9th March 2018, Volume 131 Number 1471

Lynn McBain, Anna Kyle

Dabigatran, a reversible thrombin inhibitor and novel oral anticoagulant (NOAC) became fully funded in New Zealand in 2011. The Best Practice Advocacy Centre New Zealand (bpacnz) published prescriber information on the use of dabigatran at that time.1 It was indicated for the prevention of stroke/embolism in patients with non-valvular atrial fibrillation, and prevention of venothrombotic embolism (VTE) after major orthopaedic surgery. This widened to include the prevention/treatment of deep vein thrombosis and/or pulmonary embolism in 2014.2,3

Renal impairment increases plasma dabigatran levels and risk of adverse effects, particularly bleeding and gastrointestinal problems.1,4–11 Renal function monitoring is always recommended when starting, and at least annually while taking dabigatran.1,2,4–6,9,11,12

Dabigatran is dosed twice daily at 150mg. A reduced dose of 110mg is recommended in patients 80 years or older and in renal impairment with creatinine clearance (CrCl) of 30–50ml/min to reduce risk of adverse effects.1,2,4–6,9,13 Dabigatran is contraindicated if creatinine clearance is <30ml/min.1–6,8,12,13

The Clinical Quality Board (CQB) of Compass Health PHO wanted to demonstrate dabigatran was being prescribed/monitored in line with best practice guidance to ensure patient safety.1,4,11,12

In July 2013, the CQB asked every PHO practice to participate in an accredited clinical audit to review all patients prescribed dabigatran in the previous five months to check if:

a) renal function had been recorded at least once in the previous 12 months

b) dabigatran was used for one of the two approved indications.12,14

Practices and individual general practitioners were given feedback reports on completion of the audit. A cardiologist-led education session on NOACs was held in September 2014, encouraging appropriate prescribing and monitoring and included an update on expanded indications for dabigatran use.

A 2015 study by Thorne et al showed only 67% of 70 patients taking dabigatran for at least 12 months had an annual renal function check.14

A second-cycle quality improvement activity in 2014–2016 re-audited renal function monitoring and indications for use in all patients prescribed dabigatran across the PHO.

Method

Audit 1

The first cycle accredited quality improvement audit occurred during July 2013–May 2014. This audit was based on the Best Practice Advocacy Centre (bpacnz) audit “Renal function testing in people taking dabigatran”. It was modified with permission.12

Every practice in the Compass Health PHO was invited to participate in the audit to review all patients prescribed dabigatran in the previous five months.

Eligible patients were identified via prescribing information from the electronic practice management system (PMS). PHO clinical pharmacists assisted practices when requested.

Individual patient records were reviewed and the following data was collected:

  • age
  • gender
  • ethnicity
  • daily dabigatran dose*
  • height (cm)
  • weight (kg) recorded in the previous 12 months
  • serum creatinine (mmol/L) recorded in the previous 12 months. Renal function was calculated using the Cockcroft-Gault equation to determine creatinine clearance (CrCl) in millilitres/minute (ml/ min). This required valid height and weight recordings.
  • indication for use (Table 1).

*A dose was considered “appropriate” if correct for patient age and renal function (creatinine clearance ml/min) and/or if it had been reduced due to adverse effects.

Table 1: Approved indications for use.1,2,11,12

Approved indication

Audit 1

Audit 2

Prevention of stroke/embolism in patients

with non-valvular atrial fibrillation

Yes

Yes

Prevention of venothrombotic embolism (VTE)

after major orthopaedic surgery

Yes

Yes

Prevention/and treatment of deep vein thrombosis (DVT)

and/or pulmonary embolism (PE)

No

Yes

Prevention and treatment of pulmonary embolism (PE)

No

Yes 

Data was recorded in a template (see Appendix) by either a PHO pharmacist or the practice via individual clinicians, including general practitioners, practice nurses, PHO pharmacists and other clinical officers. Some practices submitted aggregated data only so there was incomplete demographic/clinical data at an individual patient level.

Data was collated by the PHO pharmacists. Aggregated anonymised results were reported to all GPs, every practice, the Compass Health CQB and the Capital and Coast District Health Board.

Any anomalous issues regarding dose, adverse effects or potential interactions were noted by the auditors in the written reports/comments provided in the feedback to GPs.

