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Amlodipine for all undergoing PCI? The evidence is unconvincing
C. Berry, J. McMurray / International Journal of Cardiology 84 (2002) 30 – 32
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[8] Han P, Boatwright C, Ardlie NG. Effect of the calcium-entry blocking agent nifedipine on activation of human platelets and comparison with verapamil. Throm Haemost 1983;50:513–7. [9] Uehara S, Handa H, Hirayama A. Effects of the calcium antagonist nifedipine on thromboxane B2 level platelet aggregation in hypertensive patients. Arzneimittelforschung 1986;36:1687–9. [10] Jackson CL, Bush RC, Bowyer DE. Inhibitory effect of calcium antagonists on balloon catheter-induced arterial smooth muscle cell proliferation and lesion size. Atherosclerosis 1988;69:115–22. [11] Nomoto A, Mutoh S, Hagihara H, Yamaguchi I. Smooth muscle migration induced by inflammatory cell products and its inhibition by a potent calcium antagonist, nilvadipine. Atherosclerosis 1988;72:213–9. [12] Jorgensen B, Simonsen S, Endresen K, Forfang K, Vatne K, Hansen J et al. Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the coronary angioplasty amlodipine restenosis study (CAPARES). J Am Coll Cardiol 2000;35:592–9.
[13] Ontario drug benefit formulary comparative drug index, January 2000. [14] Ontario ministry of health schedule of benefits physician services under the health insurance act, October 1992 / February 1998. [15] Government of Ontario Eastern (Ottawa) Region. [16] Ontario Case Cost Project. [17] Reference prices for therapeutic equivalent products. Trygdeetaten, April 2000. [18] Pricelist from wholesaler. Farmasoytiske spesialpreparater & Apotekpreparater, Handelsvarer / Brosjyrer, March 2000. [19] Forskrifter of takster for offentlige poliklinikker, SINTEF. Norsk Institutt for Sykehusforskning, April 1999. [20] Normaltariff for privat legepracsis 1999–2000. Oslo: Den Norske Laegeforening, 1999. [21] Department of Social Affairs and Health, Norway. [22] Linstone H, Turoff M. The Delphi method: techniques and applications. Addison-Wesley, 1975.
Editorial comment
Amlodipine for all undergoing PCI? The evidence is unconvincing q Colin Berry, John McMurray* Clinical Research Initiative in Heart Failure, Wolfson Building, University of Glasgow, Glasgow G12 8 QQ , UK Received 15 February 2002; accepted 4 March 2002
Coronary heart disease (CHD) is a chronic progressive condition, one manifestation of which is angina pectoris. Percutaneous coronary intervention (PCI) is used, increasingly commonly, to relieve angina [1,2]. Many patients, however, will experience a return of their symptoms or an acute coronary event at some time in the future [3]. This is generally believed to happen because of either (a) recurrence of the culprit coronary stenosis or (b) the development or progression of another stenosis. The former, socalled ‘re-stenosis’, is usually apparent within 6 months of PCI and frequently requires repeat angiography and further intervention (either PCI or bypass surgery) [4]. Asymptomatic restenosis also occurs q
PII of linked article: S0167-5273(02)00113-4 *Corresponding author. Tel. / fax: 144-141-330-6588. E-mail address: [email protected] (J. McMurray).
