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1.
CMAJ ; 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357997
2.
Diabetes Obes Metab ; 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32383792

RESUMO

AIMS: The United States Food and Drug Administration has warned of an increased risk of serious urinary tract infection (UTI) and Fournier's gangrene in patients with diabetes mellitus type 2 treated with sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, evidence on these risks is limited. We aimed to compare urosepsis rates in SGLT2i users with users of dipeptidyl peptidase-4 inhibitors (DPP4i) in a real-world setting. METHODS: We conducted a matched cohort study using a prevalent new-user design with time-conditional propensity scores. New users of SGLT2i from seven Canadian provinces and the United Kingdom were matched to DPP4i users. The primary outcome was hospitalization with a diagnosis of urosepsis, and the secondary outcome was Fournier's gangrene. Site-specific hazard ratios for urosepsis comparing SGLT2i with DPP4i were estimated using Cox proportional hazards models and pooled using a random-effects meta-analysis. RESULTS: We included 208 244 users of SGLT2i and 208 244 users of DPP4i. Among SGLT2i users, 42% initiated canagliflozin, 31% dapagliflozin, and 27% empagliflozin. During a mean follow-up of 0.9 years, patients initiating SGLT2i had a lower rate of urosepsis compared with those receiving DPP4i. The pooled adjusted hazard ratio was 0.58; 95% confidence interval (CI): 0.42-0.80. The incidence rates of Fournier's gangrene were numerically similar in SGLT2i (0.08 per 1000 person-years; 95% CI: 0.05-0.13) and DPP4i users (0.14; 95% CI: 0.09-0.21). CONCLUSIONS: In this large multi-site study, we did not observe an increased risk for urosepsis associated with SGLT2i compared with DPP4i among patients with type 2 diabetes in a real-world setting.

4.
Value Health ; 23(4): 434-440, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32327160

RESUMO

OBJECTIVES: Outcomes-based contracts tie rebates and discounts for expensive drugs to outcomes. The objective was to estimate the utility of outcomes-based contracts for diabetes medications using real-world data and to identify methodologic limitations of this approach. METHODS: A population-based cohort study of adults newly prescribed a medication for diabetes with a publicly announced outcomes-based contract (ie, exenatide microspheres ["exenatide"], dulaglutide, or sitagliptin) was conducted. The comparison group included patients receiving canagliflozin or glipizide. The primary outcome was announced in the outcomes-based contract: the percentage of adults with a follow-up hemoglobin A1C <8% up to 1 year later. Secondary outcomes included the percentage of patients diagnosed with hypoglycemia and the cost of a 1-month supply. RESULTS: Thousands of adults newly filled prescriptions for exenatide (n = 5079), dulaglutide (n = 6966), sitagliptin (n = 40 752), canagliflozin (n = 16 404), or glipizide (n = 59 985). The percentage of adults subsequently achieving a hemoglobin A1C below 8% ranged from 83% (dulaglutide, sitagliptin) to 71% (canagliflozin). The rate of hypoglycemia was 25 per 1000 person-years for exenatide, 37 per 1000 person-years for dulaglutide, 28 per 1000 person-years for sitagliptin, 18 per 1000 person-years for canagliflozin, and 34 per 1000 person-years for glipizide. The cash price for a 1-month supply was $847 for exenatide, $859 for dulaglutide, $550 for sitagliptin, $608 for canagliflozin, and $14 for glipizide. CONCLUSION: Outcomes-based pricing of diabetes medications has the potential to lower the cost of medications, but using outcomes such as hemoglobin A1C may not be clinically meaningful because similar changes in A1C can be achieved with generic medications at a far lower cost.

6.
Ann Intern Med ; 172(7): 463-473, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32150751

RESUMO

Background: Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking. Objective: To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation. Design: New-user, active-comparator, retrospective cohort study. Setting: A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019. Patients: Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706). Measurements: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding. Results: 39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.98]; rate difference, 1.4 fewer events per 1000 person-years [CI, 0.0 to 2.7]). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1). Limitation: Unmeasured confounding, incomplete laboratory data. Conclusion: In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban. Primary Funding Source: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital.

