Comparative effectiveness and safety of direct oral anticoagulants versus vitamin K antagonists in nonvalvular atrial fibrillation: a Canadian multicentre observational cohort study

Dear Authors

I read with interest your article on long term oral anticoagulation for Canadian patients with nonvalvular atrial fibrillation. Thank you for publishing large sample size, real world, Canadian data on the progress being made to reduce the very serious adverse event experience in this vulnerable patient population. We now have a Canadian DOAC report card.

You clearly make the point that during the period 2009-2017, in the Canadian real world, the DOACs have provided no improvement in the incidence of ischemic strokes and systemic embolisms, myocardial infarctions or major GI hemorrhages compared to warfarin. But there has been improvement in the incidence of intracranial and other major hemorrhages.

Although you were unable to calculate average INR time in therapeutic range (TTR) for your study population, you noted that "randomized controlled trials have established non-inferiority of DOACs and superiority in some cases compared to vitamin K antagonists with respect to stroke prevention and major bleeding risk". These findings were at TTRs of 55%-66%(1,2,3). The problem with the DOACs is their efficacy and safety are fixed at this TTR range. The advantage of warfarin is that efficacy, safety and TTR can be significantly improved through the employment of better warfarin management tools. Furthermore, warfarin has been found to be superior to the DOACs at TTRs>66%(4) demonstrating that even small increases in TTR are of clinical importance.

The question now is what would have happened if we had invested the same amount of money spent on the DOACs (hundreds of millions of dollars in the last decade) in improving the management of warfarin through government funding of new warfarin management tools (near patient INR testing in physician's offices and pharmacies; decision support software that actually measures TTRs, improves patient safety and provides a registry of warfarin management including the tracking of adverse events; patient self-management programs and training programs for health care professionals in advanced warfarin management techniques).

The answer is provided by the Community Pharmacy Anticoagulation Management Services (CPAMS) in Nova Scotia and New Zealand. CPAMS enables pharmacists to manage patients on warfarin using near patient testing and decision support software.

A report from Dr. Paul Harper, Haematologist, New Zealand, entitled CPAMS at 10(5) reports a TTR of 75% based on >50,000 INR results using the CPAMS model of warfarin management.

A recent pilot project in Nova Scotia (2018-2019) sponsored by the Pharmacy Association of Nova Scotia (PANS) and funded by the Government of Nova Scotia, using CPAMS(6,7) , achieved a (TTR) for patients with atrial fibrillation of 75% and an overall TTR>75% during the last five months of the study. Together, these two report cards demonstrated improved TTRs achieved through the employment of these improved warfarin management tools.

What does improvement in TTR mean to the efficacy and safety of oral anticoagulation management?

White H.D., Gruber M., Feyzi J. et al. in analyzing the results from Sportif III and Sportif V (8), compared two groups of patients: those with poor control (TTR<60%) and those with good control (TTR>75%). The 15 percentage point improvement in TTR resulted in a 49% reduction in stroke and systemic embolism, a 70% reduction in hemorrhagic stroke, and a 59% reduction in major bleeding. In addition, there was a 60% decrease in overall mortality and a 55% decrease in myocardial infarctions. These are major improvements in the efficacy and safety of warfarin not possible with the DOACs.

Can we achieve a 15 percentage point improvement in TTR? The authors of the PANS CPAMS reports in Nova Scotia made the following observation from their study. <1/3 of patients were unable to achieve a TTR >65% and they suggested that these patients be transitioned to a DOAC. >2/3 of patients were able to achieve a TTR of 65% or more and they suggested this group should remain on warfarin. The reason? The TTR for this latter group was 85%. The pooled TTR for the two groups was 78%, 15 percentage points higher than the baseline TTR (55%-66%).

In conclusion, if we are to reduce the incidence of ischemic stroke and systemic embolism, which is the primary objective of this entire enterprise, then new warfarin management tools must be employed and government funded. If the Nova Scotia algorithm is adopted, the savings from the reduction in DOAC use and laboratory INR testing would be more than sufficient to offset the associated costs. In addition, there would be large savings from reducing the immense load of strokes and systemic embolisms on our overburdened health care system.

As the rat said to the farmer, while gazing-up the barrel of the pointed shotgun "perhaps we should try warfarin again?" Indeed we should.

Sincerely,

Murray Trusler

Murray Trusler, MD, MBA, FCFP, FRRMS Fairmont Hot Springs, BC 250 688-1367 [email protected]

December 24, 2020

References:

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139- 1151. 2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891. 3. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992. 4. Burn J, Pirmohamed M. Direct oral anticoagulants versus warfarin: is new always better than old? Open Heart 2018;5:e000712.doi:10.1136/openhrt- 2017-000712. 5. http://inronline.net/wp-content/uploads/2020/05/CPAMS-at-10.pdf CPAMS at 10 Report. 6. https://pans.ns.ca/cpams PANS website reports: CPAMS Final Evaluation Report. 7. Healthcare Management Forum 1-6. 2020 The Canadian College of Health Leaders. DOI: 10.1177/0840470420969444. 8. White H.D., Gruber M., Feyzi J. et al. Arch. Int. Med. Vol 167 Feb 12, 2007 in analyzing the results from Sportif III and Sportif V.

Conflict of Interest:

President INR Online Canada Ltd.