Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Via Enrico dal Pozzo, 06126 Perugia, Italy
Received August 6, 2004; revised August 6, 2004; accepted August 12, 2004 * Correspondence to: Prof. Paolo Gresele Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia. Via Enrico dal Pozzo, 06126 Perugia, Italy. Tel.: 075/5783989; fax: 075/5716083 (E-mail: grespa{at}unipg.it).
This editorial refers to "Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2 year mortality in diabetics with peripheral arterial disease: the DAVID study"" by GGN Serneri et al. on page 1845.
It is only in the last decade or so that peripheral arterial disease (PAD) has come to the general attention of clinicians as a condition that can greatly increase the risk of ischaemic cardiovascular events and mortality, and it is only lately that actions have been undertaken to increase the awareness of this clinical condition and to institute appropriate therapies aimed at reducing the incidence of adverse cardiovascular events. Thus, PAD has rapidly transformed from a largely overlooked condition, managed solely by a 5-word prescription (stop smoking and go walking), to a disease requiring multi-therapeutic interventions and extensive programmes of detection.
The initial lack of attention to these patients is witnessed by the small number of PAD patients enrolled in the early studies of prevention of cardiovascular events by antiplatelet agents in patients at risk. Indeed, no direct evidence on the efficacy of aspirin in patients with PAD exists, and the indication to use aspirin in this clinical condition1 comes mainly from the meta-analysis of the antithrombotic trialists' collaboration2 or from extrapolation of trial results from similar high risk conditions.3
More recently, the concept of atherothrombosis as an underlying condition common to cerebrovascular, cardiac and peripheral arterial disease has emerged and many more patients with PAD have been included in secondary or primary prevention trials.2,46 The analysis of the subgroup of PAD patients in these trials has shown that those with intermittent claudication and a reduced ankle/brachial index (<0.9) have a worse cardiovascular prognosis. For instance, in the HOPE study that has established the efficacy of ramipril (10 mg/d) in the secondary prevention of ischaemic cardiovascular events in patients at risk, the number needed to treat to prevent one major ischaemic event is lower in patients with clinical or subclinical PAD than in the rest of the enrolled patients, as a consequence of the higher event rate.5 This has led to the paradox that while there is proof of efficacy for the most recently introduced, and more expensive, treatments (clopidogrel, ramipril, statins), aspirin treatment in PAD is still based on indirect evidence.
Type II diabetes also represents an established risk factor for the development of atherosclerosis, and its prevalence is particularly high in patients with PAD. Not only diabetics have a higher morbidity and mortality in the setting of established atherosclerosis, but they also show a number of alterations of platelet function which constitute a logical basis for aggressive antiplatelet treatment.
Similar to PAD, little direct evidence of aspirin's efficacy in the prevention of ischaemic events in diabetics exists and post-hoc analyses of some large clinical trials of secondary or primary prophylaxis7,8 suggest a lack of efficacy of aspirin in diabetics. On the other hand, while it is true that aspirin therapy was associated with a lower proportional reduction of serious vascular events in diabetics in the Antiplatelet Trialists' Collaboration meta-analysis, the width of the confidence intervals, due to the low number of patients studied (only 5000 out of 150 000 in the ATT), was still consistent with the reduction of about one quarter observed in all other categories of patients at risk.2 Therefore, the guidelines of the American Diabetes Association for medical care in diabetes strongly advise the use of aspirin in diabetic patients at high risk of vascular events.
