Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, which may shed indi-rect light on the merit of use of amiodarone on the grounds of its superior efficacy. On the other hand, a longer duration of follow-up would allow sufficient time for development of amiodarone organ toxicity with its attendant significant costs. The major adverse effects of sotalol and propafenone are predominantly seen early in the treatment course, a time frame that the current study would have captured. The long-term toxicity of amiodarone may result in irreversible organ damage with significant chronic care cost implications. Although surveillance testing for amio-darone toxicity was accounted for in the current analysis, this cost may escalate over time as the cumulative dose increases, accompanied by a progressive increase in lung, thyroid and ocular abnormalities.
Finally, the low cost estimates in this study for certain procedures may actually underestimate the beneficial effect of amiodarone. Thirty Canadian dollars for a Cardiology consultation ($19 US, 22 Euros) or $63 for a cardioversion ($39 US, 44 Euros) represents a significant undervaluation of physician and hospital services in most areas. For example, the US Medicare fee schedule lists $118 US dollars as the charge for a typical clinical consultation. The resultant cost difference between the two treat-ment strategies in most practice settings is likely significantly higher than the estimate from this trial.
Most clinicians are not surprised by these data, with superior efficacy of amiodarone suggested by other trials and clinical experience showing efficacy in refractory patients. Many will still choose to use propafenone or sotalol as first line agents, notwith-standing these data, especially in patients that are not considered at high risk for proarrhythmia, to
mini-mize longstanding exposure to amiodarone. Despite the aforementioned limitations, the authors are to be commended for a strong study that has con-vincingly demonstrated the superior antiarrhythmic efficacy and short-term cost efficacy of amiodarone in management of atrial fibrillation compared to sotalol and propafenone. Long term follow-up of this patient population may verify the ongoing cost benefit of amiodarone in reducing the cost of atrial fibrillation management, or it may confirm the downside of prolonged exposure to amiodarone.
A. KRAHN G. KLEIN A. C. SKANES R. YEE
Division of Cardiology, University of Western Ontario, London, Ontario, Canada
References
[1] Lumer GB, Roy D, Talajic M et al. Amiodarone reduces procedures and costs related to atrial fibrillation in a controlled clinical trial. Eur Heart J 2002; 23: 1050–6.
[2] Roy D, Talajic M, Dorian P et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342: 913–20. [3] Catherwood E, Fitzpatrick WD, Greenberg ML et al.
Cost-effectiveness of cardioversion and antiarrhythmic therapy in nonvalvular atrial fibrillation. Ann Intern Med 1999; 130: 625–36.
[4] Eckman MH, Falk RH, Pauker SG. Cost-effectiveness of therapies for patients with nonvalvular atrial fibrillation. Arch Intern Med 1998; 158: 1669–77.
[5] Vorperian KR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a metanalysis. J Am Coll Cardiol 1997; 30: 791–8.
[6] Sunderji R, Kanji Z, Gin K. Pulmonary effects of low dose amiodarone: A review of the risks and recommendations for surveillance. Can J Cardiol 2000; 16: 1435–40.
European Heart Journal (2002) 23, 1002–1004
doi:10.1053/euhj.2001.3128, available online at http://www.idealibrary.com on
Intermittent claudication: how should we react to this
symptom?
See doi: 10.1053/euhj.2001.3033 for the article to which this Editorial refers
When intermittent claudication is attributed to peripheral arterial disease, the principal issue is
whether the patient should be treated specifically to improve walking distance or merely receive optimal therapy for prevention of major cardio-vascular events. If specific pharmacological therapy for claudication is utilized, the next issue is
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which medication(s) to select from the therapeutic arsenal?