Audit 2

The second cycle accredited quality improvement audit was completed during May 2014–Oct 2016 following the methods for the first-cycle audit, including the expanded indications for dabigatran use.2,12,13

Both audits were protected continuous quality assurance activities (PQAA) under the Health Practitioners Competency Assurance Act within the Compass Health PHO. Specific ethical approval was not required.

GPs could claim continuous quality improvement-professional development credits on completion of each cycle of this audit.

Results

All practices in the PHO participated. There were 941 patients prescribed dabigatran in the first audit, increasing to 1,564 patients in the second audit.

Patient demographics (Table 2) show a wide age range and a higher proportion of male patients compared to the PHO enrolled population data. More ethnicity data was recorded in the second audit with proportionately more European patients prescribed dabigatran than either Māori, Pacific or Asian patients in both audits.

Table 2: Patient demographics.

 

 

Audit 1

no. patients (%)

Audit 2

no. patients (%)

PHO

no. patients (%)

 

Total

941

1,564

288,078

Gender

N

886

1,343

 

Male

535 (60.4)

775 (57.7)

137,125 (47.6)

Female

351 (39.6)

568 (42.3)

150,953 (52.4)

Age in years

N

 893

1,342

 

Youngest–oldest

22–94

35–98

0–107

Range

72

63

107

Mean

72 (10.73 SD)

73.3 (10.21 SD)

Not applicable

Median

74

74

Not applicable

25th Centile

66

67

Not applicable

75th Centile

81

81

Not applicable

Ethnicity

N

891

1,343

288,078

European

682 (76.5)

1,134 (84.4)

205,976 (71.5)

Māori

65 (7.6)

99 (7.4)

27,367 (9.5)

Pacific

16 (2.0)

32 (2.4)

14,116 (4.9)

Asian

16 (2.0)

 28 (2.1)

25,351 (8.8)

Other

12 (1.5)

13 (1.0)

13,540 (4.7)

N.B. auditors collected different information making data sets variable). 

The clinical audit results from both cycles are presented in Table 3.

Table 3: Results of audits of patients prescribed dabigatran in the Compass Health PHO.

 

All patients

 Aged >75 years

Audit cycle

1st audit

no. patients (%)

2nd audit

no. patients (%)

1st audit

no. patients (%)

2nd audit

no. patients (%)

Total number of patients

941

1,564

417

657

Indication for use

N

 894

 1,508

 417

 657

Non-valvular atrial fibrillation

or post-orthopaedic surgery

852 (95.3)

1,400 (92.8)

402 (96.4)

640 (97.4)

Treatment or prevention of DVT

Not applicable

95 (6.3)

Not applicable

12 (1.8)

Unapproved indication

 9 (1.0)

3 (0.2)

1 (0.2)

2 (0.3)

Indication not recorded

33 (3.5)

10 (0.7)

12 (2.9)

3 (0.5)

Annual serum creatinine test

(mmol/L) recorded

826 (87.8)

1,408 (90.0)

389 (93.3)

637 (97.0)

Contraindicated

(renal function <30 ml/min)

16 (1.8)

27 (0.02)

10 (2.4)

24 (3.7)

(N.B. data sets varied due to variation in auditor and information collection). 

In the first cycle, 826 patients (87.8%) had an annual renal function recorded, just below the recommended best practice standard of 90%.12

Overall, 852 of 941 patients (90.5%) were prescribed dabigatran for an approved indication in Audit 1. Sixteen patients (1.8%) had a calculated renal function below 30ml/min, making dabigatran contraindicated.

In Audit 2, 1,408 patients (90.0%) had an annual renal function check. A total of 1,508 patients (96%) were prescribed dabigatran for an approved indication. Dabigatran was contraindicated in 27 patients (0.02%) with a calculated renal function below 30 ml/min.

Most patients prescribed dabigatran had an annual renal function check (see Table 4).

Table 4: Annual renal function checked in patients prescribed dabigatran.

Patients prescribed dabigatran

Audit 1

Audit 2

 

 Practices (%)

 Practices (%)

N

 57

 56

Checked ≥90% of patients

32 (56.1)

33 (58.9)

Checked 80–89% of patients

11 (19.3)

14 (25.0)

Checked 70–79% of patients

4 (7.0)

7 (12.5)

Checked 50–69% of patients

8 (14.0)

2 (3.6)

Checked <50% of patients

1 (1.8)

1 (1.8)

N.B. In Audit 1 there were 2 practices and in Audit 2 there were 3 practices with no patients prescribed dabigatran. 

Table 5: Specific comments or anomalies noted during the audit.