Thromboxane A2 (TxA2) has been established to play a detrimental role in a variety of conditions associated with ischaemic cardiovascular events and this mediator appears to be particularly implicated in diabetes. Several studies have confirmed that the urinary excretion of platelet-derived TxA2 is greatly increased in diabetes,9 further enhanced by hyperglycaemic spikes10 and reduced by tight metabolic control.9
The increased in vivo formation of TxA2 observed in patients with PAD is largely due to the presence of associated risk factors, particularly of diabetes.11 It thus seems logical to block TxA2 synthesis or action in diabetes. Aspirin however, which suppresses TxA2 by blocking platelet cyclo-oxygenase, appears to inhibit TxA2 formation less efficiently in diabetics than in other patients.12,13 Platelet hyperreactivity increases TxA2 formation, platelet turnover and enhances oxidant stress with the generation of platelet-activating and vasoconstricting isoprostanes. In addition, increased inflammatory cells producing extraplatelet TxA2 are phenomena described in diabetes and may be involved in the resistance to aspirin.10,12,13
The detrimental effects of TxA2 are counteracted in vivo by a number of platelet-inhibitory, vasodilatory and anti-proliferative natural mediators, amongst which is prostacyclin (PGI2), a cyclo-oxygenase product of endothelium. For this reason, a number of drugs were developed in the early 1980s aimed at selectively inhibiting TxA2 synthesis and/or activity without interfering with PGI2 formation, differently from the mechanism of aspirin. It soon became clear that the enhanced activity of thromboxane synthase inhibitors/TxA2 receptor antagonists (dual TxA2 blockers) is not only due to inhibition of thromboxane biosynthesis/action but due to the increased local formation of platelet inhibitory and vasodilatory prostaglandins (mainly PGI2) derived from the metabolism of accumulated prostaglandin endoperoxides (PGH2), the precursor of TxA2. Several structurally different dual TxA2 blockers were developed and some of them were tested in controlled clinical trials.
While most clinical studies were not sufficiently powered to show a possible superiority over aspirin on mortality, the dual TxA2 blockers showed superiority in a number of secondary endpoints and a meta-analysis of two studies with ridogrel showed a 26% odds reduction of major cardiovascular events in comparison with aspirin, although with large confidence intervals compatible with non-superiority or even slight inferiority.2
The DAVID study, published in this issue of the European Heart Journal, is the first trial ever to show a significant reduction of overall mortality by a dual TxA2 blocker (Picotamide) as compared with aspirin in patients at high risk of ischaemic events, and namely in diabetics with PAD.14
The reduction in overall mortality with picotamide was remarkable (45% relative risk reduction, 2.5% absolute risk reduction in two years), with a number needed to treat of 40 patients for two years to prevent one death. While these are very promising figures, some limitations to this exciting result come from the fact that neither vascular mortality nor major ischaemic cardiovascular events were reduced by picotamide when compared with aspirin. It is likely that the relatively low size of the study did not confer enough statistical power to detect an effect on these endpoints and thus, as pointed out by the authors, confirmatory studies are required in order to substantiate reduction of mortality and also to prove an effect on ischaemic vascular endpoints. In addition, the interpretation of the important findings of the DAVID study would be enriched by a knowledge of the distribution in the two treatment groups of patients enrolled for previous amputation or invasive revascularization procedures, possibly a subgroup with an even worse prognosis in which the difference between the two treatments might be further magnified.
What could be the mechanism through which a dual TxA2 blocker affords mortality reduction in diabetic patients with PAD when compared with aspirin? Besides the aforementioned detrimental effects, TxA2 or its precursors are involved in smooth muscle cell proliferation, and thus in atherogenesis, as well as in endothelial dysfunction, a precocious event in atherothrombosis and a predictor of ischaemic events; a dual TxA2 blocker may act more effectively than aspirin against these phenomena.15 Moreover, picotamide has proven to exert an anti-vasoconstrictive activity, partly independent of TxA2 antagonism, which may also play a role in its in vivo effects.16
One open question is whether the benefit observed with picotamide in the DAVID study would still be evident in current clinical practice where other active drugs, such as ramipril or simvastatin, are largely used. The DAVID trial was indeed carried out between 1996 and 1998, well before the publication of the HOPE and HPS studies5,6 and indeed, only 30% and 15% of the DAVID patients were taking ACE-inhibitors and anti-dislipidaemic agents, respectively. While an additive benefit of the latter agents has been ascertained when used in combination with aspirin, no data exist on the possible additional benefit with a dual thromboxane blocker. Moreover, given the widespread use of aspirin in clinical practice nowadays, it is conceivable that dual thromboxane blockers will turn out to be largely inapplicable because an intact cyclo-oxygenase is required in order to fully express the antiplatelet properties of these agents.
Finally, will picotamide bear the comparison with the combination aspirin plus clopidogrel? The CHARISMA trial, in which this drug combination is compared with aspirin in a long-term study, includes a large arm of patients enrolled for PAD and/or diabetes. The good tolerability and low haemorrhagic risk associated with picotamide (ADEP study, DAVID study) may possibly turn out to make the difference.
In conclusion, in order to know whether the little picotamide David will finally defeat the giant aspirin (or aspirin/clopidogrel) Goliath, additional struggles will be required.
Footnotes
" doi:
10.1016/j.ehj.2004.07.013
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References
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