RESUMEN
BACKGROUND: Rivaroxaban plus aspirin compared with aspirin alone reduced major cardiac and ischemic limb events after lower extremity revascularization (LER) in the VOYAGER PAD (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) trial. The effect has not been described in patients undergoing endovascular LER. METHODS: The VOYAGER PAD trial randomized 6564 patients with symptomatic peripheral artery disease to a double-blinded treatment with 2.5 mg of rivaroxaban BID or matching placebo and 100 mg of aspirin daily. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular pathogenesis, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was Thrombolysis in Myocardial Infarction major bleeding. A prespecified subgroup of patients who underwent endovascular revascularization was included. RESULTS: Endovascular LER occurred in 4379 (66.7%) patients and surgical LER in 2185 (33.3%). Over a 3-year follow-up, rivaroxaban reduced the risk of the primary outcome by 15% (hazard ratio [HR], 0.85 [95% CI, 0.76-0.96]) with an absolute risk reduction of 0.92% at 6 months and 1.04% at 3 years and a consistent benefit in those receiving endovascular (HR, 0.89 [95% CI, 0.76-1.03]) or surgical LER (HR, 0.81 [95% CI, 0.67-0.98]; P interaction=0.43). For endovascular-treated patients, rivaroxaban reduced the risk of acute limb ischemia or major amputation of a vascular pathogenesis by 30% (HR, 0.70 [95% CI, 0.54-0.90]; P=0.005) with an absolute risk reduction of 1.0% at 6 months and 2.0% at 3 years compared with aspirin alone. Among endovascular-treated patients, the median duration of concomitant dual antiplatelet therapy with clopidogrel treatment was 31 days (interquartile range, 30-58). There was a consistent benefit for rivaroxaban regardless of background clopidogrel. Thrombolysis in Myocardial Infarction major bleeding was significantly higher for the rivaroxaban and aspirin group for the endovascular cohort (HR, 1.66 [95% CI, 1.06-2.59]) with an absolute risk increase of 0.9% at 3 years with no increase in intracranial or fatal bleeding observed (HR, 0.86 [95% CI, 0.40-1.87]; P=0.71). Mortality with rivaroxaban was higher in the endovascular-treated patients (HR, 1.24 [95% CI, 1.02-1.52]), although this finding was isolated to specific regions. CONCLUSIONS: Rivaroxaban added to aspirin or dual antiplatelet therapy after LER for peripheral artery disease reduces ischemic risk and increases major bleeding without an increased risk of intracranial or fatal bleeding. These benefits are consistent in those treated with endovascular and surgical approaches with significant benefits for major adverse limb events. These data support the use of rivaroxaban in addition to aspirin or dual antiplatelet therapy after endovascular intervention for symptomatic peripheral artery disease.
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Infarto del Miocardio , Enfermedad Arterial Periférica , Humanos , Aspirina/efectos adversos , Rivaroxabán/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Clopidogrel/uso terapéutico , Hemorragia/complicaciones , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/cirugía , Infarto del Miocardio/tratamiento farmacológico , Isquemia/tratamiento farmacológico , Quimioterapia CombinadaRESUMEN
Background: Anatomy is critical in risk stratification and therapeutic decision making in coronary disease. The relationship between anatomy and outcomes is not well described in PAD. We sought to develop an angiographic core lab within the VOYAGER-PAD trial. The current report describes the methods of creating this core lab, its study population, and baseline anatomic variables. Methods: Patients undergoing lower-extremity revascularization for symptomatic PAD were randomized in VOYAGER-PAD. The median follow up was 2.25 years. Events were adjudicated by a blinded Clinical Endpoint Committee. Angiograms were collected from study participants; those with available angiograms formed this core lab cohort. Angiograms were scored for anatomic and flow characteristics by trained reviewers blinded to treatment. Ten percent of angiograms were evaluated independently by two reviewers; inter-rater agreement was assessed. Clinical characteristics and the treatment effect of rivaroxaban were compared between the core lab cohort and noncore lab participants. Anatomic data by segment were analyzed. Results: Of 6564 participants randomized in VOYAGER-PAD, catheter-based angiograms from 1666 patients were obtained for this core lab. Anatomic and flow characteristics were collected across 16 anatomic segments by 15 reviewers. Concordance between reviewers for anatomic and flow variables across segments was 90.5% (24,417/26,968). Clinical characteristics were similar between patients in the core lab and those not included. The effect of rivaroxaban on the primary efficacy and safety outcomes was also similar. Conclusions: The VOYAGER-PAD angiographic core lab provides an opportunity to correlate PAD anatomy with independently adjudicated outcomes and provide insights into therapy for PAD. (ClinicalTrials.gov Identifier: NCT02504216).
