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Antiplatelet agents and anticoagulants for hypertension

GYH Lip and DC Felmeden

DOI: 10.1002/14651858

David K. Cundiff, MD

Date received: September 27, 2007

This review concludes that ASA is efficacious for secondary prevention of cardiovascular events in people with elevated blood pressure based on the ATC meta-analysis (29 trials, 10,600 patients). However, the Cochrane authors were unable to obtain the data for their own analysis of the subgroup of high risk patients with hypertension. Additionally, haemorrhagic events were not reported and may have altered the risk/benefit ratio. Cleland challenged the validity of the ATC meta-analysis, making the following points:

The Antiplatelet Trialists' Collaboration meta-analysis was state-of-the-art for its time but not robust by modern standards
The findings of the meta-analysis were driven largely by data from small positive trials, with a dearth of small negative trials.
Most clinicians agree that meta-analysis is useful for confirming robust clinical trial results—which are lacking for long-term aspirin therapy—or calculating the size of trial required to provide a robust result; however, proof depending on meta-analysis alone is now generally considered weak.¹

The Cochrane review authors argue that, since (1) the ATC meta-analysis included 100,000 high risk patients with or without elevated blood pressure and (2) there was an overall reduction in mortality demonstrated. Consequently, the benefit of antiplatelet therapy for secondary prevention extends to patients both with or without elevated blood pressure. This is a logical falacy. All of the benefit might have occurred in the subgroup of non hypertensive patients.

For all these reasons, the benefit of antiplatelet therapy for secondary prevention in patients with elevated blood pressure should not be considered established.

The primary endpoint, which determines the main conclusions of the review, should have included safety endpoints rather than just efficacy endpoints. Fatal bleeding and intracranial bleeding are particularly important and should be separately included in the primary or secondary endpoints rather than using all major bleeding events (fatal, disabling, and other non-fatal) as a composite endpoint.

Because of excluding observational and population based studies from consideration in the safety analysis of the small warfarin trials (Huynh and Throm Prev Trial '98), the bleeding complications were very likely understated. Adding the safety data concerning vitamin k inhibitors from previous RCTs, observational studies, and population based studies to the safety and efficacy results of the two warfarin RCTs reviewed here, the implications for practice should state, “Vitamin k inhibitors should be contraindicated as an antithrombotic therapy approach to improving clinical outcomes in patients with elevated blood pressure.”

Likewise, the implications for research section should state, “Because of the bleeding risk and lack of efficacy in published RCTs, further trials with vitamin k inhibitors as antithrombotic treatment to improve clinical outcome in patients with hypertension would be unethical.”

Cleland JG. Chronic Aspirin Therapy for the Prevention of Cardiovascular Events: A Waste of Time, or Worse? Nature Clinical Practice Cardiovascular Medicine. May 30, 2006;3(5):234-235

Author's reply

We thank Dr Cundiff for his comments. Many patients with hypertension have associated vascular disease or comorbidities (e.g. previous myocardial infarction (MI) or stroke), and thus, many are currently treated with aspirin as secondary prevention. He claims that the benefit of antiplatelet therapy for 'secondary prevention' in patients with elevated blood pressure should not be considered established. Given that 'secondary prevention' implies those patients who are post-event, this point is invalid.
Dr Cundiff also has concerns over the general interpretation of the Antiplatelet (now Antithrombotic) Trialists Collaboration meta-analysis. All meta-analyses are limited by the studies included (or not, as the case may be), but the counter-arguments to John Cleland's stance have been repeatedly debated in detail, with many concerns raised regarding his views and interpretation of the Antithrombotic Trialists Collaboration meta-analysis.[1,2] Indeed, many early trials of antiplatelet treatment were rather small to detect moderate benefits reliably, which is why meta-analyses were needed. Dr Cundiff's suggestion that 'all of the benefit might have occurred in the subgroup of non hypertensive patients' is not supported by the detailed subgroup data provided in the earlier Antiplatelet Trialists Collaboration meta-analysis manuscript.[3]
We agree that bleeding is an important consideration in antithrombotic therapy, and have already included discussion of this aspect in our review. However, the objective was to assess the impact of antithrombotic therapy on major adverse events in hypertension (i.e. mortality, vascular events, etc), as reported as primary endpoints in various trials, and this was agreed when we submitted our Cochrane review protocol. Our objective was not to redefine primary endpoints in the various trials, especially bleeding definitions were variable between the different trials.
Dr Cundiff comments on our inclusion of the small warfarin trials (Huynh and the Throm Prev Trial '98), and the bleeding complications were very likely understated. We already recognise the limitations of these small studies in our review, and by its nature, many randomized trials only include a small selection of those screened. There is inadequate data on warfarin in hypertension per se.
Although one may presume that warfarin is associated with more bleeding, this was not seen in the recent BAFTA clinical trial amongst elderly atrial fibrillation patients in the primary care setting, where warfarin (INR2-3) was superior to aspirin 75mg for stroke prevention but the rates of major bleeding were no different between warfarin and aspirin.[4]

1. Baigent C, Collins R, Peto R. Article makes simple errors and could cause unnecessary deaths. BMJ. 2002 Jan 19; 324(7330):167.
2. Sudlow C, Sandercock P, Warlow C. Antiplatelet therapy and atherosclerotic events. Commentary is inaccurate. BMJ. 2002 Apr 13; 324(7342):917.
3. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81-106.
4. Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, Murray E; BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007 Aug 11; 370(9586):493-503.

Contributors

David K. Cundiff, MD, Occupation Physician
Submitter agrees with default conflict of interest statement: "I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback."