Anticoagulation in clinically difficult situations: insights into safe and effective management

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts Haemostasis is crucial for the maintenance of the integrity of the cardiovascular system. Too little of it leads to bleeding, as extensively described in the case of the Tsarevich Alexei Nikolajewitsch Romanow, who was a bleeder due to a mutation in factor VII or IX. Too much haemostasis on the other hand leads to intravascular thrombus formation in either the venous or the arterial system, with often detrimental clinical consequences such as pulmonary embolisms, stroke, and death. For the prevention of the latter scenarios, anticoagulation has been introduced, initially with warfarin, a vitamin K antagonist, and more recently with novel oral anticoagulants or NOACs1 such as abixaban, edoxaban,2,3 or rivaroxaban4 interfering with factor X, and dabigatran, a thrombin antagonist.5 The dosage of these agents is crucial to be effective and avoid bleeding, as outlined in the most recent ESC Guidelines.6 With NOACs, renal function and body mass have to be considered,7 an issue addressed in the Current Opinion ‘Antithrombotic therapy and body mass’ authored by Bianca Rocca on behalf of the ESC Working Group on Thrombosis.8 The authors note that extremely low and high body weights have become common due to frailty with ageing and the epidemic of obesity, respectively. These extreme body weights affect cardiovascular risk, including mortality, as well as the pharmacokinetics and safety profiles of antithrombotic drugs. Further research is warranted to optimize antithrombotic therapy in underweight as well as in different classes of obese patients, to guide dosing, dose adjustment, and/or reference intervals, and to establish whether the balance of benefits and risks of antithrombotic drugs can be improved. Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. In a second Current Opinion entitled ‘Proposed standardized neurological endpoints for cardiovascular clinical trials’, Alexandra Jane Lansky and colleagues from the Yale School of Medicine in New Haven, Connecticut, USA9 remind us that current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit–risk assessment of such procedures should be based on well-defined neurological outcomes. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies. A traumatic injury requires proper haemostasis to avoid excessive blood loss or damage to vital organs. In their article entitled ‘Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study’ Laila Staerk and colleagues from the Gentofte University Hospital in Copenhagen, Denmark examined the risks of mortality, stroke, major bleeding, and recurrent traumatic injury associated with resumption of vitamin K antagonists or NOACs following traumatic injury in 4541 elderly patients with atrial fibrillation.10 Within 90 days after traumatic injury, 60.6% resumed vitamin K antagonists, 16.7% NOACs, and 22.7% did not resume anticoagulation, while 9.5% were switched from vitamin K antagonists to NOACs. Compared with non-resumption, vitamin K antagonists and NOAC resumption were associated with lower all-cause mortality with a hazard ratio of 0.48 and 0.55, respectively and ischaemic stroke with a hazard ratio of 0.56 and 0.54, respectively (Figure 1). On the other hand, major bleeding hazard increased, with hazard ratios of 1.30 and 1.15, respectively. Thus, atrial fibrillation patients resuming vitamin K antagonists or NOACs following traumatic injury have a lower hazard of all-cause mortality and ischaemic stroke, but an increased hazard of major bleeding, but without additional hazards of recurrent traumatic injury. Whether anticoagulation following traumatic injury should generally not be withheld in atrial fibrillation is discussed in an Editorial by Christopher B. Granger from the Duke University Medical Center in Durham, North Carolina (USA).11 Standardized absolute risks of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. For each treatment option separately, the standardized absolute risks are based on the outcome-specific multiple Cox regression models and obtained as averages of the predicted risks had all patients received this treatment. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist (from Staerk L, Fosbøl EL, Lamberts M, Bonde AN, Gadsbøll K, Sindet-Pedersen C, Holm EA, Gerds TA, Ozenne B, Lip GYH, Torp-Pedersen C, Gislason GH, Olesen JB. Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study. See pages 1698–1705). Patients with valvular heart disease requiring surgical valve replacement in the aortic position do better with mechanical valves than bioprosthesis.12 However, mechanical valves require anticoagulation with vitamin K antagonists and hence are prone to bleeding.13 A particularly difficult clinical scenario is anticoagulation in patients with mechanical heart valves after intracerebral haemorrhage. In their article entitled ‘Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves’, Hagen B. Huttner and colleagues from Universitatsklinikum Erlangen in Germany investigated anticoagulation reversal and resumption strategies and their complications to define an optimal time window for restarting anticoagulation in 137 such patients.14 In half of these patients, anticoagulation was restarted and was associated with a 26% increase in haemorrhagic complications and only a trend to decreased thrombo-embolic complications. Adjusting for crossovers provided an incidence rate ratio of 10.31 in disadvantage of anticoagulation for haemorrhages. A timing analysis showed harm until day 13 after intracerebral haemorrhage with a hazard ratio of 7.06. The hazard for both complications was increased for restarted anticoagulation until day 6 with, a hazard ratio of 2.51. Restarting anticoagulation within <2 weeks after intracerebral haemorrhage in patients with mechanical heart valves was associated with increased haemorrhagic complications. Optimal weighing between least risks for thrombo-embolic and haemorrhagic complications provided an earliest starting point of anticoagulation at day 6, but only for patients at high thrombo-embolic risk. The clinical applicability of these findings is highlighted in an Editorial by Freek W.A. Verheugt from the Onze Lieve Vrouwe Gasthuis in Amsterdam, the Netherlands.15 A further difficult clinical scenario are patients with atrial fibrillation undergoing percutaneous coronary intervention or PCI, as outlined in a recent ESC Focused Update on Dual Antiplatelet Therapy.16 In a meta-analysis entitled ‘Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention’ Deepak L. Bhatt and colleagues from the Harvard Medical School in Boston, Massachusetts (USA) studied the safety and efficacy of dual vs. triple antithrombotic therapy in 5317 patients of whom 57% received dual antiplatelet therapy.17 Compared with triple anticoagulation, TIMI bleeding was reduced by 47%, while major adverse cardiac events did not differ. Thus. compared with triple anticoagulation, dual antiplatelet therapy reduced TIMI major or minor bleeding by half with comparable outcomes. Whether dual antiplatelet therapy may be a better option than triple anticoagulation in atrial fibrillation following PCI is critically discussed in an Editorial by Gilles Montalescot from the Pitié-Salpêtrière University Hospital in Paris, France.18 Observational studies indicate that statins reduce the risk of recurrent venous thrombosis.19 However, the mechanism is unknown. In their article ‘Rosuvastatin use improves measures of coagulation in patients with venous thrombosis’, Willem Lijfering and colleagues from the Leids Universitair Medisch Centrum in Leiden, the Netherlands determined whether statin therapy improves the coagulation profile.20 A total of 247 patients who had unprovoked venous thrombosis were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. For all tested coagulation factors, mean levels were decreased by rosuvastatin, whereas they hardly differed in controls (Figure 2). Subgroup analyses revealed that the decrease in coagulation factors by rosuvastatin was more pronounced in participants with unprovoked venous thrombosis and cardiovascular risk factors. These results suggest that statin therapy might be beneficial in patients at risk of recurrent venous thrombosis. Effects of rosuvastatin on measures of coagulation (from Biedermann JS, Kruip MJHA, van der Meer FJ, Rosendaal FR, Leebeek FWG, Cannegieter SC, Lijfering WM. Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. See pages 1740–1747). The editors hope that this issue of the European Heart Journal will be of interest to its readers.