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Enfermedad de la Arteria Coronaria , Enfermedad Arterial Periférica , Humanos , Rivaroxabán/uso terapéutico , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Extremidad Inferior , Angiografía , Procedimientos Quirúrgicos Vasculares , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain. METHODS: In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome. RESULTS: A total of 6564 patients underwent randomization; 3286 were assigned to the rivaroxaban group, and 3278 were assigned to the placebo group. The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan-Meier estimates of the incidence at 3 years were 17.3% and 19.9%, respectively (hazard ratio, 0.85, 95% confidence interval [CI], 0.76 to 0.96; P = 0.009). TIMI major bleeding occurred in 62 patients in the rivaroxaban group and in 44 patients in the placebo group (2.65% and 1.87%; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P = 0.07). ISTH major bleeding occurred in 140 patients in the rivaroxaban group, as compared with 100 patients in the placebo group (5.94% and 4.06%; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P = 0.007). CONCLUSIONS: In patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the groups. The incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone. (Funded by Bayer and Janssen Pharmaceuticals; VOYAGER PAD ClinicalTrials.gov number, NCT02504216.).
Asunto(s)
Aspirina/uso terapéutico , Inhibidores del Factor Xa/uso terapéutico , Isquemia/prevención & control , Extremidad Inferior/irrigación sanguínea , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Rivaroxabán/uso terapéutico , Anciano , Aspirina/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Terapia Combinada , Método Doble Ciego , Quimioterapia Combinada , Procedimientos Endovasculares , Inhibidores del Factor Xa/efectos adversos , Femenino , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Humanos , Incidencia , Isquemia/epidemiología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/cirugía , Inhibidores de Agregación Plaquetaria/efectos adversos , Rivaroxabán/efectos adversosRESUMEN
BACKGROUND: Low dose rivaroxaban with aspirin reduced major cardiovascular events (MACE) compared to aspirin alone in patients with cardiovascular disease although effects on total events are unknown. METHODS: The COMPASS clinical trial randomized 27,395 participants with chronic coronary and/or peripheral artery disease to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg daily. We analyzed total (first and recurrent) MACE outcomes of cardiovascular death, stroke, or myocardial infarction, and the primary safety outcome of major bleeding. Exploratory analyses included on-treatment and net clinical benefit. Total MACE and safety events were modeled for each treatment. RESULTS: MACE events were lowest in rivaroxaban with aspirin (379 first MACE, 432 total MACE) compared with rivaroxaban (448 first, 508 total) or aspirin alone (496 first, 574 total). Rivaroxaban and aspirin reduced total MACE events compared with aspirin alone [HR 0.75, 95% CI 0.66-0.85, P < .0001, number needed to treat for 2 years (NNT2y) of 63]. Total major bleeding was higher for rivaroxaban with aspirin compared to aspirin, but severe bleeding was not increased. The net clinical benefit of rivaroxaban plus aspirin was 20% higher compared with aspirin alone [HR 0.80 (95% CI 16.3%-31.6%)]. Rivaroxaban alone had no benefit on MACE outcomes compared with aspirin alone. MACE outcomes were similar for those on and off randomized treatment. CONCLUSIONS: Low dose rivaroxaban with aspirin significantly reduces first and total cardiovascular events compared with aspirin alone with a NNT2y of 63 and a 20% net clinical benefit. TRIAL REGISTRATION: NCT01776424. https://clinicaltrials.gov/ct2/show/NCT01776424.
