bmj.com Rapid Responses for Aziz et al., 334 (7594) 617

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RESEARCH:
Omer Aziz, Christopher Rao, Sukhmeet Singh Panesar, Catherine Jones, Stephen Morris, Ara Darzi, and Thanos Athanasiou
Meta-analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery
BMJ 2007; 334: 617 [Abstract] [Full text]

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Rapid Responses published:

Is MIDCAB superior to stenting in MACE?: Hisato Takagi, Takuya Umemoto (27 March 2007)

Composite endpoint and misleading discussions: Artyom Sedrakyan (29 March 2007)

Re: Is MIDCAB superior to stenting in MACE?: Thanos Athanasiou, Omer Aziz (31 March 2007)

Re: Composite endpoint and misleading discussions: Thanos Athanasiou, Omer Aziz (31 March 2007)

Minimally invasive left mammary artery or percutaneous coronary stenting for isolated lesion of the left anterior descending coronary artery: Robert F Bonvini, Marc Righini, Pierre Fontana (1 April 2007)

Re: Minimally invasive left mammary artery or percutaneous coronary stenting for isolated lesion of the left anterior descending coronary artery: Thanos Athanasiou, Omer Aziz (2 April 2007)

Is MIDCAB superior to stenting in MACE? 27 March 2007

Hisato Takagi,
Consultant cardiovascular surgeon
Shizuoka Medical Centre, Shizuoka 411-8611, Japan,
Takuya Umemoto
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Re: Is MIDCAB superior to stenting in MACE?

Aziz et al(1) carried out a meta-analysis to compare the outcomes from the best percutaneous intervention (transluminal coronary artery stenting) with the least invasive surgical intervention (minimally invasive direct coronary artery bypass with left internal thoracic artery) (MIDCAB) for the management of isolated lesions of the left anterior descending artery. Their meta- analysis of 2 randomised controlled trials (RCTs) showed significantly higher incidence of major adverse coronary and cerebral events after stenting compared with MIDCAB. According to the meta-analysis by Jaffery et al(2) of 5 RCTs, however, there was no difference in the composite end point of mortality, myocardial infarction, and target vessel revascularization between stenting and MIDCAB. Although Aziz et al(1) reviewed 2 RCTs by Diegeler et al (published in 2002) and Drenth et al (2002), Jaffery et al(2) analysed 5 RCTs by Cisowski et al (2002), Drenth et al, Thiele et al (2005), Hong et al (2005), and Reeves et al (2004). We would like to know why Aziz et al(1) reviewed not 5 RCTs but merely 2 RCTs.
1. Aziz O, Rao C, Panesar SS, Jones C, Morris S, Darzi A, et al. Meta-analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. BMJ 2007;33:617.
2. Jaffery Z, Kowalski M, Weaver WD, Khanal S. A meta-analysis of randomized control trials comparing minimally invasive direct coronary bypass grafting versus percutaneous coronary intervention for stenosis of the proximal left anterior descending artery. Eur J Cardiothorac Surg 2007;31:691-7.
Competing interests: None declared

Composite endpoint and misleading discussions 29 March 2007

Artyom Sedrakyan,
MD, PhD; Senior Service Officer
AHRQ
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Re: Composite endpoint and misleading discussions

Many recent clinical trials in interventional cardiology and surgery report composite outcome for major adverse coronary and cerebral events. This has been defined by some authors as any one or more of stroke, death, myocardial infarction and need for repeat revascularization. This reporting does not seem to be justified. The use of this endpoint is open to many biased post-hoc interpretations and analyses. In one specific example it dilutes the effect (strong tendency) of less invasive coronary surgery on a specific endpoint such as stroke[1] which was later found to occur less often after less invasive surgery [2].
In the paper by Aziz and colleagues the opposite occurs. In this instance statistically significant composite endpoint of incidence of major adverse coronary and cerebral events leaves a strong impression on a reader. Both trials that were combined by Aziz and colleagues reported composite endpoint that included repeat revascularization [3,4]. However, the impression might be much less strong if one were to reveal that the difference between surgery and stenting regarding composite endpoint occurs mainly due to need for repeat revascularization (target vessel revascularization) with no effect on death, myocardial infarction or stroke. The authors did include results of the pooled meta-analytic estimate for repeat revascularization, thus summary of the composite endpoint is very misleading. One of the recent controversies related to drug eluting stents(DES) is another stark reminder about the dangers of making premature conclusions based on composite endpoints. In the evidence syntheses of the trials of DES most of the difference in composite endpoint were also attributable to reduced need for reduced need for repeat revascularization but much emphasis was put on the composite endpoint.
The authors should have avoided the composite endpoint altogether. The only goal of this exercise is an attempt to make rare events more statistically powerful but it might be very misleading when all of the endpoints do not trend in the same direction. Thus, the events are combined even though they are not necessarily related to each other physiologically or as a consequence of a procedure. In this instance composite outcomes offer little value to the study of comparative effectiveness and should not be used to evaluate this or similar procedures.
References
1.Parolari A, Alamanni F, Cannata A, Naliato M, Bonati L, Rubini P, et al. Off-Pump Versus On-Pump Coronary Artery Bypass: Meta-Analysis of the Currently Available Randomized Trials. Ann Thorac Surg 2003;76:37-40.
2.Sedrakyan A, Wu AW, Parashar A, Bass EB, Treasure T. Off-pump surgery is associated with reduced occurrence of stroke and other morbidity as compared with traditional coronary artery bypass grafting: a meta-analysis of systematically reviewed trials. Stroke. 2006 Nov;37(11):2759-69.
3.Drenth DJ, Veeger NJ, Winter JB, Grandjean JG, Mariani MA, Boven van AJ, Boonstra PW. A prospective randomized trial comparing stenting with off-pump coronary surgery for high-grade stenosis in the proximal left anterior descending coronary artery: three-year follow-up. J Am Coll Cardiol. 2002 Dec 4;40(11):1955-60.
4.Diegeler A, Thiele H, Falk V, Hambrecht R, Spyrantis N, Sick P, Diederich KW, Mohr FW, Schuler G. Comparison of stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery. N Engl J Med. 2002 Aug 22;347(8):561-6.
Dr. Artyom Sedrakyan is employed by the Agency for Healthcare Research and Quality (AHRQ). The authors of this letter are responsible for its contents. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services�.
Competing interests: None declared

