes Prevention Evaluation) trial. Methods and Results-—In this primary prevention trial, 4 healthy lifestyle factors (nonsmoking status, physical activity, optimal body weight, and healthy diet) were recorded in 12 521 participants who were at intermediate risk of cardiovascular disease (CVD) and were randomized to rosuvastatin, candesartan/hydrochlorothiazide, their combination, or matched placebos. Median follow-up was 5.6 years. The outcome was a composite of CVD events. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. Participants with ≥2 healthy lifestyle factors had a lower rate of CVD compared with those with fewer factors (HR: 0.85; 95% CI, 0.73–1.00). Rosuvastatin reduced CVD events in participants with ≥2 healthy lifestyle factors (HR: 0.74; 95% CI, 0.62–0.90) and in participants with <2 factors (HR: 0.79; 95% CI, 0.61–1.01). Consistent results were observed with combination therapy (≥2 factors: HR: 0.74; 95% CI, 0.57–0.97; <2 factors: HR: 0.61; 95% CI, 0.43–0.88). Candesartan/hydrochlorothiazide tends to reduce CVD only in participants with <2 healthy lifestyle factors (HR: 0.78; 95% CI, 0.61–1.00). Conclusions-—Healthy lifestyles are associated with lower CVD. Rosuvastatin alone and combined with candesartan/hydrochlorothiazide is beneficial regardless of healthy lifestyle status; however, the benefit of antihypertensive treatment appears to be limited to patients with less healthy lifestyles.
- PublicaciónAcceso abiertoLong-term Effects of Statins, Blood Pressure-Lowering, and Both on Erectile Function in Persons at Intermediate Risk for Cardiovascular Disease : A Substudy of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) Randomized Controlled Trial(2018-01) Joseph, Philip; Lonn, Eva; Bosch, Jackie; Lopez-Jaramillo, Patricio; Zhu, Jun; Keltai, Matyas; Dans, Antonio; Reid, Christopher M.; Khunti, Kamlesh; Toff, William D.; Piegas, Leopoldo S.; Kim, Jae Hyung; Swaminathan, Balakumar; Bohm, Michael; Yusuf, Salim; HOPE-3 InvestigatorsBackground: It is unclear whether modifying cholesterol, blood pressure, or both affect erectile dysfunction. Also, there are concerns that erectile dysfunction is worsened by common medications used to treat these risk factors. In this study, we evaluated the effect of: (1) cholesterol-lowering with a statin; (2) pharmacologic blood pressure reduction; and (3) their combination, on erectile function. Methods: A priori, this was a secondary analysis of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) randomized controlled trial. Men were 55 years of age or older with at least 1 cardiovascular risk factor. Erectile function was measured using the erectile function domain of the International Index of Erectile Function (IIEF-EF) score. Men with incomplete scores, or who did not engage in sexual activity, were excluded. Using a 2 × 2 factorial design, participants were randomized to rosuvastatin (10 mg/d) or placebo, and to candesartan with hydrochlorothiazide (HCTZ; 16 mg/12.5 mg/d; Cand+HCTZ) or placebo. Primary outcome was change in IIEF-EF from baseline to end of study follow-up. Results: Two thousand one hundred fifty-three men were included; mean age was 61.5 years, and mean follow-up was 5.8 years. Mean IIEF-EF score at baseline was 23.0 (SD 5.6). Least square mean change in the IIEF-EF score did not differ with rosuvastatin compared with placebo (−1.4; standard error [SE], 0.3 vs −1.5; SE, 0.3; P = 0.74), Cand+HCTZ compared with placebo (−1.6; SE, 0.3 vs −1.3; SE, 0.3; P = 0.10), or combination therapy compared with double placebo (P = 0.35). Conclusions: Cholesterol-lowering using a statin, and blood pressure-lowering using Cand+HCTZ, either alone or in combination, do not improve or adversely affect erectile function.
- 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).