Description of the Validation Population
Participants with nonvalvular AF who took aspirin at dosages ranging between 75 and 325 mg daily in 6 prospective trials made up the validation cohort . To validate the risk stratification
schemes in an independent cohort of AF patients, patient data that were used to derive any of the 4 classification schemes were excluded from this analysis.
We used patient data from 6 prospective randomized trials. In 4 trials, participants were prescribed aspirin alone: the Atrial Fibrillation, Aspirin, Anticoagulation I (AFASAK-I; n--336) study, 28 the Primary Prevention of Arterial Thromboembolism in patients with nonrheumatic Atrial Fibrillation in primary care study (PATAF; n-- 319), 29 the European Atrial Fibrillation Trial (EAFT; n--404), 30
and the low-risk SPAF III study (n--891; 1 additional SPAF patient was excluded for missing information). From the fifth trial, AFASAK-2, we included participants who were prescribed aspirin,
either alone (n--169) or in combination with an ineffective, 1.25-mg dose of warfarin (n--171). 31 From the sixth trial, high-risk SPAF-III, 32 we included participants (n--290) who were prescribed aspirin
in combination with low-dose warfarin (median dose 2 mg/d) if their international normalized ratio never exceeded 1.4 during follow-up.
Adherence to aspirin therapy exceeded 85% in the studies in which it was reported.
Research coordinators and physicians recorded baseline patient characteristics at the time of enrollment in the original trials. We classified participants into the appropriate strata of each scheme
using baseline clinical characteristics (Appendix). These characteristics included age, previous stroke or TIA, hypertension, cardiac disease, and diabetes. Patients were classified as hypertensive if they
were taking medications given to lower blood pressure or if blood pressure exceeded 140/90 mm Hg. Because echocardiographic information was not available, we were unable to apply one of the stroke
risk factors (decreased systolic function) of the ACCP and SPAF schemes. Likewise, because we could not ascertain the duration of congestive heart failure, we substituted any congestive heart failure
for recent heart failure in the SPAF and CHADS 2 schemes.
During follow-up in these trials, physicians assessed patients with suspected stroke. To identify etiology, a brain CT scan was done in 98% of incident neurological events. Strokes were defined as
neurological deficits that persisted for more than 24 hours and that were not associated with an intracranial hemorrhage.
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Statistical Analysis
Incidence rates for ischemic stroke were calculated as the number of strokes per 100 patient-years of observation. 34 For this calculation, observation started when participants were randomized to aspirin and ended when they experienced an ischemic stroke or were censored. Participants were censored for nonstroke death or study termination.
To calculate 95% CIs, we used the Poisson distribution. We used the weighted к-statistic to compare the agreement between schemes corrected for chance agreement. Because the к-statistic requires the same number of risk strata for all schemes, we collapsed CHADS 2 scores into 3 strata (0, 1 to 2, and 3 to 6) and the Framingham scores into 3 strata (0 to 7, 8 to 13, and -13) for this comparison.
We quantified the discrimination of each stratification scheme using the log-rank test, the Wald х 2 statistic from a Cox proportional hazards model, and the c-statistic. Discrimination is the ability of the stratification schemes to separate the AF population into strata that have distinct stroke rates. A c-statistic of 1.0 indicates perfect discrimination, which means that patients with different stroke risks are always correctly distinguished, whereas a value of 0.5 is noninformative. We bootstrapped 200 samples (with replacement) of the х 2 and c-statistic values using a publicly available macro (http://ftp.sas.com/techsup/download/stat/) and compared the differences values between schemes by paired t tests. Statistical analyses were done with SAS software (SAS Institute Inc). All statistical tests were 2 sided, and probability values --0.05 were considered significant. The Institutional Review Board of participating institutions approved the study.
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