Asunto(s)
Enfermedad de la Arteria Coronaria , Enfermedad Arterial Periférica , Humanos , Aspirina , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Quimioterapia Combinada , Inhibidores del Factor Xa , Hemorragia/inducido químicamente , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/efectos adversos , RivaroxabánRESUMEN
BACKGROUND: Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results from the VOYAGER PAD (efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities) trial have demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit for patients undergoing surgical revascularization. However, the efficacy and safety for those treated by surgical bypass, including stratification by bypass conduit (venous or prosthetic), has not yet been described. METHODS: In the VOYAGER PAD trial, patients who had undergone surgical and endovascular infrainguinal LER to treat PAD were randomized to rivaroxaban 2.5 mg twice daily or placebo on top of background antiplatelet therapy (aspirin 100 mg to be used in all and clopidogrel in some at the treating physician's discretion) and followed up for a median of 28 months. The primary end point was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was major bleeding using the TIMI (thrombolysis in myocardial infarction) scale. The index procedure details, including conduit type (venous vs prosthetic), were collected at baseline. RESULTS: Among 6564 randomized patients, 2185 (33%) had undergone surgical LER. Of these 2185 patients, surgical bypass had been performed for 1448 (66%), using a prosthetic conduit for 773 patients (53%) and venous conduit for 646 patients (45%). Adjusting for the baseline differences and anatomic factors, the risk of unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving a prosthetic conduit vs a venous conduit (adjusted hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.65-3.90; P < .001), and the risk of acute limb ischemia was three times greater (adjusted HR, 3.07; 95% CI, 1.84-5.11; P < .001). The use of rivaroxaban reduced the primary outcome for the patients treated with bypass surgery (HR, 0.78; 95% CI, 0.62-0.98), with consistent benefits for those receiving venous (HR, 0.66; 95% CI, 0.49-0.96) and prosthetic (HR, 0.87; 95% CI, 0.66-1.15) conduits (Pinteraction = .254). In the overall trial, major bleeding using the TIMI scale was increased with rivaroxaban. However, the numbers for those treated with bypass surgery were low (five with rivaroxaban vs nine with placebo; HR, 0.55; 95% CI, 0.18-1.65) and not powered to show statistical significance. CONCLUSIONS: Surgical bypass with a prosthetic conduit was associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjustment for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduced this risk, with an increase in the bleeding risk, but had a favorable benefit risk for patients treated with bypass surgery, regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain.
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Infarto del Miocardio , Enfermedad Arterial Periférica , Humanos , Rivaroxabán/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Aspirina/uso terapéutico , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/cirugía , Hemorragia/inducido químicamente , Infarto del Miocardio/tratamiento farmacológico , Isquemia/diagnóstico por imagen , Isquemia/tratamiento farmacológico , Isquemia/cirugía , Extremidad Inferior/irrigación sanguínea , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Previous lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking. METHODS: The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD; rNCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan-Meier estimates, and Cox proportional hazards models were used to generate hazard ratios and associated CIs. Analyses were performed as intention-to-treat. RESULTS: Among 6564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, previous LER, baseline ankle-brachial index <0.50, surgical LER, and longer target lesion length were associated with increased risk of ALI. Incident ALI was associated with subsequent all-cause mortality (hazard ratio [HR], 2.59 [95% CI, 1.98-3.39]) and major amputation (HR, 24.87 [95% CI, 18.68-33.12]). Rivaroxaban reduced ALI relative to placebo by 33% (absolute risk reduction, 2.6% at 3 years; HR, 0.67 [95% CI, 0.55-0.82]; P=0.0001), with benefit starting early (HR, 0.45 [95% CI, 0.24-0.85]; P=0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and intensive care unit stay, HR, 0.58 [95% CI, 0.40-0.83]; P=0.003) and regardless of LER type (surgical versus endovascular revascularization, P interaction=0.42) or clopidogrel use (P interaction=0.59). CONCLUSIONS: After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.
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Isquemia/terapia , Extremidad Inferior/irrigación sanguínea , Rivaroxabán/administración & dosificación , Enfermedad Aguda , Anciano , Aspirina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Números Necesarios a TratarRESUMEN
BACKGROUND: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. METHODS: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. RESULTS: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (P-interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P=0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding (P-interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding (P-interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P=0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (P=0.95) and postprocedural bleeding requiring intervention (P=0.93) was not significantly increased. CONCLUSIONS: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.