7.
Ann Intern Med ; 172(3): 186-194, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31931526

RESUMO

Background: Hyperuricemia is common in patients with type 2 diabetes mellitus and is known to cause gout. Sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent glucose reabsorption and lower serum uric acid levels. Objective: To compare the rate of gout between adults prescribed an SGLT2 inhibitor and those prescribed a glucagon-like peptide-1 (GLP1) receptor agonist. Design: Population-based new-user cohort study. Setting: A U.S. nationwide commercial insurance database from March 2013 to December 2017. Patients: Persons with type 2 diabetes newly prescribed an SGLT2 inhibitor were 1:1 propensity score matched to patients newly prescribed a GLP1 agonist. Persons were excluded if they had a history of gout or had received gout-specific treatment previously. Measurements: The primary outcome was a new diagnosis of gout. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of the primary outcome and 95% CIs. Results: The study identified 295 907 adults with type 2 diabetes mellitus who were newly prescribed an SGLT2 inhibitor or a GLP1 agonist. The gout incidence rate was lower among patients prescribed an SGLT2 inhibitor (4.9 events per 1000 person-years) than those prescribed a GLP1 agonist (7.8 events per 1000 person-years), with an HR of 0.64 (95% CI, 0.57 to 0.72) and a rate difference of -2.9 (CI, -3.6 to -2.1) per 1000 person-years. Limitation: Unmeasured confounding, missing data (namely incomplete laboratory data), and low baseline risk for gout. Conclusion: Adults with type 2 diabetes prescribed an SGLT2 inhibitor had a lower rate of gout than those prescribed a GLP1 agonist. Sodium-glucose cotransporter-2 inhibitors may reduce the risk for gout among adults with type 2 diabetes mellitus, although future studies are necessary to confirm this observation. Primary Funding Source: Brigham and Women's Hospital.

11.
PLoS Med ; 16(10): e1002930, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31634354

RESUMO

BACKGROUND: Desmopressin was approved by the Food and Drug Administration (FDA) in 1978 for use in diabetes insipidus and bleeding disorders, but it is also prescribed off-label for patients with nocturia. Quantifying the potential risks facing adult patients taking desmopressin has taken on added importance because a new intranasal formulation of desmopressin was approved by the FDA in 2017. Like the old formulation, the main active ingredient is desmopressin acetate, but the new formulation also contains an excipient designed to enhance absorption. Our objective was to quantify the rate of hyponatremia in routine clinical care for patients prescribed the older formulation of desmopressin. METHODS AND FINDINGS: We conducted a population-based new-user cohort study from 1 February 2006 to 1 February 2017 using a nationwide commercial health plan database. Patients newly prescribed the older formulation of desmopressin were propensity-score (PS)-matched to patients newly prescribed oxybutynin. As a sensitivity analysis, tamsulosin was used as the comparator rather than oxybutynin. The primary outcome was a primary position diagnosis of hyponatremia. Proportional hazard models after 1:1 PS matching were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). We identified 3,137 adults who were newly prescribed desmopressin and matched them to 3,137 adults who were newly prescribed oxybutynin. Mean age was 70, 55% were male, 13% filled a prescription for a diuretic during the baseline time period, and the mean baseline sodium prior to receiving either study drug was 140 mmol/L (normal: 135-145). The rate of hyponatremia was 146 per 1,000 person-years for adults prescribed desmopressin compared to 11 per 1,000 person-years for adults prescribed oxybutynin, corresponding to a 13-fold higher rate (HR 13.19; 95% CI 6.69, 26.01; p < 0.01). When follow-up was truncated at 30 days, a similar increased rate was observed (HR 19.41; 95% CI 7.11, 52.99; p < 0.01). A higher rate of hyponatremia was also observed with desmopressin when tamsulosin was the comparator (HR 12.10; 95% CI 6.54, 22.37; p < 0.01). Important limitations of our study include unmeasured confounding (for example, over-the-counter medication use, dietary intake), missing data (i.e., only 20% of patients had a baseline serum sodium), and a lack of data on the newer formulation of desmopressin. CONCLUSIONS: Use of an older formulation of desmopressin was associated with a marked increased rate of subsequent hyponatremia compared to use of other medications indicated for lower urinary tract symptoms. Such risks should be clearly communicated to patients prescribed this formulation of desmopressin.