[5]. However, more mundane factors may also account for recurrent symptoms. Incomplete ‘revascularisation’ (with residual myocardial ischaemia) may be common after PCI where usually only one or two ‘culprit’ stenoses are dilated [6]. In addition, antianginal therapy may be reduced or stopped after PCI, possibly aggravating the effect of residual ischaemia. Though obviously linked, the prevention of restenosis, the prevention of recurrent angina and the prevention of coronary events are not the same and may require different treatments (and may have different targets, i.e., the culprit stenosis versus the other coronary vessels) [4]. All three are, however, worthy objectives (though prevention of restenosis should only be considered as a means of preventing recurrent symptoms and acute coronary events). Stents reduce the risk of restenosis and repeat intervention [7,8]. Statins [9,10] and ACE inhibitors
0167-5273 / 02 / $ – see front matter 2002 Published by Elsevier Science Ireland Ltd. PII: S0167-5273( 02 )00114-6
C. Berry, J. McMurray / International Journal of Cardiology 84 (2002) 30 – 32
[11] prevent acute coronary events but neither prevents restenosis. ACE inhibitors do not prevent angina though statins may [8,9]. Now the recent Coronary Angioplasty Amlodipine Restenosis Study (CAPARES) [12] suggests that the long acting dihydropyridine calcium channel blocker, amlodipine reduces the need for repeat PCI (implying reduced angina) without preventing restenosis. Clearly, prevention of recurrent symptoms after PCI and the need for further intervention (with its financial consequences) is a desirable objective, assuming this can be achieved in a cost-effective manner and without any increased risk of acute coronary events in the longer term. Does CAPARES, on closer inspection, really help us in attaining this objective? In CAPARES, 635 patients were randomised to receive either placebo or amlodipine 10 mg daily, starting 2 weeks before PCI and continuing until 4 months after PCI [12]. Baseline antianginal therapy was continued during the trial, with the exception of calcium channel blockers (CCBs). The protocol excluded treatment with a CCB and non-study CCB treatment was stopped prior to study enrolment. At baseline 85% of patients were taking a b-blocker and 48% a nitrate. Coronary stenting was not routinely employed and only used for ‘bale-out’. On intention to treat analysis, 23 patients (17.3%) in the placebo group required repeat PCI, whereas only 10 patients (3.1%) in the amlodipine group required a further intervention of this type. The indication for repeat PCI is not given. Nor is the rate of angina recurrence. The rate of death, myocardial infarction and coronary artery bypass grafting were not reduced by amlodipine In the current report [13], and in a similar one elsewhere [14], the CAPARES investigators describe an economic analysis of their study. Using a per protocol rather than intention to treat analysis, which exaggerates the apparent benefit of amlodipine, they conclude that this pharmacological intervention is cost-effective. This analysis also uses non-significant reductions in MI and CABG to offset the cost of amlodipine. The design and analysis of CAPARES render the significance of the authors’ conclusions uncertain. What exactly was the indication for repeat PCI? Was it recurrence of angina, an acute coronary syndrome
31
or some other reason? Did withdrawal of CCB therapy at baseline contribute to recurrent angina in the placebo group? Would amlodipine have been nearly as effective if intra-coronary stenting had been employed, as is now routinely the case during PCI? Had an intention to treat analysis been performed, taking account only of events that were reduced significantly (i.e., repeat PCI), would adjunctive amlodipine therapy still have been cost-effective? Would another, less expensive antianginal agent (e.g., a nitrate) have had the same effect as amlodipine? What might the longer term outcomes be with a strategy of using adjunctive amlodipine? CAPARES lasted for only 4 months. Should we still be concerned about an increased risk of acute coronary events with CCBs? CAPARES on its own cannot justify a routine strategy of adjunctive CCB therapy in patients undergoing PCI, either on grounds of clinical effectiveness or cost-effectiveness.
References [1] Smith SC, Dove JT, Jacobs AK et al. ACC /AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—Executive summary—A report of the American College of Cardiology /American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty)—Endorsed by the Society for Cardiac Angiography and Interventions. Circulation 2001;103(24):3019–41. [2] National service framework for coronary heart disease. http: / / www.doh.gov.uk / nsf / coronarych5 [3] Bucher HC, Hengstler P, Schindler C, Guyatt GH. Percutaneous transluminal coronary angioplasty versus medical treatment for nonacute coronary heart disease: meta-analysis of randomised controlled trials. Br Med J 2000;321:73–7. [4] Orford JL, Selwyn AP, Ganz P, Popma JJ, Rogers C. The comparative pathobiology of atherosclerosis and restenosis. Am J Cardiol 2000;86:6H–11H. [5] Ruygrok PN, Webster MW, de Valk V et al. Clinical and angiographic factors associated with asymptomatic restenosis after percutaneous coronary intervention. Circulation 2001;104:2289–94. [6] Lowe HC, Oesterle SN, Khachigian LM. Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol 2002;39:183–93. [7] Serruys PW, Sejaegere P, Kiemeneij F et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary-artery disease. New Engl J Med 1994;331(8):489–95. [8] Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary-artery disease. New Engl J Med 1994;331(8):496–501.
