Cardiovascular highlights from non-cardiology journals
- Alistair C Lindsay, Editor
Rocket AF: rivaroxaban shows efficacy
While warfarin has served as the oral anticoagulant of choice for some decades, a variety of new agents that hold several advantages (fewer interactions with other drugs, no need for therapeutic drug monitoring and simpler dosing regimen) are now in late-stage development.
The latest of these warfarin competitors to complete Phase III trials is the factor Xa inhibitor rivaroxaban. In the double-blind, double-dummy ROCKET AF trial, the investigators randomly assigned 14 264 patients with non-valvular atrial fibrillation—who were at moderate to high risk of stroke—to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. Blinding was maintained through encrypted INR monitoring for all participants, allowing for sham adjustment of placebo for those in the rivaroxaban arm. The primary clinical end point was stroke or systemic embolism, and the principal safety end point was a composite of major and non-major clinically relevant bleeding. The study was powered to demonstrate non-inferiority of rivaroxaban, and the median follow-up was 2 years. The primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 patients in the warfarin group (2.2% per year) (HR, 0.79; 95% CI 0.66 to 0.96; p<0.001 for non-inferiority). In the safety analysis, bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 patients in the warfarin group (14.5% per year) (HR, 1.03; 95% CI 0.96 to 1.11; p=0.44). However, the important end points of intracranial haemorrhage (0.5% vs 0.7%, p=0.02) and fatal bleeding (0.2% vs 0.5%, p=0.003) demonstrated significant reductions in favour of rivaroxaban treatment.
In patients with atrial fibrillation, the oral factor Xa inhibitor rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism. Rivaroxaban also demonstrated significant reductions in the important safety end points of intracranial and fatal bleeding.
▶ Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
Bicuspid aortic valves and aortic disease
Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1.3% of the population. Although it is now well recognised that having a BAV can lead to early valve dysfunction, the association between BAV and aortic pathology has remained less clear.
The aim of this retrospective cohort study was to assess the incidence of aortic complications in a cohort of patients with BAV. Long-term follow-up of patients diagnosed as having definite BAV by echocardiography from 1980 to 1999 was studied, and the authors also searched for aortic complications of patients whose bicuspid valves had gone undiagnosed. The main outcome measure was the incidence of thoracic aortic dissection, ascending aortic aneurysm or aortic surgery.
The cohort included 416 consecutive patients with BAV diagnosed by echocardiography, with a mean follow-up of 16 years (6530 patient-years). Aortic dissection occurred in 2 of 416 patients (age-adjusted RR 8.4, p=0.003) compared with the general population. Aortic dissection incidence for patients 50 years or older at baseline and bearers of aortic aneurysms at baseline was 17.4 and 44.9 cases per 10 000 patient-years, respectively. A comprehensive search for aortic dissections in undiagnosed bicuspid valves revealed two additional patients, allowing the estimation of aortic dissection incidence in bicuspid valve patients irrespective of diagnosis status. Of 384 patients without baseline aneurysms, 49 developed aneurysms at follow-up, which is an incidence of 84.9 cases per 10 000 patient-years (age-adjusted RR 86.2, p=0.001 compared with the general population). The 25-year rate of aortic surgery was 25% (95% CI 17.2% to 32.8%).
This study found that in patients with BAV, the incidence of aortic dissection is low but is significantly higher than that of the general population.
▶ Michelena HI, Khanna AD, Mahoney D, et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA 2011;306:1104–13.
Cardiac biomarkers and prognosis in COPD
Cardiovascular disease is common in patients with chronic obstructive pulmonary disease (COPD), with the two conditions often being linked by the common aetiology of smoking. Moreover, dysfunction in one organ system can be transmitted to the other, with severe hypoxaemia, pulmonary hypertension and systemic inflammation all potentially impacting on cardiac function. However, the interplay between lung and cardiac disease is still incompletely understood, and little is known about the prognosis of patients whose presentation with acute exacerbations of COPD also suggests involvement of the cardiac system.
In these two studies, the authors investigated patients with biochemical evidence of cardiac involvement when presenting with symptoms of COPD. In the first prospective study, patients presenting with COPD to a single centre had their troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels measured, with 30-day mortality being the primary outcome measure. Elevated NT-proBNP was present in 65 (27.5%) of 244 patients and significantly predicted 30-day mortality (OR 9.0; 95% CI 3.1 to 26.2, p<0.001). Elevated troponin T was found in 40 (16.6%) of 241 patients and also predicted 30-day mortality (OR 6.3; 95% CI 2.4 to 16.5, p<0.001). Moreover, NT-proBNP and troponin T levels appeared to have additive associations with 30-day mortality among patients, with the abnormalities of both being 15-fold higher than among patients with normal values.
In a second similar prospective study, the authors measured high-sensitivity troponin T (hs-cTnT) in patients presenting acutely with COPD and then followed them up for a median period of 1.9 years. Of 99 patients, 97 (98%) had measurable levels of hs-cTnT and 73 (74%) had hs-cTnT above the normal range. During follow-up, 57 (58%) patients died, with crude death rates in patients having hs-cTnT levels <14.0, 14.0–39.9 and ≥40 ng/l being 4.6, 30.2 and 58.3 per 100 patient-years, respectively, thus demonstrating a strong increase in risk with higher values of hs-cTnT.
Therefore, while neither study is able to provide information about the pathophysiological basis for the increases in mortality, both show a convincing link between increased risk and the presence of raised cardiac biomarkers in patients with COPD.
The presence of even mildly increased cardiac-specific biomarkers in patients presenting with exacerbations of COPD identifies a group with a much poorer prognosis and substantially increased mortality. Further work is required to ascertain the pathophysiology underlying this phenomenon and what interventions, if any, might be beneficial in mitigating this risk.
▶ Chang CL, Robinson SC, Mills GD, et al. Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD. Thorax 2011;66:764–8.
▶ Høiseth AD, Neukamm A, Karlsson BD, et al. Elevated high-sensitivity cardiac troponin T is associated with increased mortality after acute exacerbation of chronic obstructive pulmonary disease. Thorax 2011;66:775–81.
American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Lancet; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax.
Dr Alistair C Lindsay, Dr Hussain Contractor and Dr Jubin Joseph.
Provenance and peer review Commissioned; internally peer reviewed.