Assuntos
Desamino Arginina Vasopressina/efeitos adversos , Hemostáticos/efeitos adversos , Hiponatremia/induzido quimicamente , Administração Intranasal , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Ácidos Mandélicos/administração & dosagem , Pessoa de Meia-Idade , Noctúria/tratamento farmacológico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Fatores de Risco , Tansulosina/administração & dosagem , Resultado do Tratamento
13.
Ann Intern Med ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31357213

RESUMO

Background: Prior studies evaluating risk for severe urinary tract infections (UTIs) with sodium-glucose cotransporter-2 (SGLT-2) inhibitors have reported conflicting findings. Objective: To assess whether patients initiating use of SGLT-2 inhibitors were at increased risk for severe UTI events compared with those initiating use of dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 receptor (GLP-1) agonists. Design: Population-based cohort study. Setting: 2 large, U.S.-based databases of commercial claims (March 2013 to September 2015). Participants: Within each database, 2 cohorts were created and matched 1:1 on propensity score. Patients were aged 18 years or older, had type 2 diabetes mellitus, and were initiating use of SGLT-2 inhibitors versus DPP-4 inhibitors (cohort 1) or GLP-1 agonists (cohort 2). Measurements: The primary outcome was a severe UTI event, defined as a hospitalization for primary UTI, sepsis with UTI, or pyelonephritis; the secondary outcome was outpatient UTI treated with antibiotics. Hazard ratios [HRs] were estimated in each propensity score-matched cohort, with adjustment for more than 90 baseline characteristics. Results: After 1:1 matching on propensity score, 123 752 patients were identified in cohort 1 and 111 978 in cohort 2 in the 2 databases. In cohort 1, persons newly receiving SGLT-2 inhibitors had 61 severe UTI events (incidence rate [IR] per 1000 person-years, 1.76), compared with 57 events in the DPP-4 inhibitor group (IR, 1.77) (HR, 0.98 [95% CI, 0.68 to 1.41]). In cohort 2, those receiving SGLT-2 inhibitors had 73 events (IR, 2.15), compared with 87 events in the GLP-1 agonist group (IR, 2.96) (HR, 0.72 [CI, 0.53 to 0.99]). Findings were robust across sensitivity analyses; within several subgroups of age, sex, and frailty; and for canagliflozin and dapagliflozin individually. In addition, SGLT-2 inhibitors were not associated with increased risk for outpatient UTIs (cohort 1: HR, 0.96 [CI, 0.89 to 1.04]; cohort 2: HR, 0.91 [CI, 0.84 to 0.99]). Limitation: Generalizability of the study findings may be limited to patients with commercial insurance. Conclusion: In a large cohort of patients seen in routine clinical practice, risk for severe and nonsevere UTI events among those initiating SGLT-2 inhibitor therapy was similar to that among patients initiating treatment with other second-line antidiabetic medications. Primary Funding Source: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.

16.
Ann Intern Med ; 170(3): 155-163, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30597484

RESUMO

Background: Sodium-glucose cotransporter-2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral density and a potential increased risk for fracture. Objective: To estimate risk for nonvertebral fracture among new users of canagliflozin compared with a glucagon-like peptide-1 (GLP-1) agonist. Design: Population-based new-user cohort study. Setting: Two U.S. commercial health care databases providing data on more than 70 million patients from March 2013 to October 2015. Patients: Persons with type 2 diabetes who initiated use of canagliflozin were propensity score-matched in a 1:1 ratio to those initiating use of a GLP-1 agonist. Measurements: The primary outcome was a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention. Secondary outcomes included fractures at other sites. A fixed-effects meta-analysis that pooled results from the 2 databases provided an overall hazard ratio (HR). Results: 79 964 patients initiating use of canagliflozin were identified and matched to 79 964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1000 person-years) and GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) (overall HR, 0.92 [CI, 0.83 to 1.02]). Limitation: Unmeasured confounding, measurement error, and low fracture rate. Conclusion: In this study of middle-aged patients with type 2 diabetes and relatively low fracture risk, canagliflozin was not associated with increased risk for fracture compared with GLP-1 agonists. Primary Funding Source: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.