Potential interactions

 

  • Amiodarone—may increase dabigatran level—monitor.
  • Verapamil—may increase dabigatran level—monitor.
  • Concomitant antiplatelet, eg, aspirin, clopidogrel: usually accidental, ie, not stopped when dabigatran started and/or authorised by specialist.
  • SSRI antidepressants—increased risk of abnormal bleeding.
  • NSAIDs—increased risk of abnormal/gastrointestinal bleeding and decreased renal function.

Unapproved dose/use

  • Specialist recommendation/initiation.
  • 75mg BD for prevention of stroke in atrial fibrillation.
  • Once daily use—often due to transcription error.
  • 75mg OD in patients with CrCl <30ml/min and/or adverse effects at 110mg BD dose.
  • DVT prophylaxis on long-haul flight in first audit (unapproved indication). 

In Audit 1, 32 practices (56% of the PHO) had checked renal function annually in 90% or more of their patients. A cumulative total of 43 practices (75% of the PHO) had completed an annual renal function check in 80% or more of patients prescribed dabigatran.

In Audit 2 results improved with 33 practices (59% of the PHO) checking renal function annually in 90% or more of their patients. A cumulative total of 47 practices (84% of the PHO) completed an annual renal function check in 80% or more of patients prescribed dabigatran.

In each audit, only one small practice had checked renal function annually in less than 50% of their patients.

Discussion

Our results showed there was a high level of renal function monitoring across the PHO in both audits, 88% and 90% respectively for all patients prescribed dabigatran.

In both audits, patients >75 years had high levels of renal function monitoring, 93% and 97% respectively.

Renal function monitoring across practices ranged from 100% to 43% of patients prescribed dabigatran. Results reported as percentages impacted smaller practices disproportionately if one or two patients had not had an annual serum creatinine test.

Setup and implementation of effective practice protocols via alerts and/or a recall process was encouraged if not already in place.

There was a 66% increase in the number of patients prescribed dabigatran in the second audit. It is reassuring that after five years, 90% of all patients received an annual renal function check in line with clinical recommendations and best practice guidelines.

Ongoing high levels of renal function monitoring may be due to:

  • feedback/encouragement from the first audit or
  • improved clinical practice and processes for management and/or screening of long-term conditions, eg, diabetes or cardiovascular risk assessment.

The Cockcroft Gault Creatinine Clearance (CrCl) equation remains the gold standard for calculating renal function and making medication dose adjustments, but is not always calculated for patients.11,13,15,16

eGFR is not validated in the New Zealand population for medication dose adjustments, as it can overestimate renal function particularly in the elderly and/or patients with reduced muscle mass.15,17

Several patients had an estimated renal function of eGFR >30ml/min/1.73m2 or >50ml/min/1.73m2. Calculation using the Cockcroft Gault equation showed significant renal impairment, where a lower dose of dabigatran was indicated or contraindicated its use, particularly in females or where renal function had declined since initial prescribing.

Feedback from the audits encouraged GPs to record height and annual weight to allow calculation of CrCl (ml/min), to provide a more accurate measure of renal function. This allows dose adjustments of renally excreted medication, eg, dabigatran, metformin, bezafibrate, nitrofurantoin and gabapentin, and avoids overdosing and reduces potential adverse effects.16,17

Most patients were prescribed dabigatran for approved indications in the audits; 95% and 96% respectively, usually for atrial fibrillation.

Only 33 patients (3.5%) did not have an indication for use recorded in Audit 1, where dabigatran had usually been started by specialists/secondary care. This number reduced to 10 patients (0.7%) in Audit 2 after prevention and treatment of DVT/ PE became approved indications.

A few patients were given 75mg doses of dabigatran due to reduced renal function or adverse effects/intolerance of higher doses. The efficacy of these doses in atrial fibrillation is unknown.

There were cases of concomitant aspirin and/or clopidogrel use with dabigatran due to an acute cardiovascular event and started by secondary care/specialists or when the patient’s long-term medication list had not been updated after aspirin was stopped.

Some patients were prescribed concomitant NSAID analgesics or venlafaxine or SSRI antidepressants causing an increased risk of abnormal bleeding and reduced renal function with concomitant NSAIDs.

Concomitant amiodarone and verapamil can increase bleeding risk, but our audits found dabigatran doses were not decreased (in line with clinical guidelines).

GPs were advised of potential interactions, the need for more/closer monitoring and to update long-term medications in feedback reports.

