CARDIOVASCULAR JOURNAL OF AFRICA • Volume 33, No 4, July/August 2022 190 AFRICA The incidence rate of major bleeding was 3.79 per 100 personyears, while that of CRNM and minor bleeding was 3.1 and 10.34 per 100 person-years, respectively. This is similar to the results of the Dresden NOAC registry (a large, prospective registry in the administrative district of Dresden, Germany), which found major bleeding rates of 4.1 per 100 patient-years.17 More than 80% of all the NOAC-associated bleeding was non-major bleeding, with major bleeds accounting for 17.2% of all the events. Themost commonsiteof majorbleedingwas thegastrointestinal system (2.07 per 100 person-years). These gastrointestinal bleeds required blood transfusions and endoscopic interventions to stop the bleeding, and one case was fatal. One case of major gastrointestinal bleeding occurred in a patient with gastrointestinal cancer, necessitating conversion to LMWH. Several mechanisms have been postulated as causes of gastrointestinal bleeding while on NOACs. The anticoagulant effect can be local and may inhibit gastrointestinal mucosal healing. These findings are similar to those of a metaanalysis by Holster et al., which reported a higher tendency to gastrointestinal bleeding among patients receiving NOACs compared to standard therapy with VKA.15 A retrospective review of patients with gastrointestinal malignancy and VTE treated with either rivaroxaban or LMWH revealed a higher incidence of gastrointestinal bleeding among patients on rivaroxaban.18 Menorrhagia (prolonged or heavy menstrual bleeding) was the most common form of all bleeding, with an incidence rate of 8.27 per 100 person-years. More than 90% were managed conservatively, mainly by a dose reduction or temporary interruption of NOAC therapy, use of antifibrinolytic agents, or insertion of an intra-uterine device. The high rates of menorrhagia reported in this study may reflect that the study population consisted of young, fertile women rather than a mixed older population. These bleeds caused significant discomfort to the point of temporary discontinuation of the NOACs. This discontinuation could cause a recurrence of VTE. A study done in Sweden to assess the frequency of minor bleeding symptoms and menorrhagia among 90 fertile women between the ages of 15 and 49 years revealed that the mean duration of menses increased from 5.6 to 6.1 days (p < 0.01) and reported menorrhagia from 44.2 to 70.8% (p < 0.001). Eighteen per cent were treated for menorrhagia before and 29.9% during oral anticoagulant treatment (p < 0.01).19 In a retrospective study done to assess the management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on new oral anti-factor Xa inhibitor therapy, 32% of the patients had vaginal bleeding events.19 Even if our study did not include the impact on quality of life, it is possible to infer that these bleeds had an impact on the quality of life of the patients. There were no reports of intracranial bleeding in this study. Intracranial bleeding was observed in 0.2% (six out of 2 619) of patients in a prospective study assessing the safety and effectiveness of rivaroxaban in DVT (XALIA).4 In an observational study conducted to assess the safety and efficacy of rivaroxaban for VTE in routine care, there were no intracranial bleeds in the rivaroxaban group.10 However, in the EINSTEINPE study, there were three cases of intracranial bleeds, of which two were fatal.15 Younger age was associated with an increased risk of major and CRNM bleeding. This is in contrast to what most other studies have revealed, that elderly patients who tend to have more co-morbidities, such as renal dysfunction, bleed more than younger patients.4,10 Even after adjusting for the effect of menorrhagia, the younger population was still at increased risk of bleeding. Upon further analysis of the six patients under 40 years who had major and CRNM events, all were female. Of the six, two were due to menorrhagia, three were haemoptysis and one was gastrointestinal bleeding. The patient who had a major gastrointestinal bleed had metastatic gastric cancer. One patient with the major bleed due to haemoptysis had microcytic anaemia with severe heart failure, and the other patient was on dual antiplatelet therapy for the management of peripheral vascular disease secondary to antiphospholipid syndrome. The numbers are therefore too small to draw an inference, and these patients had risk factors that could explain the incidence of major bleeding events, such as gastric cancer. It is therefore likely that younger age is not a risk factor for bleeding. Aspirin and other antiplatelet use were associated with an increased risk of bleeding. It is one of the components of the HAS-BLED score and therefore a validated risk factor for VTE bleeding. The incidence rate of CRNM and major bleeding among patients on both NOACs and aspirin was 56.66 per 100 person-years. The non-indicated use of aspirin in combination with NOAC therapy for non-valvular atrial fibrillation or VTE increases the risk of bleeding, with a trend toward higher rates of bleeding that is life threatening. If both an antiplatelet and a NOAC need to be prescribed, for instance in coronary artery disease with atrial fibrillation or VTE, the clinician and patients need to balance the benefit and risk from intensive and antithrombotic therapy. Anaemia with haemoglobin levels below 10 g/dl is associated with an increased risk of CRNM and major bleeding. Anaemia has been validated as a risk factor for atrial fibrillation bleeding in the ATRIA, OBRI and HEMORR2HAGES scores.20-22 The incidence rate of bleeding among patients with anaemia was 21.26 per 100 person-years. PE (78.93%) was the most common indication for initiating NOAC therapy, with most of the patients being initiated on rivaroxaban (91.4%). This is similar to findings of a retrospective study among NOAC users done in Canada, where 95% of the cohort were on rivaroxaban.23 Many reasons could account for this, the major one being that rivaroxaban is often readily available and cheaper compared to dabigatran and apixaban. Rivaroxaban may have higher market penetration, has cheap generic formulations, and has a convenient once-a-day dosing regime. Apixaban is the latest to be introduced to the Kenyan market, which accounts for the low usage in the study cohort. There appears to be a trend towards an association between dyslipidaemia and bleeding outcome (p = 0.08, CI = 0.88–5.65). A few studies have reported an increased risk of bleeding with statin use. Statins have been thought to possess potentially unique antithrombotic properties. Mazen et al. revealed that the concomitant use of statins with warfarin is associated with a higher risk of bleeding than with warfarin alone.24 In a large retrospective study done in the USA, statin users had an elevated risk of gastrointestinal haemorrhage.25 However, other studies have found no association between statin use and increased bleeding risk.26,27 There was no significant association between heart failure, hypertension, liver dysfunction, renal dysfunction and bleeding.
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