Apixaban Drug Utilization Study In Stroke Prevention In Atrial Fibrillation (Spaf)

The primary research question is to evaluate the apixaban utilization according to the approved SPAF indication and recommendations by EMA.

In addition a comparison with a cohort of NVAF patients treated with VKA, dabigatran and rivaroxaban for the SPAF indication will also be performed.

Objective 1: To characterize patients using apixaban according to demographics, comorbidity, risk of thromboembolic events (CHADS2 and CHA2DS2-Vasc scores), risk of bleeding events (HAS-BLED score), comedications and compare it with the profile of patients treated with VKA, dabigatran and rivaroxaban.

Objective 2: Describe the level of appropriate usage according to the posology recommended in the apixaban SmPC.

Objective 3: Describe the potential interactions with other drugs prescribed concomintatly according with the SmPC recommendations.

Objective 4: Estimate the level of apixaban adherence by the medication possession ratio (MPR) and discontinuation rates and compare it with VKA, dabigatran and rivaroxaban cohort.

Objective 5: To analyze INR (International Normalized Ratio) values during the last 12 months and to obtain TTR (Time in Therapeutic Range) values in patients previously treated with VKA, and during the whole study period for those in the cohort treated with VKA.

• apixaban (Drug): current or new medication
• dabigatran (Drug): current or new medication
• VKA (Drug): current or new medication
• rivaroxaban (Drug): current or new medication