Asunto(s)
Aspirina/uso terapéutico , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/cirugía , Rivaroxabán/uso terapéutico , Anciano , Aspirina/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rivaroxabán/farmacologíaRESUMEN
BACKGROUND: Peripheral artery disease (PAD) affects 200 million people worldwide and is associated with impaired quality of life, increased morbidity, and mortality. Supervised exercise therapy (SET) and lower-extremity revascularization (LER) are both proven strategies to improve patient symptoms. Short and long-term functional outcomes after LER for symptomatic PAD in a large, international cohort have not previously been described. METHODS: The VOYAGER PAD trial (ClinicalTrials.gov identifier: NCT02504216) enrolled subjects after LER for symptomatic PAD (Rutherford category 2-6). Participants completed the Walking Impairment Questionnaire (WIQ) at baseline, 1, 3 and 6 months, and every 6 months thereafter. The primary outcome analysis was degree of difficulty walking two blocks at each of the aforementioned time points. Difficulty walking three blocks and climbing one flight of stairs at these time points was also analyzed. Data about supervised and home exercise therapy before or after revascularization were not collected in the VOYAGER PAD trial. RESULTS: Of the 5614 VOYAGER PAD participants completing the WIQ at baseline, three-quarters presented with claudication and one-quarter with critical limb ischemia. Of these, the majority (62% with claudication and 74% with CLI) reported inability or much difficulty walking two blocks prior to LER. Walking improved after LER regardless of revascularization strategy, but one-fifth with claudication and one-third with CLI reported continued inability or much difficulty walking two blocks 1 month after LER. Participants who reported improved walking ability 1 month after LER experienced a durable functional result out to 3 years. Although the proportion of participants reporting significant baseline difficulty climbing one flight of stairs or walking three blocks differed, the trend in immediate and sustained improvement after LER was similar to that observed for walking two blocks. CONCLUSION: In this large, international cohort undergoing LER for symptomatic PAD, nearly two-thirds reported inability or much difficulty walking two blocks at baseline. Although many participants reported improved walking ability after LER, a substantial proportion remained severely disabled. These observations may help motivate providers, patients, and medical systems to improve awareness and engagement in SET referral after LER.
Asunto(s)
Enfermedad Arterial Periférica , Calidad de Vida , Humanos , Claudicación Intermitente/diagnóstico , Claudicación Intermitente/cirugía , Limitación de la Movilidad , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/cirugía , Resultado del Tratamiento , CaminataRESUMEN
AIMS: In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described. METHODS AND RESULTS: The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding). CONCLUSION: Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.
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Isquemia Encefálica , Enfermedad Arterial Periférica , Accidente Cerebrovascular , Anciano , Aspirina/efectos adversos , Quimioterapia Combinada , Inhibidores del Factor Xa/efectos adversos , Humanos , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/cirugía , Inhibidores de Agregación Plaquetaria/efectos adversos , Rivaroxabán/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
BACKGROUND: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described. METHODS: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization. RESULTS: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity (P for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use (P for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel (P for trend=0.06). CONCLUSIONS: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.