30
[8] Han P, Boatwright C, Ardlie NG. Effect of the calcium-entry blocking agent nifedipine on activation of human platelets and comparison with verapamil. Throm Haemost 1983;50:513–7. [9] Uehara S, Handa H, Hirayama A. Effects of the calcium antagonist nifedipine on thromboxane B2 level platelet aggregation in hypertensive patients. Arzneimittelforschung 1986;36:1687–9. [10] Jackson CL, Bush RC, Bowyer DE. Inhibitory effect of calcium antagonists on balloon catheter-induced arterial smooth muscle cell proliferation and lesion size. Atherosclerosis 1988;69:115–22. [11] Nomoto A, Mutoh S, Hagihara H, Yamaguchi I. Smooth muscle migration induced by inflammatory cell products and its inhibition by a potent calcium antagonist, nilvadipine. Atherosclerosis 1988;72:213–9. [12] Jorgensen B, Simonsen S, Endresen K, Forfang K, Vatne K, Hansen J et al. Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the coronary angioplasty amlodipine restenosis study (CAPARES). J Am Coll Cardiol 2000;35:592–9.
[13] Ontario drug benefit formulary comparative drug index, January 2000. [14] Ontario ministry of health schedule of benefits physician services under the health insurance act, October 1992 / February 1998. [15] Government of Ontario Eastern (Ottawa) Region. [16] Ontario Case Cost Project. [17] Reference prices for therapeutic equivalent products. Trygdeetaten, April 2000. [18] Pricelist from wholesaler. Farmasoytiske spesialpreparater & Apotekpreparater, Handelsvarer / Brosjyrer, March 2000. [19] Forskrifter of takster for offentlige poliklinikker, SINTEF. Norsk Institutt for Sykehusforskning, April 1999. [20] Normaltariff for privat legepracsis 1999–2000. Oslo: Den Norske Laegeforening, 1999. [21] Department of Social Affairs and Health, Norway. [22] Linstone H, Turoff M. The Delphi method: techniques and applications. Addison-Wesley, 1975.
Editorial comment
Amlodipine for all undergoing PCI? The evidence is unconvincing q Colin Berry, John McMurray* Clinical Research Initiative in Heart Failure, Wolfson Building, University of Glasgow, Glasgow G12 8 QQ , UK Received 15 February 2002; accepted 4 March 2002
Coronary heart disease (CHD) is a chronic progressive condition, one manifestation of which is angina pectoris. Percutaneous coronary intervention (PCI) is used, increasingly commonly, to relieve angina [1,2]. Many patients, however, will experience a return of their symptoms or an acute coronary event at some time in the future [3]. This is generally believed to happen because of either (a) recurrence of the culprit coronary stenosis or (b) the development or progression of another stenosis. The former, socalled ‘re-stenosis’, is usually apparent within 6 months of PCI and frequently requires repeat angiography and further intervention (either PCI or bypass surgery) [4]. Asymptomatic restenosis also occurs q
PII of linked article: S0167-5273(02)00113-4 *Corresponding author. Tel. / fax: 144-141-330-6588. E-mail address: [email protected] (J. McMurray).