Primary outcomes

• Number of Participants by Their Sociodemographic Characteristics: Smoking Habit [Day 1]: Socio-demographics were characteristics of a population. One of the socio-demographics characteristics included smoking habit.
• Number of Participants by Their Sociodemographic Characteristics: Alcoholic Habit [Day 1]: Socio-demographics were characteristics of a population. One of the socio-demographics characteristics included alcoholic habit.
• Number of Participants by Their Sociodemographic Characteristics: MEDEA [Day 1]: Socio-demographics were characteristics of a population. One of the socio-demographics characteristics included MEDEA. MEDEA was a deprivation index that was associated with overall mortality in urban areas. It included factors like job, education, housing conditions and single parent homes. The MEDEA index was categorized in quintiles for urban areas, with quintile 1 corresponding to the least deprived population and quintile 5, the most deprived.
• Number of Participants by Their Sociodemographic Characteristics: Body Mass Index (BMI) [Day 1]: Socio-demographics were characteristics of a population. One of the socio-demographics characteristics included BMI. BMI was defined as an index for assessing overweight and underweight and was obtained by dividing body weight in kilograms (kg) by height in meters squared (m\^2).
• Number of Participants by Comorbidity [Up to 12 months after date of first prescription]: Comorbidity was defined as the presence of one or more additional diseases or disorders co-occurring with (that is, concomitant or concurrent with) a primary disease or disorder.
• Risk of Bleeding Events: HAS-BLED Score [Up to 12 months prior to enrollment]: Risk of bleeding events was assessed by using HAS-BLED score. HAS-BLED was a scoring system that was developed to assess 1 year risk of occurrence of major hemorrhage. HAS-BLED score was assessed by combining score of 9 risk factors: hypertension history, renal disease, liver disease, stroke history, prior major bleeding or predisposition to bleeding, labile international normalized ratio (INR), age >65 years, medication usage predisposing to bleeding and alcohol or drug usage history. The total score ranged from 0 to 9 where 0 = low risk of bleed per 100 participants-year and >3 = high risk of bleed per 100 participants-year.
• Risk of Thromboembolic Events: CHADS2 Score [Up to 12 months prior to enrollment]: Thromboembolic events were defined as an embolic stroke that occurred when a blood clot that formed elsewhere in the body breaks loose and travels to the brain via bloodstream. Risk of thromboembolic events was calculated using CHADS2 score. CHADS2 score was assessed by combining score of 5 risk factors (congestive heart failure history, hypertension history, age >=75 years, diabetes mellitus history and stroke/transient ischemic attack symptoms previously). Total CHADS2 score ranged from 0-6 where 0 =low risk and 6 =high risk of stroke.
• Risk of Thromboembolic Events: CHA2DS2Vasc Score [Up to 12 months prior to enrollment]: Thromboembolic events were defined as an embolic stroke that occurred when a blood clot that formed elsewhere in the body breaks loose and travels to the brain via bloodstream. Risk of thromboembolic events was calculated using CHA2DS2Vasc score. CHA2DS2Vasc score was assessed by combining score of 8 risk factors (female, >=65 and <75 years, congestive heart failure history, hypertension history, diabetes mellitus history, vascular disease history, age >=75 years and stroke/TIA symptoms previously). Total CHA2DS2Vasc score ranged from 0-9 where 0=low risk and 9=high risk of stroke.
• Number of Participants by Comedications [Up to 30 days after date of first prescription]: Comedication was defined as the second or alternative medication used to relieve the side-effects of another medicine.
• Number of Participants With Apixaban Adherence With VKA, Dabigatran and Rivaroxaban as Assessed by Medication Possession Ratio (MPR) [Up to 12 months after date of first prescription]: MPR was one of the methods of measuring adherence and was defined as the ratio of all days supply to elapsed days, during the 12-month observation period. All days supply defined as sum of number of days supply between the start date and last prescription dispensed. Elapsed days defined as number of days between the start date and the last prescription dispensed. There were three categories of adherence: poor defined as <80% of MPR, good defined as between 80% and 120% of MPR and over adherence defined as >120% of MPR.
• Number of Participants With Apixaban Adherence With VKA, Dabigatran and Rivaroxaban as Assessed by Discontinuation Throughout the Year [Up to 12 months after date of first prescription]: Discontinuation rate was defined as the lack of subsequent prescription of the index drugs within 2 months after last supply day of the last prescription. It was analyzed by calculating the treatment withdrawal or switch rate.
• Apixaban Adherence With VKA, Dabigatran and Rivaroxaban by Number of Defined Daily Dose (NDDD) [Up to 12 months after date of first prescription]: NDDD was a measure that represented the average daily maintenance dose for the main indication of a drug.
• International Normalized Ratio (INR) Values During the Last 12 Months Values in Participants Previously Treated With VKA [Up to 12 months after date of first prescription]: INR was defined as the ratio of the participant's prothrombin time and the normal mean prothrombin time. Prothrombin time defined as a time taken by the blood to clot in participants receiving oral anticoagulant medication. INR was categorized according to the risk level: risk for coagulation (INR<2); optimal range (2<INR<3); and risk of hemorrhages (INR>3).
• Time in Therapeutic Range (TTR) Values During the Last 12 Months Values in Participants Previously Treated With VKA [Up to 12 months after date of first prescription]: TTR was defined as the duration of time in which the participant's INR values were within a desired range (2 to 3). INR was defined as the ratio of the participant's prothrombin time and the normal mean prothrombin time. Prothrombin time defined as a time taken by the blood to clot in participants receiving oral anticoagulant medication. INR was categorized according to the risk level: risk for coagulation (INR<2); optimal range (2<INR<3); and risk of hemorrhages (INR>3).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Patients more than 18 years-old.
2. Patients diagnosed with NVAF registered in primary care according to ICD-10.
3. Patients initiating apixaban (naïve or VKA experienced), VKA (naïve or VKA experienced), dabigatran or rivaroxaban for the SPAF indication.
4. Continuous enrolment in the 12 months pre-index.

Exclusion Criteria:

1. Patients with valvular heart disease (ICD 10: I05.0-I05.09, I08.0-I08.9) including patients with mitral prosthetic valves.
2. Lost to follow-up (e.g. transfer to primary care center non-ICS).