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Aspirina/administración & dosificación , Clopidogrel/administración & dosificación , Inhibidores del Factor Xa/administración & dosificación , Extremidad Inferior/irrigación sanguínea , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Rivaroxabán/administración & dosificación , Anciano , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND: The COMPASS trial (Cardiovascular Outcomes for People using Anticoagulation Strategies) demonstrated that dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily reduced the primary major adverse cardiovascular event (MACE) outcome of cardiovascular death, myocardial infarction, or stroke, as well as, mortality, in patients with chronic coronary syndromes or peripheral arterial disease. Whether this remains true in patients with a history of percutaneous coronary intervention (PCI) is unknown. METHODS: In a prespecified subgroup analysis from COMPASS, we examined the outcomes of patients with chronic coronary syndrome with or without a previous PCI treated with DPI versus aspirin alone. Among patients with a previous PCI, we studied the effects of treatment according to the timing of the previous PCI. RESULTS: Of the 27 395 patients in COMPASS, 16 560 patients with a chronic coronary syndrome were randomly assigned to DPI or aspirin, and, of these, 9862 (59.6%) had previous PCI (mean age 68.2±7.8, female 19.4%, diabetes mellitus 35.7%, previous myocardial infarction 74.8%, multivessel PCI 38.0%). Average time from PCI to randomization was 5.4 years (SD, 4.4) and follow-up was 1.98 (SD, 0.72) years. Regardless of previous PCI, DPI versus aspirin produced consistent reductions in MACE (PCI: 4.0% versus 5.5%; hazard ratio [HR], 0.74 [95% CI, 0.61-0.88]; no PCI: 4.4% versus 5.7%; HR, 0.76 [95% CI, 0.61-0.94], P-interaction=0.85) and mortality (PCI: 2.5% versus 3.5%; HR, 0.73 [95% CI, 0.58-0.92]; no PCI: 4.1% versus 5.0%; HR, 0.80 [95% CI, 0.64-1.00], P-interaction=0.59), but increased major bleeding (PCI: 3.3% versus 2.0%; HR, 1.72 [95% CI, 1.34-2.21]; no PCI: 2.9% versus 1.8%; HR, 1.58 [95% CI, 1.15-2.17], P-interaction=0.68). In those with previous PCI, DPI compared with aspirin produced consistent (robust) reductions in MACE irrespective of time since previous PCI (as early as 1 year and as far as 10 years; P-interaction=0.65), irrespective of having a previous myocardial infarction (P-interaction=0.64). CONCLUSIONS: DPI compared with aspirin produced consistent reductions in MACE and mortality but with increased major bleeding with or without previous PCI. Among those with previous PCI 1 year and beyond, the effects on MACE and mortality were consistent irrespective of time since last PCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.
Asunto(s)
Isquemia Crónica que Amenaza las Extremidades , Procedimientos Endovasculares , Rivaroxabán , Procedimientos Quirúrgicos Vasculares , Humanos , Isquemia Crónica que Amenaza las Extremidades/tratamiento farmacológico , Isquemia Crónica que Amenaza las Extremidades/etiología , Isquemia Crónica que Amenaza las Extremidades/cirugía , Procedimientos Endovasculares/efectos adversos , Isquemia/diagnóstico por imagen , Isquemia/tratamiento farmacológico , Isquemia/cirugía , Recuperación del Miembro , Extremidad Inferior/irrigación sanguínea , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/cirugía , Factores de Riesgo , Rivaroxabán/uso terapéutico , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoAsunto(s)
Aspirina , Enfermedad de la Arteria Coronaria , Inhibidores del Factor Xa , Extremidad Inferior , Enfermedad Arterial Periférica , Rivaroxabán , Humanos , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/cirugía , Rivaroxabán/uso terapéutico , Rivaroxabán/administración & dosificación , Aspirina/uso terapéutico , Aspirina/administración & dosificación , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/cirugía , Extremidad Inferior/irrigación sanguínea , Masculino , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/administración & dosificación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Femenino , Anciano , Quimioterapia Combinada , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk. METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation. RESULTS: There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28-0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609-2528). CONCLUSIONS: In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424.
Asunto(s)
Anticoagulantes/efectos adversos , Enfermedades Cardiovasculares/prevención & control , Hemorragia Gastrointestinal/prevención & control , Pantoprazol/administración & dosificación , Úlcera Péptica/prevención & control , Inhibidores de la Bomba de Protones/administración & dosificación , Administración Oral , Anciano , Anticoagulantes/administración & dosificación , Aspirina/administración & dosificación , Aspirina/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Femenino , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Úlcera Péptica/inducido químicamente , Úlcera Péptica/epidemiología , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial. METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up. RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant. CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.
