Current use and safety of novel oral anticoagulants in adults with congenital heart disease: results of a nationwide analysis including more than 44 000 patients

Current use and safety of novel oral anticoagulants in adults with congenital heart disease: results of a nationwide analysis including more than 44 000 patients.

Freisinger E, Gerß J, Makowski L, Marschall U, Reinecke H, Baumgartner H, Koeppe J, Diller GP.Eur Heart J. 2020 Nov 14;41(43):4168-4177. doi: 10.1093/eurheartj/ehaa844.PMID: 33184662


Take Home Points

  • Observational dataset of 44,000 ACHD patients between 2005-2018.
  • 5,465 ACHD patients on oral anticoagulant treatment were within the dataset.
  • ACHD patients identified from a German health insurance dataset which covered 9 million insured persons (Total population Germany 83 million).
  • It is unclear the proportion of patients in this dataset under specialist ACHD care – it is possible, many were not.
  • Evaluation of the use of DOAC agents compared to vitamin K antagonists.
  • Use of oral anticoagulants (NOAD/DOAC and vitamin K antagonists) doubled from 6% to 12%.
  • In this German dataset, DOACs accounted for 45% of prescribed anticoagulants by 2018 – most frequently prescribed agents were rivaroxaban and apixaban (80% of dataset).
  • ACHD patients on DOACs had higher thromboembolic (3.8% vs 2.8%); MACE (7.8% vs 6%); bleeding rates (11.7% vs 9%) and all-cause mortality (4% vs 2.8%) after 1 year of therapy compared to vitamin K antagonists.
  • After adjustment for patient characteristics, DOACs remained associated with a greater risk of MACE (HR 1.22; 95% CI 1.09-1.36), all-cause mortality (HR 1.43; 95% CI 1.24-1.65; both P<0.001) and bleeding (HR 1.16; 95% CI 1.04-1.29; p=0.007).



Commentary from Dr. Damien Cullington (Liverpool, United Kingdom), section editor of ACHD Journal Watch: Novel oral anticoagulant agents (NOACs) have been approved for use for approximately a decade which means they are not so novel and more commonly referred to direct oral anticoagulant agents (DOACs). DOACs are a revolution in anticoagulant management. Take once or twice a day plus no irritating visits to the INR clinic, plus avoidance of the rollercoaster of INRs and shifting warfarin dose means there is all round delight with the therapeutic simplicity. Not all patients welcome DOACs with open arms. Some patients who have been treated with warfarin for long periods of time are skeptical and the lack of ‘knowing’ how anticoagulated they are with a DOAC causes concern and so often prefer to stay on warfarin (or other vitamin K antagonists), feeling more confident in its reliability (and predictability). Naturally, DOACs are not to be used in patients with mechanical valves.


Following the introduction of most medicines, comes potential indication creep. DOACs were and are often prescribed outside the limits of their original licensing indication. This is only natural. This is a part of a more generic therapeutics issue in the world of ACHD where vanishingly few large randomised controlled trials of drug therapy exist and essentially most medical therapy indication is logically extrapolated from ‘acquired’ cardiology datasets. Rightly pointed out by the authors of this paper, “medical adherence, reach of effective doses or INRs, as well as potential pharmacological interactions in a real-world scenario may relevantly differ from controlled study settings.”


This large observational ACHD dataset (n=44, 097) by Freisinger et al. makes one reflect about our prescribing habits with respect to choosing DOACs instead of vitamin K antagonists in ACHD patients. More specifically, using DOACs in an ‘off license’ fashion and in ACHD patient groups who have not been fully evaluated in randomised clinical trials. Figure 1 shows growth of DOAC use in this dataset between 2005-2018.


Figure 1. Temporal growth of DOAC use in ACHD patients within a large German insurance dataset.



The characteristics of the dataset are shown in Table 1. The total dataset comprised 44,097 ACHD patients. Of the total cohort, 12% (n=5465) were on anticoagulant treatment in 2018. As one would expect, the vast majority of patients (93%) had ‘simple’ or ‘moderate’ ACHD lesions. Increasing complexity of ACHD lesion was associated with a higher likelihood of being treated with an anticoagulant – 9% in simple lesions; 11% in moderate lesions and 14% in complex lesions (p <0.001). By 2018, the number of patients prescribed a DOAC in each of the complexity groups was similar. Patients with mechanical heart valves were excluded from longitudinal analysis. Median follow up time from first prescription of VKA was 90 months and 39 months for DOAC. The commonest reason for anticoagulation was atrial arrhythmias – two thirds of the group.



Results (Table 2)

The primary outcome data relating to bleeding, thromboembolic events and MACE are shown in Table 2. After adjustment for patients’ characteristics, there was increased bleeding risk for DOACs vs VKAs in follow up – HR 1.16; 95% CI 1.04-1.29; p=0.007. Of note, however, it is unclear the efficacy of anticoagulation in patients prescribed a VKA i.e. how much time is in range. One would expect lower rates of bleeding if anticoagulation were sub-therapeutic compared to DOACs where anticoagulation is ‘complete’. The adjusted risk of major bleeding or thromboembolism did not differ between treatment groups.



MACE (HR 1.23; 95% CI 1.10-1.37; p<0.001) and all-cause mortality (HR 1.43; 95% CI 1.24-1.65; p<0.001) were significantly higher in ACHD patients prescribed a DOAC vs VKA. Univariable Cox regression analysis is shown in Figure 2. The authors comment that patients with chronic kidney or liver disease were particularly prone to complications. No interaction was seen between complexity of ACHD and risk posed by anticoagulation – complications were independent to anatomical lesion.


Figure 2


This is a sizable dataset but it is observational, so caution is needed to draw absolute conclusions compared to RCTs. However, in the absence of any large RCTs comparing DOACs to VKA in patients with ACHD, the ‘signal’ from the results should be reflected upon. There is a significant amount of extra data in supplementary material which the reader is advised to scrutinise alongside the paper. Patients within this analysis are not specifically followed up in an ACHD specialist centre – the authors comment that up to a third of ACHD patients in Germany are not followed up in centres specialising in ACHD. This may well have a significant bearing on outcomes since it has been shown that care of ACHD patients in non-specialist centres is associated with worse outcomes. Other co-variates are missing from the analysis, such as ventricular dysfunction.



This large observational dataset has shown that after adjustment for patients’ characteristics, the HR for MACE (acute MI; ischaemic stroke; VF; resuscitation or death) was 1.2 and the HR=1.4 for all-cause death. Given this, as I am sure we all do, the results should be reflected upon and considered when prescribing DOACs to ACHD patients, particularly in the absence of clear RCT evidence.


As I write my last sentence I feel the need to pull out an all too frequent trope which I state in all things ACHD, particularly with relation to medical treatment – randomised controlled data is needed to ensure results are not by chance and reflective of usual guideline based care of ACHD patients in specialist centres.