Participant flow

Outcome results

• Number of Participants by Their Sociodemographic Characteristics: Smoking Habit (Primary), Count of participants, Participants: Apixaban: Naive 207; Apixaban: Non Naive 23; Acenocoumarol: Naive 1844; Acenocoumarol: Non-Naive 7; Warfarin: Naive 112; Warfarin: Non-Naive 14; Dabigatran: Naive 225; Dabigatran: Non-Naive 23; Rivaroxaban: Naive 354; Rivaroxaban: Non-Naive 38 (p 0.000)
• Number of Participants by Their Sociodemographic Characteristics: Alcoholic Habit (Primary), Count of participants, Participants: Apixaban: Naive 2162; Apixaban: Non Naive 353; Acenocoumarol: Naive 11299; Acenocoumarol: Non-Naive 40; Warfarin: Naive 839; Warfarin: Non-Naive 91; Dabigatran: Naive 1263; Dabigatran: Non-Naive 211; Rivaroxaban: Naive 2475; Rivaroxaban: Non-Naive 366 (p 0.000)
• Number of Participants by Their Sociodemographic Characteristics: MEDEA (Primary), Count of participants, Participants: Apixaban: Naive 190; Apixaban: Non Naive 90; Acenocoumarol: Naive 1754; Acenocoumarol: Non-Naive 16; Warfarin: Naive 120; Warfarin: Non-Naive 28; Dabigatran: Naive 110; Dabigatran: Non-Naive 57; Rivaroxaban: Naive 230; Rivaroxaban: Non-Naive 145 (p 0.000)
• Number of Participants by Their Sociodemographic Characteristics: Body Mass Index (BMI) (Primary), Count of participants, Participants: Apixaban: Naive 1424; Apixaban: Non Naive 261; Acenocoumarol: Naive 6898; Acenocoumarol: Non-Naive 34; Warfarin: Naive 509; Warfarin: Non-Naive 87; Dabigatran: Naive 960; Dabigatran: Non-Naive 178; Rivaroxaban: Naive 1746; Rivaroxaban: Non-Naive 311 (p 0.000)
• Number of Participants by Comorbidity (Primary), Count of participants, Participants: Apixaban: Naive 3695; Apixaban: Non Naive 1316; Acenocoumarol: Naive 26450; Acenocoumarol: Non-Naive 173; Warfarin: Naive 1819; Warfarin: Non-Naive 318; Dabigatran: Naive 2030; Dabigatran: Non-Naive 870; Rivaroxaban: Naive 3731; Rivaroxaban: Non-Naive 1417 (p 0.000)
• Risk of Bleeding Events: HAS-BLED Score (Primary), Mean, bleed per 100 participants-year: Apixaban: Naive 1.7 +/- 1.0; Apixaban: Non Naive 2.7 +/- 1.1; Acenocoumarol: Naive 2.2 +/- 1.1; Acenocoumarol: Non-Naive 2.5 +/- 1.0; Warfarin: Naive 1.9 +/- 1.1; Warfarin: Non-Naive 2.4 +/- 1.2; Dabigatran: Naive 1.5 +/- 1.0; Dabigatran: Non-Naive 2.6 +/- 1.0; Rivaroxaban: Naive 1.6 +/- 1.0; Rivaroxaban: Non-Naive 2.6 +/- 1.1 (p 0.000)
• Risk of Thromboembolic Events: CHADS2 Score (Primary), Mean, stroke risk per year: Apixaban: Naive 1.7 +/- 1.3; Apixaban: Non Naive 2.8 +/- 1.4; Acenocoumarol: Naive 1.9 +/- 1.3; Acenocoumarol: Non-Naive 2.3 +/- 1.3; Warfarin: Naive 1.8 +/- 1.3; Warfarin: Non-Naive 2.5 +/- 1.5; Dabigatran: Naive 1.5 +/- 1.3; Dabigatran: Non-Naive 2.6 +/- 1.4; Rivaroxaban: Naive 1.5 +/- 1.2; Rivaroxaban: Non-Naive 2.6 +/- 1.4 (p 0.000)
