This was a single-center retrospective review of VTE patients on NOACs assessing bleeding outcomes in a Sub-Saharan African setting. The study found that the incidence rate for bleeding was 22.1 per 100 patient-years, with the most common site of major bleeding being the gastrointestinal system. Female sex was associated with a higher risk of major and clinically relevant non-major bleeding.
The major bleeding rate was 4.1 per 100 patient-years, similar to the Dresden NOAC registry (a large, prospective registry in the administrative district of Dresden, Germany) study, 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. The most common site of major bleeding was the gastrointestinal system (2.1%). These G.I. bleeds required blood transfusions and endoscopic interventions to stop the bleeding, and one case was fatal. One case of major GI bleeding occurred in a patient with gastrointestinal cancer, necessitating conversion to LMWH. These findings are similar to a meta-analysis by Holster et al., which reported a higher tendency to GIB among patients receiving NOACs than standard therapy with VKA[15]. A retrospective review of patients with G.I. malignancy and VTE treated with rivaroxaban or LMWH revealed a higher GIB incidence among rivaroxaban users (19).
Menorrhagia was the most common form of non-major bleeding, accounting for 35.9% of all bleeding. 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 intrauterine device (IUD). The high rates of menorrhagia reported in this study may reflect that the study population consists 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 amongst ninety fertile women between the age of 15–49 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 percent were treated for menorrhagia before and 29.9% during oral anticoagulant treatment (P < 0.01)[18].In a retrospective study to assess the management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on NOACs, 32% of the patients had vaginal bleeding events [19]. Even if our study did not include the impact on the quality of life, it is still possible to infer that these bleeds impacted the patients' quality of life.
There were no reports of intracranial bleeding in this study. Intracranial bleeding was observed in 0.2% (6 out of 2619) of patients in a prospective study assessing the safety and effectiveness of rivaroxaban in DVT (XALIA) (4). In an observational study conducted to assess rivaroxaban's safety and efficacy for VTE in routine care, there were no intracranial bleeds in the rivaroxaban group (10). However, in the EINSTEIN-PE study, there were three cases of intracranial bleeds, of which two were fatal (15).
Female sex was associated with a higher risk of major and clinically relevant non-major bleeding. Gender differences have been reported in patients with acute VTE treated with antithrombotic drugs. A meta-analysis was done to assess the relationship between gender and NOACS related bleeding. A higher risk of bleeding was found in women than men[20]. In another meta-analysis, women bled more than men while on NOACs[21]. Several reasons account for this finding. Doses of drugs are frequently not well adapted to the smaller body size, higher body fat content, or hepatic metabolism in women, or lower kidney function in older women [22]. Risk factors for adverse drug events, such as polytherapy, aging, and depression, are also more frequent in women than men. It is also important to note that sixty percent of all patients admitted to the hospital for adverse drug events are women [23].
Pulmonary embolism (78.93%) was the most common indication for initiating NOAC therapy, with most of the patients started on rivaroxaban (91.4%).95% of patients in a retrospective study in Canada were on rivaroxaban[24]. Many reasons could account for this; the major one is that rivaroxaban is often readily available and cheaper than dabigatran and apixaban. Rivaroxaban may have higher market penetration, has cheap generic formulations, and has a convenient once-a-day dosing. Apixaban was the latest to be introduced to the Kenyan market, which accounts for the low usage in the study cohort.
There appears to be an association between dyslipidemia and bleeding outcome (P < 0.01). A few studies done have reported an increased risk of bleeding with statin use. Statins are 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 warfarin alone[25].In a large retrospective study in the USA, statin users had an elevated risk of gastrointestinal hemorrhage[26]. However, other studies have found no association between statin use and increased bleeding risk[27, 28].There was no significant association between heart failure, hypertension, liver dysfunction, renal dysfunction, and bleeding. An observational study from France was comparing rivaroxaban and VKA for symptomatic venous thromboembolism (REMOTEV).In this study, fragile patients defined by age > 75 years, eGFR < 50 ml/min, or low body weight ≤ 50 kg did not have more bleeding events than non-fragile patients [10].
One of the major bleeding events was fatal (0.4%), similar to the EINSTEIN DVT and EINSTEIN PE studies where there was one case of fatal bleeding (< 0.1% in EINSTEIN- P.E. study) [3, 29]. No fatal bleeding events occurred in patients receiving rivaroxaban in REMOTEV[10].
This study has several strengths. It included all patients irrespective of underlying risk factors attempting to confirm whether the phase 3 trials' findings had external validity in daily patient care in an East African setting. The randomized control trials included strict inclusion criteria, specific and well-balanced patients. For instance, in the RECOVER 1 trial [7] of dabigatran use versus warfarin, exclusion criteria included liver disease with aminotransferase levels of > 2* the upper limit of normal, estimated GFR of < 30ml/min, the requirement for long term antiplatelet therapy, recent unstable cardiovascular disease and high risk of bleeding. In the AMPLIFY trial [9] of apixaban use versus warfarin, subjects with uncontrolled high blood pressure, known cancer subjects with planned long term use of low molecular weight heparin, low hemoglobin < 9, glomerular filtration rate of < 25 were excluded. In this trial, only 3% of the subjects had cancer. Our study included all patients with VTE and therefore was more inclusive. Moreover, to our knowledge, this is the first study on NOAC use in Eastern Africa.
One limitation of this study is the lack of a direct comparator group such as VKA treated patients. However, there being several large-scale VKA studies, a reliable indirect comparison can be made as in the DRESDEN NOAC study[17]. Moreover, this being a retrospective study, data such as INR values would be challenging to obtain, especially if the patients are on subsequent follow-up at a different facility. We also noted that the uptake of NOACs has increased over the past five years, with a subsequent decline in VKA use for VTE. Perhaps the numbers would be too few and patients put on VKA may differ in patient characteristics and socio-economic class.
There was an imbalance of patients between treatment groups. Our study population mostly included patients on rivaroxaban, and a few were on apixaban and dabigatran. As a retrospective review of the patients’ charts, it was subject to missing information. The type and degree of bleeding may have been insufficiently recorded.
In terms of the data collected by telephone interviews, a standardized telephone questionnaire was used. This information was subject to recall bias and subjective evaluation of factors such as bleeding severity. However, interviews were carried out by appropriately trained professionals with the appropriate medical knowledge, and further information was sought from the patient's medical practitioners.