Assuntos
Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fraturas Ósseas/etiologia , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Idoso , Feminino , Seguimentos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Medição de Risco
17.
JAMA Intern Med ; 179(2): 224-230, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30615021

RESUMO

Importance: In 2010, the US Food and Drug Administration (FDA) approved a combination of dextromethorphan hydrobromide and quinidine sulfate for the treatment of pseudobulbar affect after studies in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This medication, however, may be commonly prescribed in patients with dementia and/or Parkinson disease (PD). Objective: To investigate the prescribing patterns of dextromethorphan-quinidine, including trends in associated costs. Design, Setting, and Participants: This population-based cohort study of patients prescribed dextromethorphan-quinidine used data from 2 commercial insurance databases, Optum Clinformatics Data Mart and Truven Health MarketScan. The Medicare Part D Prescription Drug Program data set was used to evaluate numbers of prescriptions and total reported spending by the Centers for Medicare & Medicaid Services. Patients were included if they were prescribed dextromethorphan-quinidine from October 29, 2010, when the drug was approved, through March 1, 2017, for Optum and December 31, 2015, for Truven. Data were analyzed from December 1, 2017, through August 1, 2018. Main Outcomes and Measures: The proportion of patients prescribed dextromethorphan-quinidine with a diagnosis of MS, ALS, or dementia and/or PD, as well as the number of patients with a history of heart failure (a contraindication for the drug). Results: In the commercial health care databases, 12 858 patients filled a prescription for dextromethorphan-quinidine during the study period. Mean (SD) age was 66.0 (18.5) years, 66.7% were women, and 13.3% had a history of heart failure. Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD. In the Medicare Part D database, the number of patients prescribed dextromethorphan-quinidine increased 15.3-fold, from 3296 in 2011 to 50 402 in 2016. Reported spending by Centers for Medicare & Medicaid Services on this medication increased from $3.9 million in 2011 to $200.4 million in 2016. Conclusions and Relevance: Despite approval by the FDA for pseudobulbar affect based on studies of patients with ALS or MS, dextromethorphan-quinidine appears to be primarily prescribed for patients with dementia and/or PD.


Assuntos
Demência/tratamento farmacológico , Dextrometorfano/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Paralisia Pseudobulbar/tratamento farmacológico , Quinidina/uso terapêutico , Idoso , Esclerose Amiotrófica Lateral/complicações , Combinação de Medicamentos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Paralisia Pseudobulbar/etiologia , Estados Unidos , United States Food and Drug Administration
18.
JAMA Neurol ; 76(2): 144-151, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419085

RESUMO

Importance: Concussion is the most common form of traumatic brain injury (TBI). While most patients fully recover within 1 week of injury, a subset of patients might be at a higher risk of suicide. Objective: To assess the risk of suicide after concussion. Data Sources: We performed a systematic search of Medline (PubMed), Embase, PsycINFO, and Published International Literature on Traumatic Stress (PILOTS) from 1963 to May 1, 2017. We also searched Google Scholar and conference proceedings and contacted experts in the field to seek additional studies. Study Selection: Studies that quantified the risk of suicide, suicide attempt, or suicidal ideation after a concussion and/or mild TBI were included. Studies that included children and adults, including military and nonmilitary personnel, were included. Two authors independently reviewed all titles and abstracts to determine study eligibility. Data Extraction and Synthesis: Study characteristics were extracted independently by 2 trained investigators. Study quality was assessed using the Newcastle-Ottawa Scale. Study data were pooled using random-effects meta-analysis. Main Outcomes and Measures: The primary exposure was concussion and/or mild TBI, and the primary outcome was suicide. Secondary outcomes were suicide attempt and suicidal ideation. Results: Data were extracted from 10 cohort studies (n = 713 706 individuals diagnosed and 6 236 010 individuals not diagnosed with concussion and/or mild TBI), 5 cross-sectional studies (n = 4420 individuals diagnosed and 11 275 individuals not diagnosed with concussion and/or mild TBI), and 2 case-control studies (n = 446 individuals diagnosed and 8267 individuals not diagnosed with concussion and/or mild TBI). Experiencing concussion and/or mild TBI was associated with a 2-fold higher risk of suicide (relative risk, 2.03 [95% CI, 1.47-2.80]; I2 = 96%; P < .001). In 2 studies that provided estimates with a median follow-up of approximately 4 years, 1664 of 333 118 individuals (0.50%) and 750 of 126 114 individuals (0.59%) diagnosed with concussion and/or mild TBI died by suicide. Concussion was also associated with a higher risk of suicide attempt and suicide ideation. The heightened risk of suicide outcomes after concussion was evident in studies with and without military personnel. Conclusions and Relevance: Experiencing concussion and/or mild TBI was associated with a higher risk of suicide. Future studies are needed to identify and develop strategies to decrease this risk.