[5]. However, more mundane factors may also account for recurrent symptoms. Incomplete ‘revascularisation’ (with residual myocardial ischaemia) may be common after PCI where usually only one or two ‘culprit’ stenoses are dilated [6]. In addition, antianginal therapy may be reduced or stopped after PCI, possibly aggravating the effect of residual ischaemia. Though obviously linked, the prevention of restenosis, the prevention of recurrent angina and the prevention of coronary events are not the same and may require different treatments (and may have different targets, i.e., the culprit stenosis versus the other coronary vessels) [4]. All three are, however, worthy objectives (though prevention of restenosis should only be considered as a means of preventing recurrent symptoms and acute coronary events). Stents reduce the risk of restenosis and repeat intervention [7,8]. Statins [9,10] and ACE inhibitors
0167-5273 / 02 / $ – see front matter 2002 Published by Elsevier Science Ireland Ltd. PII: S0167-5273( 02 )00114-6
C. Berry, J. McMurray / International Journal of Cardiology 84 (2002) 30 – 32
[11] prevent acute coronary events but neither prevents restenosis. ACE inhibitors do not prevent angina though statins may [8,9]. Now the recent Coronary Angioplasty Amlodipine Restenosis Study (CAPARES) [12] suggests that the long acting dihydropyridine calcium channel blocker, amlodipine reduces the need for repeat PCI (implying reduced angina) without preventing restenosis. Clearly, prevention of recurrent symptoms after PCI and the need for further intervention (with its financial consequences) is a desirable objective, assuming this can be achieved in a cost-effective manner and without any increased risk of acute coronary events in the longer term. Does CAPARES, on closer inspection, really help us in attaining this objective? In CAPARES, 635 patients were randomised to receive either placebo or amlodipine 10 mg daily, starting 2 weeks before PCI and continuing until 4 months after PCI [12]. Baseline antianginal therapy was continued during the trial, with the exception of calcium channel blockers (CCBs). The protocol excluded treatment with a CCB and non-study CCB treatment was stopped prior to study enrolment. At baseline 85% of patients were taking a b-blocker and 48% a nitrate. Coronary stenting was not routinely employed and only used for ‘bale-out’. On intention to treat analysis, 23 patients (17.3%) in the placebo group required repeat PCI, whereas only 10 patients (3.1%) in the amlodipine group required a further intervention of this type. The indication for repeat PCI is not given. Nor is the rate of angina recurrence. The rate of death, myocardial infarction and coronary artery bypass grafting were not reduced by amlodipine In the current report [13], and in a similar one elsewhere [14], the CAPARES investigators describe an economic analysis of their study. Using a per protocol rather than intention to treat analysis, which exaggerates the apparent benefit of amlodipine, they conclude that this pharmacological intervention is cost-effective. This analysis also uses non-significant reductions in MI and CABG to offset the cost of amlodipine. The design and analysis of CAPARES render the significance of the authors’ conclusions uncertain. What exactly was the indication for repeat PCI? Was it recurrence of angina, an acute coronary syndrome
31
or some other reason? Did withdrawal of CCB therapy at baseline contribute to recurrent angina in the placebo group? Would amlodipine have been nearly as effective if intra-coronary stenting had been employed, as is now routinely the case during PCI? Had an intention to treat analysis been performed, taking account only of events that were reduced significantly (i.e., repeat PCI), would adjunctive amlodipine therapy still have been cost-effective? Would another, less expensive antianginal agent (e.g., a nitrate) have had the same effect as amlodipine? What might the longer term outcomes be with a strategy of using adjunctive amlodipine? CAPARES lasted for only 4 months. Should we still be concerned about an increased risk of acute coronary events with CCBs? CAPARES on its own cannot justify a routine strategy of adjunctive CCB therapy in patients undergoing PCI, either on grounds of clinical effectiveness or cost-effectiveness.
References [1] Smith SC, Dove JT, Jacobs AK et al. ACC /AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—Executive summary—A report of the American College of Cardiology /American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty)—Endorsed by the Society for Cardiac Angiography and Interventions. Circulation 2001;103(24):3019–41. [2] National service framework for coronary heart disease. http: / / www.doh.gov.uk / nsf / coronarych5 [3] Bucher HC, Hengstler P, Schindler C, Guyatt GH. Percutaneous transluminal coronary angioplasty versus medical treatment for nonacute coronary heart disease: meta-analysis of randomised controlled trials. Br Med J 2000;321:73–7. [4] Orford JL, Selwyn AP, Ganz P, Popma JJ, Rogers C. The comparative pathobiology of atherosclerosis and restenosis. Am J Cardiol 2000;86:6H–11H. [5] Ruygrok PN, Webster MW, de Valk V et al. Clinical and angiographic factors associated with asymptomatic restenosis after percutaneous coronary intervention. Circulation 2001;104:2289–94. [6] Lowe HC, Oesterle SN, Khachigian LM. Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol 2002;39:183–93. [7] Serruys PW, Sejaegere P, Kiemeneij F et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary-artery disease. New Engl J Med 1994;331(8):489–95. [8] Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary-artery disease. New Engl J Med 1994;331(8):496–501.