Asunto(s)
Aspirina/administración & dosificación , Enfermedades Cardiovasculares/tratamiento farmacológico , Inhibidores del Factor Xa/administración & dosificación , Hemorragia Gastrointestinal/prevención & control , Pantoprazol/administración & dosificación , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de la Bomba de Protones/administración & dosificación , Rivaroxabán/administración & dosificación , Anciano , Aspirina/efectos adversos , Enfermedades Cardiovasculares/diagnóstico , Método Doble Ciego , Esquema de Medicación , Enterocolitis Seudomembranosa/inducido químicamente , Enterocolitis Seudomembranosa/microbiología , Inhibidores del Factor Xa/efectos adversos , Femenino , Hemorragia Gastrointestinal/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Pantoprazol/efectos adversos , Enfermedad Arterial Periférica/diagnóstico , Inhibidores de Agregación Plaquetaria/efectos adversos , Estudios Prospectivos , Inhibidores de la Bomba de Protones/efectos adversos , Medición de Riesgo , Factores de Riesgo , Rivaroxabán/efectos adversos , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Pantoprazol , Inhibidores de la Bomba de Protones , Humanos , Pantoprazol/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/efectos adversos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Tasa de Filtración Glomerular/efectos de los fármacos , Resultado del TratamientoAsunto(s)
Aterosclerosis , Enfermedad Arterial Periférica , Tromboembolia Venosa , Aspirina/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Quimioterapia Combinada , Inhibidores del Factor Xa/efectos adversos , Humanos , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Rivaroxabán/uso terapéutico , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/prevención & controlRESUMEN
BACKGROUND: No study has investigated the perioperative management and clinical outcomes in patients who are receiving rivaroxaban 2.5 mg twice a day and acetylsalicylic acid (ASA) 81 to 100 mg daily. OBJECTIVE: To assess perioperative management and outcomes in patients who are receiving low-dose rivaroxaban, 2.5 mg twice-daily, and low-dose ASA, 81 to 100 mg daily. To assess perioperative management and outcomes in patients who are receiving low-dose rivaroxaban, 2.5 mg twice-daily, and low-dose ASA, 81 to 100 mg daily. METHODS: Subanalysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was performed to assess perioperative management and clinical outcomes in patients with stable coronary or peripheral artery disease who were randomized to receive rivaroxaban 2.5 mg twice a day plus ASA 100 mg daily, rivaroxaban 5 mg twice a day, or ASA 100 mg daily. Patients studied required a surgery/procedure during the trial. The study outcomes, which included myocardial infarction, angina, stroke, acute limb ischemia, bleeding, and death, were assessed according to treatment allocation. RESULTS: There were 2632 patients studied (mean age, 68 years; 80% male) who had a surgery/procedure, comprising percutaneous coronary interventions (â¼43%), carotid or other arterial angioplasty (â¼15%), pacemaker or internal cardiac defibrillator implantation (â¼9%), and coronary artery bypass graft surgery (â¼7%). Perioperative study drug management varied, with about one-third of patients not interrupting study drug and the remainder interrupting it between 1 and ≥10 days preprocedure. The incidences of adverse outcomes across treatment groups were 12.7% to 15.3% for myocardial ischemia, 0.8% to 1.2% for stroke, 0.1% to 0.2% for venous thromboembolism, and 3.1% to 4.2% for any bleeding. There was no statistically significant difference in outcome rates across treatment groups. CONCLUSION: In patients in the COMPASS trial who required a surgery/procedure, there was no significant difference in perioperative adverse outcomes whether patients were receiving rivaroxaban 2.5 mg twice a day and ASA 100 mg daily, rivaroxaban 5 mg twice a day, or ASA alone.