Limitations and strengths of the study

This is the first reported quality audit of an entire primary health organisation. The results are very reassuring for patient safety across the Compass Health PHO.

The audits only recorded the renal function monitoring in patients taking dabigatran in the previous 12 months and did not show trends/variations over a longer period.

We did not investigate the incidence of adverse effects requiring dose reduction or the reasons for a 110mg BD dose in those with renal function >50 ml/min and younger than 80 years.

This was a pragmatic audit using different data collectors, eg, general practitioners, practice nurses, PHO pharmacists and other clinical officers, who recorded different data.

The strength of these audits was the participation of every practice, and a high level of practice engagement with quality improvement across the PHO. Within practices, the data collectors improved their audit and quality improvement processes and capability.

Conclusion

Our results showed a continuing high level of renal function monitoring across the PHO in 90% of patients prescribed dabigatran. Dabigatran was prescribed for approved indications in 96% of patients. These results are in line with recommended best practice and clinical guidelines.

A calculated renal function (ml/min) is more accurate than an estimated GFR (eGFR ml/min/1.73m2) and allows dose adjustment to be made for renally excreted medications, but it requires height and annual weight recordings.

The CQB continues to encourage prescribers and general practices to set up and maintain good recall/alert protocols for drug monitoring and management of long-term conditions as part of best practice.

Appendix

Data collection template

Clinical audit: DABIGATRAN—renal function testing and dose adjustment date (Medical Centre Name):

  • Creatinine clearance (CrCl) should be checked in all patients before commencing treatment with dabigatran
  • Renal function should be assessed annually especially in those aged over 75 years or with moderate renal impairment (CrCl 30–50ml/min)
  • If CrCl >50ml/min no dose adjustment is required
  • If CrCl 30–50ml/min or aged ≥80 years—use 110mg BD in atrial fibrillation
  • If CrCl <30ml/min—dabigatran is contraindicated
  • Calculated CrCl has been estimated using the Cockcroft-Gault equation, which is the recommended method for drug dose adjustments
  • eGFR has been included in the table for comparison purposes

c 

Summary

The Compass Health Primary Health Organisation checked every patient prescribed the anticoagulant (blood thinner) dabigatran twice during 2014 and 2016. There was a big increase in patients prescribed dabigatran during this time. Kidney function needs to be monitored if dabigatran is being taken. Ninety-six (96%) percent of patients prescribed dabigatran were taking it for approved reasons and 90% of patients had their kidney function checked each year, which is recommended by treatment guidelines.

Abstract

Aim

To assess annual renal function monitoring and clinical indications for use in patients prescribed dabigatran.

Method

A quality improvement activity included all patients in the Compass Health Primary Health Organisation (PHO) prescribed dabigatran. Information recorded: demographics; indication for use; daily dose; height; weight; serum creatinine; and estimated glomerular filtration rate (eGFR). The first audit occurred during July 2013 – May 2014, the second during May 2014 – October 2016.

Results

Across the PHO, all patients prescribed dabigatran were reviewed: 941 patients and 1,564 respectively. At the time of the second pass audit, renal function monitoring improved from 88% to 90%, and 96% were prescribed dabigatran for an approved indication.

Conclusion

Results showed a continuing high level of renal function monitoring across the PHO in 90% of patients prescribed dabigatran. Practitioners were reminded to use creatinine clearance as a marker of renal function. Dabigatran was prescribed for an approved indication in 96% of patients. Our results are in line with recommended best practice and clinical guidelines.

Author Information

Lynn McBain, General Practitioner Brooklyn Medical Centre, Wellington; Senior Lecturer, Primary Health Care & General Practice, University of Otago, Wellington;
Anna Kyle, Clinical Advisory Pharmacist, Compass Health, Wellington.

Acknowledgements

We would like to acknowledge the participation, data collection and commitment of Practice personnel at all levels in both audits as well as the PHO pharmacists, Marilyn Tucker and Hilary Krebs. Compass Health PHO acknowledges and thanks Bpac for allowing us to
use a modified version of their audit “Renal function testing in people taking dabigatran”.

Correspondence

Anna Kyle, Compass Health, PO Box 27 380, Marion Square, Wellington.

Correspondence Email

anna.kyle@compasshealth.org.nz

Competing Interests

AK and LM are employed at Compass Health PHO; Dr McBain is a practicing general practitioner, there are patients included in the audit who are enrolled at Dr McBain's practice.

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