It's a WASH: Trial finds neither aspirin nor warfarin cut heart-failure thrombotic risk

Kingston upon Hull, UK - Neither aspirin nor warfarin prevent death, MI, or stroke when given prophylactically to patients with heart failure (HF), and aspirin may elevate the risk of hospitalization, according to a randomized, placebo-controlled trial reported in the July 2004 issue of the American Heart Journal^[1].

The open-label Warfarin/Aspirin Study in Heart failure (WASH) "casts doubt on the utility of antithrombotic agents, especially aspirin, for the treatment of patients with heart failure, but provides no conclusive evidence of harm," write Dr John GF Cleland (University of Hull, UK) and colleagues. Such prophylaxis is widely used in HF, although its effectiveness hasn't been shown in a randomized, controlled setting.

WASH randomized 279 patients with HF to no antithrombotic therapy, aspirin at 300 mg/day, or warfarin to a target INR of 2.5. There were no significant differences in the primary end point of death, nonfatal MI, or nonfatal stroke over a mean of 27 months.

Primary outcomes in WASH, intention-to-treat analysis

Outcome	Control (n=99)	Aspirin (n=91)	Warfarin (n=89)
Death/MI/stroke (%)	26	32	26
Hazard ratios (95% CI)	0.96 (0.60-1.54)	1.16 (0.74-1.85)	0.88 (0.54-1.43)

Ratios are for control relative to any antithrombotic therapy, aspirin relative to no aspirin, and warfarin relative to no warfarin, respectively.

"WASH is the best and largest prospective trial, other than WATCH, that has looked at antithrombotic therapy in heart failure. And it does have an untreated control group," Dr Barry Massie (University of California, San Francisco) said to heartwire . "It wasn't double-blind, but I think the data have to be considered seriously."

From WATCH to WASH

The randomized WATCH trial, reported by Massie at the March 2004 American College of Cardiology meeting and covered by heartwire , compared open-label warfarin with double-blind aspirin or clopidogrel in 1587 patients with HF. Rates of the primary end pointalso a composite of death, MI, or strokewere similar in the three groups over an average of 23 months.

In a secondary WASH finding, aspirin was associated with a significantly increased all-cause hospitalization risk, "particularly for worsening heart failure," write Cleland and colleagues.

Prespecified secondary outcomes in WASH, intention-to-treat analysis

Outcome	Control	Aspirin	Warfarin	p
All-cause hospitalization (%)	48	64	47	0.044*
Death or CV hospitalization (%)	37	49	37	NS
Death or all-cause hospitalization (%)	56	69	57	NS

*Aspirin vs either other group

 The adverse aspirin result in WASH is similar to a post hoc finding in WATCH. In that trial, Massie noted, 27% fewer patients were hospitalized for worsening HF in the warfarin group, who had 31% fewer overall admissions, as compared with the aspirin group. He called this result "potentially important...with the proviso that it was not a primary or secondary end point."

Because WATCH wasn't placebo-controlled, it couldn't be shown whether the difference stemmed from a warfarin benefit or a detrimental aspirin effect, Massie said. "I think WASH gives you a hint that maybe the aspirin was responsible for the increase in hospitalizations."

There are "sound reasons" for why chronic aspirin therapy would have adverse effects in HF patients, Cleland told heartwire. For example, he said, aspirin may counter the HF-related activation of vasodilating prostaglandins.

Massie concurs. "I suspect it is actually an effect of prostaglandin inhibition in heart-failure patients and that it may not extend to patients without heart failure." Although "there has been considerable controversy about an interaction between aspirin and ACE inhibitors based on such a finding in the SOLVD trial," he added, "prostaglandin inhibition alone may be sufficient to explain most of those results."

The WASH trial, Massie said, suggests "aspirin may be harmful in terms of exacerbating heart failure, but for major irreversible end points like death, MI, and stroke, there doesn't seem to be an apparent difference." However, he added, "there is no reason to use aspirin in patients with heart failure who don't have a specific indication for it," such as coronary artery disease or vascular disease. "It may be deleterious in this group."

An antithrombotic other than aspirin

Moreover, "and this is a very personal view," Massie said, for patients with advanced, medically refractory HF or those with repeated hospitalizations, "I would consider an antithrombotic other than aspirin." Based on the available data, he said, one cannot argue that aspirin worsens overall HF outcomes or that it should be routinely avoided in this population. "But in those for whom worsening heart failure is the dominant clinical problem, using an antithrombotic other than aspirin may make it easier to treat the patient."

Both WASH and WATCH were plagued by a shortfall in patient enrollment. In WASH, Cleland and colleagues suggested it stemmed from clinicians' reluctance to have HF patients potentially randomized to an arm that did not include antithrombotic therapy.

Massie doubts there will be any further placebo-controlled antithrombotic trials in HF. "That's why WASH is important even with its limitations. From now on, whatever prospective data we get is going to be from aspirin vs another antithrombotic agent."

Heartwire from Medscape © 2004 

Cite this: It's a WASH: Trial finds neither aspirin nor warfarin cut heart-failure thrombotic risk - Medscape - Jul 09, 2004.