Asunto(s)
Aspirina , Inhibidores del Factor Xa , Hemorragia , Atención Perioperativa , Enfermedad Arterial Periférica , Inhibidores de Agregación Plaquetaria , Rivaroxabán , Humanos , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Aspirina/administración & dosificación , Aspirina/efectos adversos , Aspirina/uso terapéutico , Anciano , Masculino , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Hemorragia/inducido químicamente , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/terapia , Enfermedad Arterial Periférica/cirugía , Esquema de Medicación , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/cirugía , Factores de Tiempo , Factores de Riesgo , Quimioterapia CombinadaRESUMEN
AIMS: Guidelines recommend extended dual pathway inhibition (DPI) with aspirin and rivaroxaban in patients with chronic coronary syndrome (CCS) at high ischaemic risk. The CHADS-P2A2RC score improves risk prediction and enables antithrombotic treatment allocation in these patients. This study evaluated the net clinical benefit of DPI treatment according to baseline risk as classified by the CHADS-P2A2RC score in patients with CCS included in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. METHODS AND RESULTS: COMPASS patients with CCS (n = 14 670), randomized to aspirin alone or DPI, were stratified according to cardiovascular risk using the CHADS-P2A2RC score. Endpoints were major adverse cardiovascular events (MACE), all-cause death, fatal/critical organ bleeding, and composite adverse events (MACE and bleeding). Net clinical benefit was the 30-month risk difference of MACE and bleeding. Thirty-month incidences of MACE [7.9% vs. 3.9%, hazard ratio (HR) 2.01, 95% confidence interval (CI) 1.83-2.18] and fatal/critical organ bleeding (1.2% vs. 0.8%, HR 1.49, 95% CI 1.06-1.92) were higher in high-risk (CHADS-P2A2RC ≥ 4) than in low/moderate-risk (CHADS-P2A2RC < 4) patients. DPI reduced MACE (low/moderate risk: HR 0.62, 95% CI 0.47-0.82; high risk: HR 0.82, 95% CI 0.68-0.99, P for interaction 0.09) and all-cause death (low/moderate risk: HR 0.65, 95% CI 0.46-0.91; high risk: HR 0.81, 95% CI 0.65-1.00, P for interaction 0.29), without substantially increasing fatal/critical organ bleeding (low/moderate risk: HR 1.35, 95% CI 0.72-2.53; high risk: HR 1.18, 95% CI 0.73-1.90, P for interaction 0.73). DPI provided net clinical benefit of similar magnitude in low/moderate-risk (-1.81%, 95% CI -3.00 to -0.62) and high-risk (-1.96%, 95% CI -3.60 to -0.33) CCS patients. CONCLUSION: As classified by the CHADS-P2A2RC score, low/moderate- and high-risk patients with CCS derived similar net clinical benefit and reduction in all-cause death from DPI treatment.
Asunto(s)
Aspirina , Inhibidores del Factor Xa , Hemorragia , Inhibidores de Agregación Plaquetaria , Rivaroxabán , Humanos , Masculino , Femenino , Anciano , Medición de Riesgo , Hemorragia/inducido químicamente , Resultado del Tratamiento , Persona de Mediana Edad , Factores de Tiempo , Aspirina/efectos adversos , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/uso terapéutico , Rivaroxabán/efectos adversos , Rivaroxabán/administración & dosificación , Enfermedad Crónica , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Terapia Antiplaquetaria Doble/efectos adversos , Factores de Riesgo de Enfermedad CardiacaRESUMEN
BACKGROUND: Win ratio (WR) is a newer analytic approach for trials with composite end points that accounts for the relative importance of individual components. Our objective was to compare the results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial analyzed using WR with those obtained using conventional statistical approaches. METHODS: We used an unmatched WR analysis for first and total (first plus recurrent) events to examine effects of rivaroxaban with aspirin and rivaroxaban alone vs aspirin alone on primary efficacy (cardiovascular death, stroke, myocardial infarction), safety (modified International Society on Thrombosis and Haemostasis major bleeding), and net clinical benefit (primary efficacy plus fatal or critical organ bleeding) end points. We compared the WR results with those obtained using the Cox proportional hazards regression model for first events and Anderson-Gill method for total events. We calculated the win difference to estimate absolute treatment effects. RESULTS: The WR approach produced results consistent with those obtained using conventional statistical methods for the primary composite end point (first event: WR, 1.32 [95% confidence interval (CI), 1.14-1.52]; 1/Cox hazard ratio, 1.32 [95% CI, 1.16-1.52]; total [first plus recurrent] events: WR, 1.32 [95% CI, 1.14-1.52]; 1/Anderson-Gill hazard ratio, 1.32 [95% CI, 1.16-1.54]) as well as for main safety and net clinical benefit end points. The absolute benefits of the combination of rivaroxaban and aspirin compared with aspirin alone calculated using the win difference were greatest in those with multiple high-risk features. CONCLUSIONS: Reanalysis of the COMPASS trial results using WR produced results that were consistent with those obtained using conventional statistical approaches. CLINICAL TRIAL REGISTRATION: NCT01776424.