Response to Letter Regarding Article, “Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Patients With Chronic Heart Failure: The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial”
Dr Kan and colleagues have raised several issues relative to our report of the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.1 Although all patients were in sinus rhythm at the time of entry, Dr Kan et al raise the important issue of the potential for the undetected occurrence of primarily paroxysmal atrial fibrillation (PAF) or persistent AF to have increased the risk of thromboembolic events, particularly strokes, which occurred in 12 patients (2.3%) in both the aspirin and clopidogrel groups and 3 patients (0.6%) in the warfarin group (both comparisons achieved nominal statistical significance with P=0.016).
Because there was no systematic ECG monitoring for AF occurrence in WATCH, it is certainly possible that some of thromboembolic events may have been precipitated by the postrandomization occurrence of PAF, for which ongoing anticoagulation may have lessened the risk of stroke more than antiplatelet agents. Indeed, increased risk of AF is one of the reasons clinicians have used warfarin in this population. In WATCH, patients with prior embolic events were excluded, as were those with any known AF events within the prior 12 months.2
Furthermore, although AF may have occurred between visits, patients were seen at least every 3 months, and the protocol specified that rhythm irregularities were to be sought and assessed by ECGs to facilitate the recognition of persistent AF, which was detected in similar numbers of patients in the 3 groups (10.3%, 10.3%, and 9.3% for aspirin, clopidogrel, and warfarin, respectively). Dr Kan and his colleagues suggest that this may be an underestimate because more aspirin and clopidogrel than warfarin patients discontinued the study drug (15, 14, and 2, respectively), but we suspect they may have added numbers for the incidence and discontinuation for AF when, in fact, the latter is just a subset of the former. A major reason for discontinuation in the aspirin and clopidogrel groups was the onset of AF or atrial flutter and cerebrovascular or other embolic events, and most patients were then started on warfarin. Only 5 patients discontinued warfarin for such events, reflecting the fact they were already receiving, unblinded, the indicated treatment.
Dr Kan et al point out that abnormal signal-averaged P-wave ECG and elevated atrial natriuretic peptide levels have been reported to predict the onset of PAF,3,4 but there is limited prospective corroboration of these findings, and the value of prophylactic anticoagulation based on them has not been examined. This approach warrants further investigation.
Lastly, Kan et al suggest that the higher rates of heart failure hospitalization may reflect decompensation caused by PAF. PAF can lead to worsening heart failure, but it would be unlikely to explain the lower rate of heart failure admissions in the warfarin group, given the similar incidence of AF in the 3 groups. Although it is true that PAF may not be evident on admission, all end-point events were adjudicated by a blinded end-point committee, and AF was only infrequently considered the precipitating cause.
Clinical Trial Information: http://www.clinicaltrials.gov. Unique identifier: NCT00007683.
Sources of Funding
This trial was supported and conducted by the Cooperative Studies Program of the Office of Research and Development, Department of Veteran Affairs. Study drugs and unrestricted grants were provided by Bristol Myers Squibb, Sanofi-Synethelabo, and Dupont pharmaceutical companies.
Dr Massie has research grants from Bristol-Myers Squibb and Sanofi-Aventis. Dr Schulman has research grants from Bristol-Myers Squibb, Sanofi-Aventis, and USLLC and has served as a consultant to Sanofi-Aventis. Dr Ezeckowitz has served as consultant to Bristol-Myers Squibb and Sanofi-Aventis. The other authors report no conflicts.
Massie BM, Collins JF, Ammon SE, Cleland JG, Ezekowitz M, Jafri SM, Krol WM, O'Connor CM, Schulman KA, Teo K, Warren S, for the WATCH Trial Investigators. A randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation. 2009; 119: 1616–1624.
Massie BM, Krol WF, Ammon SE, Armstrong PW, Cleland JG, Collins JF, Ezekowitz M, Jafri SM, O'Connor CM, Packer M, Schulman KA, Teo K, Warren S. The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics. J Cardiac Fail. 2004; 10: 101–112.