• Risk of Thromboembolic Events: CHA2DS2Vasc Score (Primary), Mean, stroke risk per year: Apixaban: Naive 3.0 +/- 1.7; Apixaban: Non Naive 4.4 +/- 1.6; Acenocoumarol: Naive 3.2 +/- 1.7; Acenocoumarol: Non-Naive 3.7 +/- 1.6; Warfarin: Naive 2.9 +/- 1.8; Warfarin: Non-Naive 3.9 +/- 1.9; Dabigatran: Naive 2.7 +/- 1.8; Dabigatran: Non-Naive 4.0 +/- 1.7; Rivaroxaban: Naive 2.7 +/- 1.7; Rivaroxaban: Non-Naive 4.1 +/- 1.7 (p 0.000)
• Number of Participants by Comedications (Primary), Count of participants, Participants: Apixaban: Naive 4712; Apixaban: Non Naive 1406; Acenocoumarol: Naive 32212; Acenocoumarol: Non-Naive 188; Warfarin: Naive 2286; Warfarin: Non-Naive 352; Dabigatran: Naive 2855; Dabigatran: Non-Naive 947; Rivaroxaban: Naive 5132; Rivaroxaban: Non-Naive 1532 (p 0.008)
• Number of Participants With Apixaban Adherence With VKA, Dabigatran and Rivaroxaban as Assessed by Medication Possession Ratio (MPR) (Primary), Count of participants, Participants: Apixaban: Naive 162; Apixaban: Non Naive 151; Acenocoumarol: Naive 5634; Acenocoumarol: Non-Naive 31; Warfarin: Naive 103; Warfarin: Non-Naive 57; Dabigatran: Naive 241; Dabigatran: Non-Naive 177; Rivaroxaban: Naive 147; Rivaroxaban: Non-Naive 131 (p 0.000)
• Number of Participants With Apixaban Adherence With VKA, Dabigatran and Rivaroxaban as Assessed by Discontinuation Throughout the Year (Primary), Count of participants, Participants: Apixaban: Naive 881; Apixaban: Non Naive 236; Acenocoumarol: Naive 11326; Acenocoumarol: Non-Naive 85; Warfarin: Naive 1009; Warfarin: Non-Naive 127; Dabigatran: Naive 1002; Dabigatran: Non-Naive 248; Rivaroxaban: Naive 1191; Rivaroxaban: Non-Naive 322 (p 0.000)
• Apixaban Adherence With VKA, Dabigatran and Rivaroxaban by Number of Defined Daily Dose (NDDD) (Primary), Median, milligrams per day: Apixaban: Naive 15.0 (15.0 to 30.0); Apixaban: Non Naive 30.0 (15.0 to 30.0); Acenocoumarol: Naive 16.0 (16.0 to 32.0); Acenocoumarol: Non-Naive 16.0 (16.0 to 32.0); Warfarin: Naive 53.0 (53.0 to 53.0); Warfarin: Non-Naive 16.0 (5.0 to 53.0); Dabigatran: Naive 22.0 (22.0 to 29.0); Dabigatran: Non-Naive 22.0 (22.0 to 29.0); Rivaroxaban: Naive 21.0 (15.0 to 28.0); Rivaroxaban: Non-Naive 28.0 (21.0 to 28.0) (p 0.000)
• International Normalized Ratio (INR) Values During the Last 12 Months Values in Participants Previously Treated With VKA (Primary), Mean, ratio: Acenocoumarol: Naive 2.5 +/- 0.4; Acenocoumarol: Non-Naive 2.5 +/- 0.4; Warfarin: Naive 2.5 +/- 0.3; Warfarin: Non-Naive 2.6 +/- 0.4
• Time in Therapeutic Range (TTR) Values During the Last 12 Months Values in Participants Previously Treated With VKA (Primary), Median, days: Acenocoumarol: Naive 60.2 (47.2 to 71.8); Acenocoumarol: Non-Naive 59.6 (47.7 to 68.4); Warfarin: Naive 66.2 (52.2 to 77.4); Warfarin: Non-Naive 58.9 (43.2 to 68.2)

Adverse events

Time frame: Not applicable as safety data was not planned to be collected during the study

• Study Protocol and Statistical Analysis Plan (PDF, 2016-11-07)

• Pfizer CT.gov Call Center, Study director, Pfizer