Before addressing these questions, three important facts should be recalled. First, peripheral arterial disease is associated with a high risk of fatal and non-fatal cardiovascular ischaemic events, in direct proportion to the severity of the disease evaluated by the ankle–brachial pressure index[1,2]. Indeed, one fourth of claudicants will die within 5 years following diagnosis, mostly as a consequence of myocardial infarction, stroke or aortic aneurysm rupture, and another 25% will experience a non-fatal cardiovascu-lar event during that period. Second, in spite of this poor prognosis, peripheral arterial disease appears to be the orphan cardiovascular disease, half of claudi-cants being not recognized as such. Moreover, once diagnosed, they have significantly less chance of receiving appropriate antithrombotic prophylaxis than patients with coronary or cerebrovascular dis-ease[3]. Thus, awareness of the disease should be
promoted, as should simple diagnostic tools, in order to identify a larger population of high risk patients who should be given appropriate cardiovascular counselling to aid prevention[3]. Third, the poor gen-eral prognosis of claudicants contrasts sharply with the relatively benign course of the local disease: only one fourth of claudicants experience symptomatic deterioration, and 2% eventually lose the affected leg[4], which legitimizes a nihilistic therapeutic attitude among some practitioners.
Nevertheless, patients complain of a reduction of walking distance that impairs the quality of daily life. Three options are theoretically available to relieve symptoms: (1) revascularization (either surgically or by interventional radiology), (2) walking exercise, and/or (3) specific medication. All but walking exer-cise can produce side effects or complications. They should therefore be proposed only to patients in whom the potential benefits outweigh the risks of treatment. Thus, revascularization procedures can be discussed when the walking distance is so short that it is unlikely to be increased substantially by walking exercise and/or when the lesion is localized on the iliac artery with unlikely collateral vessel develop-ment. On the other hand, walking exercise is often a true practical alternative to revascularization, especially if the lesions are located on the femoropop-liteal segment. In such patients, a substantial increase in the walking distance can be achieved by supervised walking exercise[5]. Few randomized trials, however, have compared directly supervised and unsupervised walking training, but advice alone is often considered insufficient[4]
. The greatest likelihood of success, with at least a doubling of the initial walking distance, is thought to be obtainable by walking to near
maxi-mum pain in a supervised programme lasting at least 6 months[5].
Besides physical training, dozens of medications have been proposed over the last three decades to improve the symptoms of claudication, including suloctidil, pentoxiphylline, buflomedil, naftidrofuryl, ketanserin, ticlopidine, cilostazol, and, as highlighted in the present issue, sulodexide[6]. Initial studies on the effects of oral medication on claudication were meth-odologically poor[7], and their results did not convince clinicians to prescribe the drugs on a large scale except in a few countries. Nevertheless, larger, methodologi-cally sound studies have shown that pentoxiphylline[8],
and cilostazol[9]are able to increase walking distance in
a statistically and clinically meaningful manner, while the potential benefit of ketanserin was unequivocally refuted[10]. Interestingly, ticlopidine was shown both to
increase walking distance and reduce cardiovascular risk, but this was the result of a pooled analysis of small studies[11]. However, this agent causes rare but
serious haematological side effects, and is also cumber-some to use because it requires monitoring the white blood cell count every 2 weeks.
On the other hand, because claudicants must be considered at high risk of cardiovascular events, they should be prescribed antiplatelet agents such as aspirin — as evidenced indirectly by a meta-analysis[12]— or clopidogrel, which was found to be slightly superior to aspirin in a large scale trial[13]. These agents markedly reduce the risk of coronary events and stroke, an effect that might be enhanced by the use of statins. None of them, however, has a proven effect on claudication symptoms.
