Page 168 - Haematologica July

G. Grimnes et al.
Figure 1. Case-crossover study design. Relevant risk factors and levels of C-reactive protein were recorded for each case of venous thromboembolism, in the 90-day hazard period prior to the event and in four preceding 90-day control periods, separated by a 90-day washout period.
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15 Even though chronic diseases such as autoimmune dis- eases carry an increased VTE risk, the risk of VTE is more pronounced during disease flare-ups, where inflamma- tion is predominant.14 Acute infection triggers an acute inflammatory response, and several studies have found an increased risk of VTE associated with infections.16,17 We have previously investigated the role of infection dur- ing hospitalization in a case-crossover design, and found that acute infection was a frequent and strong trigger for VTE, also after adjustment for immobilization and other transient risk factors.18 Taken together, this points towards an association between inflammation and VTE which is dependent on the degree of the inflammatory response within a shorter time perspective than as observed in arterial thrombotic disease.
The objective of this study was to investigate the role of acute inflammation, assessed by CRP, as a trigger for VTE using a case-crossover design. In this study design, each case serves as his or her own control, and the design is therefore well suited for studying transient risk fac- tors.19 We hypothesized that increased CRP, independent of cause, was a trigger of VTE.
Methods
For an extensive description of the methods, please see the Online Supplementary Methods. We conducted a case-crossover study including all incident VTE cases (n=707) diagnosed among the participants of the fourth Tromsø Study during 1994-2012. The study was approved by the regional ethics committee, and all participants provided informed written consent. A hazard period of 90 days preceding the incident VTE was compared to four preceding 90-day control periods. To avoid carry-over effects, we included a 90-day washout period between the haz- ard and control periods (Figure 1). For every VTE case, trained medical personnel searched the hospital medical records for rel- evant risk factors, diagnostic procedures, surgical and medical treatment, laboratory test results and diagnoses during hospital admissions, day care and outpatient clinic visits in any of the hazard or control periods. We did not have access to medical records from general practice. A transient risk factor, or trigger, was defined by its presence during the defined 90-day period. If
an exposure occurred over several days, it was considered to have occurred if any of the days of exposure fell within the spec- ified 90-day time period.
CRP was analyzed in serum with a particle-enhanced immunoturbidimetric assay. CRP measurements from the last two days before the date of VTE were not included in the analy- ses to avoid reverse causation, as CRP in these cases could be caused by an inflammatory response to the VTE itself. If a par- ticipant had several CRP-measurements during a control or haz- ard period, the maximum CRP value for each period was used.
Statistical analyses were carried out using STATA version 14.0 (Stata corporation, College station, Texas, USA). Natural log (ln) transformation was used for CRP to achieve normal distribu- tions. Only cases who had their CRP measured in both the haz- ard and a control period were included in the main analyses. Since CRP was measured upon request, this would yield the most conservative risk estimate. We used conditional logistic regression to obtain β coefficients with 95% confidence intervals (CI) for change in ln-CRP from control to hazard periods, and to calculate odds ratios (ORs) with 95% CI per one-unit change in ln-CRP. The analyses were adjusted for immobilization and infection in two different models. Further, we performed analy- ses comparing CRP in the hazard period with each individual control period, to investigate whether time to event influenced the association between acute inflammation and VTE.
In the main analyses, we included only hazard and control periods in which CRP had been measured. The risk estimates from this conservative approach could be underestimations, as subjects with no hospital contact during a hazard or control peri- od, or with a hospital contact without a CRP measurement, most likely had a low CRP at that time. To address this concern, we performed sensitivity analyses where missing CRP values were set at the lower reported cut-off level of 5 mg/L. We also performed sensitivity analyses where we included only those CRP-measurements performed more than seven days before the date of VTE, to address potential bias due to reverse causation.
Results
In total, 707 incident VTEs were identified, of which there were 408 DVTs and 299 PEs (with or without con- current DVT). The median age at time of VTE-diagnosis
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