Intermediate Dose Dabigatran for Atrial Fibrillation
Abstract & Commentary
By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco does research for Medtronic, is a consultant for Medtronic, Novartis, and St. Jude, and is a speaker for Boston Scientific.
RE-LY randomized 18,113 patients to one of its three arms. In the entire study group, dabigatran 110 mg twice per day compared with warfarin was associated with lower risks of major bleeding (2.87% vs 3.57 %), intracranial bleeding (0.23% vs 0.76%), and life-threatening bleeding (1.24% vs 1.85%). Dabigatran 150 mg twice per day and warfarin had comparable risks for major bleeding (3.31% vs 3.57%) and extracranial bleeding (3.02% vs 2.84%). However, again compared to warfarin, dabigatran 150 mg twice per day was associated with more gastrointestinal bleeding (1.85% vs 1.25%) but less intracranial bleeding (0.32% vs 0.76%). In terms of stroke protection, dabigatran 110 mg bid was non-inferior and dabigatran 150 mg bid was superior to warfarin.
The authors then analyzed the data by patient age. They noted an increased risk of bleeding in older patients. By using an age cutoff of 75 years to define age subgroups, there was a strong interaction between age and treatment effect for major and extracranial bleeding with dabigatran 110 mg bid showing less bleeding risk in those older than age 75. There was no interaction with age when protection from stroke was the endpoint.
The authors conclude that for patients older than 75 years of age with an increased risk for bleeding, the lower dabigatran dose might be considered an effective means to reduce the risk of stroke and control risks for bleeding.
Dabigatran has many advantages over warfarin. When the RE-LY trial data were first analyzed by the FDA, they agency concluded that there was no substantial overall lowering of bleeding risk at the 110 mg bid dose compared to 150 mg bid and efficacy was superior at the higher dose. The data presented in this substudy, however, suggest that selective use of a lower dose of dabigatran may have some advantages in older patients or those at high risk for bleeding. The lower dose would preserve many of the efficacy benefits associated with dabigatran yet allow physicians to mitigate risks for bleeding. Dabigatran at both 110 and 150 mg doses is available in several other countries. We will have to see if the FDA reconsiders its position. n
The authors excluded 5012 implants that required thoracotomy for lead placement, leaving a final study cohort of 268,701 implants. In these patients, there were 8559 acute procedure-related complications (3.2%). The most common complications were: hematoma (0.93%), lead dislodgement (0.93%), pneumothorax (0.42%), and cardiac arrest (0.03%). Other complications noted at lower frequencies included: cardiac perforation, myocardial infarction, pericardial tamponade, and infection. The in-hospital mortality rate was 0.38%. Patients who were admitted for reasons other than elective ICD implants had a significantly higher risk for both any complication or death (4.58% vs 2.51%, P < 0.0001) and of in-hospital death alone (0.91% vs 0.12%, P < 0.0001). Patients were more likely to suffer complications or death if they were older, female, had a lower left ventricular ejection fraction, or had a prolonged QRS duration on ECG. Complications were more common in those with nonischemic dilated cardiomyopathy, congestive heart failure, atrial fibrillation or flutter, prior valve surgery, cerebral vascular disease, chronic kidney disease, and chronic lung disease. The complexity of the procedure was also associated with an increased complication rate with the lowest rates seen with simple device changes for generator replacement and single-chamber ICDs and higher rates with dual-chamber or biventricular devices. Ten variables were strongly associated with increased risk for complications and were assigned points in the scoring system. These included: age older than 70 years (1 point); female gender (2 points); New York Heart Association heart failure class III (1 point) or IV (3 points); atrial fibrillation or flutter (1 point); prior valve surgery (3 points); dual chamber (2 points) or biventricular (4 points) devices; chronic lung disease (2 points); BUN greater than 30 mg/dL (2 points); previous ICD reimplantation (6 points); and non-elective ICD implantation (3 points). The risk for any in-hospital complication increased from 0.6% with a total risk score < 5 (8.4% of the total population) to 8.4% among patients with a risk score of > 19. There was an almost linear increase in rate of complications as the risk score rose. A similar model using seven factors was constructed for in-hospital mortality.
The authors conclude that the risk for acute ICD complications can be predicted using a simple scoring system. For patients with the highest risk for complications, knowledge of this increased risk might change the risk-benefit equation leading to device implantation.
This is a useful paper for both implanting physicians and those who refer patients for ICD implants. For implanting physicians, this scoring system allows them to risk-adjust their own or their institution's performance against a national standard. For referring physicians, knowledge of the risk for complications will allow them to be more transparent in their discussions with patients about the risks and benefits of the procedure. We also must recognize that the data here refer to only in-hospital complications and are a lower estimate of the actual risks. Elective procedures are usually performed on an overnight stay basis. This, at least partly, explains why complications are lower with elective implants in patients admitted solely for the procedure. We also need to remember that some complications often typically occur outside the 1-2 day window often reported in the ICD registry. Pocket infections, lead dislodgements, and lead malfunctions, particularly with LV leads, fall into this early after discharge category.
ICDs are important tools for prevention of sudden death. However, we need to be frank with both ourselves and our patients that complications with these devices are common and the risk of complications should be part of any discussion with patients concerning an ICD procedure.