In this context, what are the lessons of the Italian study with sulodexide[6] for the clinician? First, it implies that no currently available medication can meaningfully improve claudication symptoms because the trial design used a placebo as a compari-son. One might, however, question why aspirin was only ‘allowed’ in these study patients and not given to all of them, as recommended by the American College of Chest Physicians (ACCP) Consensus Conferences on Antithrombotic Therapy[14]. Second,
it demonstrates in a well designed, double-blind study that the new agent is associated with a doubling of the pain-free walking distance three times more often than placebo. This end-point was achieved in one fourth of the patients, diabetics and non-diabetics, who received the active drug. Third, sulodexide induced a significant decrease of fibrinogen, the main component of plasma viscosity, thereby offering a plausible, and at least partial, explanation for the mechanism of action of the compound. Fourth, the objective increase in walking distance was accompanied by a subjective improvement reported Editorials 1003
by the patients. Such a finding is absolutely valid in a double-blind study, and is of great importance because treatment of symptoms should primarily improve quality of life. However, the value of doubling the walking distance may not necessarily represent a true improvement of the patient’s daily life. Fifth, perhaps the most remarkable study result was the more than 50% decrease in adverse cardio-vascular events compared to placebo (four events against 11 in each group of 143 patients). Although marginally not significant at the conventional P-level of 0·05, due to a sample size that was derived without the a priori hypothesis of studying adverse cardiovas-cular end-points, this finding supports the hypothesis of a protective cardiovascular effect of the drug as suggested in a previous trial[15]. Of course, this
hypothesis assumes that aspirin users were equally distributed between the two study groups.
In conclusion, patients with intermittent claudication due to peripheral arterial disease need (1) strict control of risk factors, especially smoking, along with antiplate-let medication; (2) walking training, preferably in a formal, supervised programme; (3) in a minority of selected cases, surgical or radiological revasculariz-ation; and (4) if the latter is not applicable or if walking training is not sufficient, a drug such as sulodexide that increases walking distance. Future trials should test this drug against a supervised exercise programme plus as-pirin for everyone and focus on claudication symptoms and adverse cardiovascular events.
H. BOUNAMEAUX
Division of Angiology and Hemostasis, Department of Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland
References
[1] Newman AB, Siscovick DS, Manolio TA et al. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Circulation 1993; 88: 837–45.
[2] Criqui MH, Langer RD, Fronek A et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: 381–6.
[3] Hirsch AT, Criqui MH, Treat-Jacobson D et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–24.
[4] Transatlantic Inter-Society Consensus (TASC). Management of peripheral arterial disease. Inter Angio 2000; 19 (Suppl 1): I-304.
[5] Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA 1995; 274: 975–80.
[6] Coccheri S, Scondotto G, Agnelli G, Palazzini E, Zamboni V. Sulodexide in the treatment of intermittent claudication. Results of a randomized, double-blind, multicentre, placebo-controlled study. Eur Heart J 2002; 23: 1057–65.
[7] Cameron HA, Waller PC, Ramsay LE. Drug treatment of intermittent claudication: a critical analysis of the methods and findings of published clinical trials, 1965–1985. Br J Clin Pharmacol 1988; 26: 569–76.
[8] Porter JM, Cutler BS, Lee BY. Pentoxifylline efficacy in the
treatment of intermittent claudication: multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients. Am Heart J 1982; 104: 66–72.
[9] Beebe HG, Dawson DL, Cutler BS et al. A new pharmaco-logical treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med 1999; 159: 2041–50.
[10] PACK Claudication Substudy Group. Randomized placebo-controlled, double-blind trial of ketanserin in claudicants. Changes in claudication distance and ankle systolic pressure. Circulation 1989; 80: 1544–87.
[11] Boissel JP, Peyrieux JC, Destors JM. Is it possible to reduce
the risk of cardiovascular events in subjects suffering from
intermittent claudication of the lower limbs? Thromb Haemost 1989; 62: 681–5.
[12] 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.
[13] CAPRIE Study Group. A randomised, blinded trial of clopi-dogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348: 1329–39.
[14] Jackson MR, Clagett GP. Antithrombotic therapy in per-ipheral arterial occlusive disease. Chest 2001; 119: 283S– 99S.
[15] Condorelli M, Chiariello M, Dagianti A et al. IPO-V2: a
prospective, multicenter, randomized, comparative clinical
investigation of the effects of sulodexide in preventing
cardio-vascular accidents in the first year after acute myocardial infarction. J Am Coll Cardiol 1994; 23: 27–34.
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