Assuntos
Concussão Encefálica/complicações , Suicídio , Concussão Encefálica/epidemiologia , Humanos , Suicídio/estatística & dados numéricos
20.
BMJ Open ; 8(7): e023761, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-30049703

RESUMO

OBJECTIVE: To examine the relative impact of three management options in patients aged <60 years with cryptogenic stroke and a patent foramen ovale (PFO): PFO closure plus antiplatelet therapy, antiplatelet therapy alone and anticoagulation alone. DESIGN: Systematic review and network meta-analysis (NMA) supported by complementary external evidence. DATA SOURCES: Medline, EMBASE and Cochrane CENTRAL. STUDY SELECTION: Randomised controlled trials (RCTs) addressing PFO closure and/or medical therapies in patients with PFO and cryptogenic stroke. REVIEW METHODS: We conducted an NMA complemented with external evidence and rated certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Ten RCTs in eight studies proved eligible (n=4416). Seven RCTs (n=3913) addressed PFO closure versus medical therapy. Of these, three (n=1257) addressed PFO closure versus antiplatelet therapy, three (n=2303) addressed PFO closure versus mixed antiplatelet and anticoagulation therapies and one (n=353) addressed PFO closure versus anticoagulation. The remaining three RCTs (n=503) addressed anticoagulant versus antiplatelet therapy. PFO closure versus antiplatelet therapy probably results in substantial reduction in ischaemic stroke recurrence (risk difference per 1000 patients over 5 years (RD): -87, 95% credible interval (CrI) -100 to -33; moderate certainty). Compared with anticoagulation, PFO closure may confer little or no difference in ischaemic stroke recurrence (low certainty) but probably has a lower risk of major bleeding (RD -20, 95% CrI -27 to -2, moderate certainty). Relative to either medical therapy, PFO closure probably increases the risk of persistent atrial fibrillation (RD 18, 95% CI +5 to +56, moderate certainty) and device-related adverse events (RD +36, 95% CI +23 to +50, high certainty). Anticoagulation, compared with antiplatelet therapy, may reduce the risk of ischaemic stroke recurrence (RD -71, 95% CrI -100 to +17, low certainty), but probably increases the risk of major bleeding (RD +12, 95% CrI -5 to +65, moderate certainty). CONCLUSIONS: In patients aged <60 years, PFO closure probably confers an important reduction in ischaemic stroke recurrence compared with antiplatelet therapy alone but may make no difference compared with anticoagulation. PFO closure incurs a risk of persistent atrial fibrillation and device-related adverse events. Compared with alternatives, anticoagulation probably increases major bleeding. PROSPERO REGISTRATION NUMBER: CRD42017081567.


Assuntos
Anticoagulantes/uso terapêutico , Isquemia Encefálica/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/métodos , Forame Oval Patente/terapia , Inibidores da Agregação de Plaquetas/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Fibrilação Atrial/epidemiologia , Isquemia Encefálica/etiologia , Terapia Combinada , Forame Oval Patente/complicações , Humanos , Metanálise em Rede , Complicações Pós-Operatórias/epidemiologia , Recidiva , Prevenção Secundária , Acidente Vascular Cerebral/etiologia
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