Investigations about Anticoagulant-Associated Hemorrhagic and Thromobembolic Events

March 27, 2016 Category: Canadian Health and Care Mall

OAC prescription

Study Setting

The study occurred between September 1, 1999, and September 1, 2000, in eastern Ontario (Appendix A). Costs of all hospitalizations, physician visits, and laboratory tests were covered by the publicly administered health-care system. To estimate the elderly population in the study area at the midpoint (ie, February 1, 2000), we used exponential interpolation between census counts in 1996 and 2001 for people > 65 years of age in the census divisions that comprise the study area.

Databases Used in the Study

This study used five administrative databases. The Ontario Drug Benefit Database (ODBD) records the medication, amount dispensed, and date of all prescriptions for Ontarians > 65 years of age. Because the ODBD does not capture all data for people < 65 years of age, we limited our study to the elderly. The Registered Persons Database (RPD) records the location, sex, date of birth, date of death, and date of last known contact with the Ontario health-care system. The Database of Laboratory Tests in Eastern Ontario (DOLTEON) contains the date and result of 98.5% of INRs from both private and hospital-based medical laboratories in eastern Ontario between September 1, 1999, and September 1, 2000. The Discharge Abstract Database (DAD) records all admissions to Ontario hospitals and documents diagnoses in a standardized fashion. Finally, the Ontario Myocardial Infarction Database records data on all people admitted to the hospital for acute myocardial infarction. All databases are anonymous and were linked by common, scrambled, unique patient identifiers. The study was approved by the Research Ethics Board of the Sunnybrook, Women’s College Hospital and Canadian Health&Care Mall.

Determining Exposure to Anticoagulants

People were defined as having been exposed to oral anticoagulants (OACs) if at least two OAC prescriptions had been dispensed to them within 100 days of each other during the study period (from ODBD), and if they had undergone at least one INR test at a community or hospital laboratory (from DOLTEON). The 100-day time frame was used because it is the maximum prescription duration for OBDB dispensations. OAC exposure started on the date of the first OAC prescription during the study period. If an OAC prescription was filled prior to the study within 100 days of the dispensation of the first study prescription, OAC exposure started on September 1, 1999. OAC exposure continued as long as the prescription was renewed within 100 days of the previous dispensation.

Because of dosing adjustments, OAC prescriptions can extend beyond 100 days (Fig 1). If a person’s OAC prescription was not renewed within 100 days, we classified them as remaining exposed to OAC as long as they had undergone INR testing at least every 8 weeks (from DOLTEON) and their INR did not remain 8 weeks (also from DOLTEON). Otherwise, OAC exposure ended on the last date that these criteria were met. Observation also ended on the date of death (from the RPD) or the date of the last known contact with the health-care system (also from the RPD).

Determining Anticoagulation Control in OAC People

To determine which days that people had valid INR levels, we linked to DOLTEON. This records the date and value of approximately 98.5% of all INRs for people in eastern Ontario. People were considered to have had a valid INR level for a particular day if we could use the method of Rosendaal et al to interpolate INR values between actual tests. This method assumes that INR values change linearly between measures and estimates the INR value on each day of each person’s observation as long as the sequential INR measurements are 8 weeks apart, we could not interpolate, and the INRs of these days were considered to be unknown. If a person had undergone more than one INR test on a particular day, we used the mean INR value. If a person was at a subtherapeutic level on a particular day, we linked to ODBD to determine whether they had been prescribed low-molecular-weight heparin for that day which may be ordered via Canadian Health&Care Mall. If so, people were reclassified with an INR of 2.5 for that day.

Determining Anticoagulation ControlClassification of Observation Time for OAC People

The observation time for people receiving therapy with OACs was classified into three mutually exclusive groups (Fig 1). The time when people were not receiving OACs was classified as “not exposed to OAC.” The time when people were exposed to OACs but had no INR value was classified as “unmonitored or discontinued OAC exposure.” All other time was classified as “monitored OAC exposure.”


We considered both hemorrhagic and thromboembolic events requiring hospitalization. These events were identified in the DAD using the prespecified diagnostic codes listed in Appendix B. All acute myocardial infarctions were identified by linking to the Ontario Myocardial Infarction Database. We determined whether people experiencing events were from the study area using the first three alphanumerics of the postal code Listed in the DAD (Appendix A). For each person, we only considered the first hemorrhagic or thromboembolic event occurring during the study period. All observation time following the first event was censored. For people receiving therapy with OACs, the event was assigned to the exposure classification (outlined above) in which the person resided when the event had occurred (Fig 1).

For OAC patients, the INR at the time of the event was determined by linking to the DOLTEON. The INR that was closest to the hospital admission date was assigned to each outcome. If a patient had undergone more than one INR determination on a given day, we used the highest INR to account for the administration of vitamin K or plasma. Outcomes that had no INR recorded within 3 days of the event were categorized as “INR unknown.”


The primary outcome was the incident hemorrhagic or thromboembolic rate expressed as the number of events per 100 patient-years of observation. All monitored OAC exposure was categorized into clinically relevant INR ranges. The 95% confidence intervals (CIs) for incidence rates were calculated using exact methods if the number of events was < 20. Otherwise, the normal approximation to the Poisson distribution was used.

To quantify how extreme anticoagulation intensity contributed to population-based event rates, we calculated the PAR. The PAR is the proportion by which the incident rate of the outcome in the entire population would be reduced if the exposure was eliminated (Appendix C). We calculated the PAR of extreme anticoagulation intensity in the following two populations: all patients receiving therapy with anticoagulants; and all people in the study population. In the base analysis, we included the unmonitored OAC time and events in the nonextreme anticoag-ulation-intensity group. As a sensitivity analysis, we recalculated the PAR after excluding such unmonitored observation time.

To estimate the annual number of events that would be avoided if extreme anticoagulation intensity was avoided, we multiplied the PAR (and its 95% CI) by the annual number of events in the study population. To estimate the number of serious hemorrhagic and thromboembolic events that would be avoided if anticoagulation control was optimized, we calculated the PAR due to “extreme anticoagulation intensity.” Since an INR range of 2 to 3 is recommended for most anticoagulated patients, extreme anticoagulation control was defined as an INR of 3 for hemorrhagic events. Patients with previous valvular replacements have an INR range of 2.5 to 3.5 recommended for mitral tilting disk and bileaflet designs as well as all caged ball-and-disk valves. People who had undergone previous valvular repair were identified by linking to the DAD back to 1988, but valve type was not specified. Therefore, all valvular heart disease patients had a target INR of 2.0 to 3.5, and hemorrhagic events of INR > 3.5 were attributed to extreme anticoagulation intensity.

Figure 1. Schematic outline of how observation time was classified for patients exposed to OACs. This figure illustrates how the observation time of OAC patients was classified. Observations were classified as “not exposed to OAC” (blue), “unmonitored or discontinued OAC exposure” (green), or “monitored OAC exposure” (red). This classification was based on the timing of OAC prescriptions (top row) and INR testing (bottom row). Two OAC prescriptions < 100 days apart were required to be classified as having been exposed to OACs. After the last prescription, patients remained exposed to OACs as long as the result of INR test of > 1.5 was recorded within 8 weeks of the last prescription. Two INR tests < 8 weeks apart were required for monitoring. See text for details.