Re: Is MIDCAB superior to stenting in MACE? 31 March 2007

Thanos Athanasiou,
Consultant Cardiac Surgeon
Department of Biosurgery & Surgical Technology, Imperial College London, St Mary's Hospital, W2 1NY,
Omer Aziz
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Re: Re: Is MIDCAB superior to stenting in MACE?

In our study we used the composite outcome �major adverse coronary and cerebral events� (MACCE) when comparing transluminal stenting and minimally invasive internal thoracic artery bypass for isolated left anterior descending artery lesions. In order to be included in our analysis, the study group had to report this outcome. Jaffery et al [1] report on five randomised controlled trials of which only one reports MACCE [2] as defined above. Of the remaining four, two do not report MACCE and instead report �major adverse coronary events� (MACE)[3,4] which does not include cerebral events. The remaining two studies [5,6] do not report a composite outcome at all and only report their individual components. When performing meta-analysis of composite outcome measures it is very important to use homogenous definitions across studies so as to avoid bias. We therefore made it a point to include only the two randomised study groups that reported specifically on MACCE [2,7-9], in our analysis.
1. Jaffery Z, Kowalski M, Weaver WD, Khanal S. A meta-analysis of randomized control trials comparing minimally invasive direct coronary bypass grafting versus percutaneous coronary intervention for stenosis of the proximal left anterior descending artery. Eur J Cardiothorac Surg 2007;31(4):691-7.
2. Drenth DJ, Winter JB, Veeger NJ, Monnink SH, van Boven AJ, Grandjean JG, et al. Minimally invasive coronary artery bypass grafting versus percutaneous transluminal coronary angioplasty with stenting in isolated high-grade stenosis of the proximal left anterior descending coronary artery: six months' angiographic and clinical follow-up of a prospective randomized study. J Thorac Cardiovasc Surg 2002;124(1):130-5.
3. Thiele H, Oettel S, Jacobs S, Hambrecht R, Sick P, Gummert JF, et al. Comparison of bare-metal stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery: a 5- year follow-up. Circulation 2005;112(22):3445-50.
4. Cisowski M, Drzewiecki J, Drzewiecka-Gerber A, Jaklik A, Kruczak W, Szczeklik M, et al. Primary stenting versus MIDCAB: preliminary report- comparision of two methods of revascularization in single left anterior descending coronary artery stenosis. Ann Thorac Surg 2002;74(4):S1334-9.
5. Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery. Health Technol Assess 2004;8(16):1-43.
6. Hong SJ, Lim DS, Seo HS, Kim YH, Shim WJ, Park CG, et al. Percutaneous coronary intervention with drug-eluting stent implantation vs. minimally invasive direct coronary artery bypass (MIDCAB) in patients with left anterior descending coronary artery stenosis. Catheter Cardiovasc Interv 2005;64(1):75-81.
7. Drenth DJ, Veeger NJ, Winter JB, Grandjean JG, Mariani MA, Boven van AJ, et al. A prospective randomized trial comparing stenting with off- pump coronary surgery for high-grade stenosis in the proximal left anterior descending coronary artery: three-year follow-up. J Am Coll Cardiol 2002;40(11):1955-60.
8. Drenth DJ, Veeger NJ, Grandjean JG, Mariani MA, van Boven AJ, Boonstra PW. Isolated high-grade lesion of the proximal LAD: a stent or off-pump LIMA? Eur J Cardiothorac Surg 2004;25(4):567-71.
9. Diegeler A, Thiele H, Falk V, Hambrecht R, Spyrantis N, Sick P, et al. Comparison of stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery. N Engl J Med 2002;347(8):561-6.
Competing interests: None declared

Re: Composite endpoint and misleading discussions 31 March 2007

Thanos Athanasiou,
Consultant Cardiothoracic Surgeon
Department of Biosurgery & Surgical Technology, Imperial College London, St. Mary's Hospital, W2 1NY,
Omer Aziz
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Re: Re: Composite endpoint and misleading discussions

We acknowledge Dr. Sedrekyan�s comments on the limitations of composite outcomes and chose to include MACCE in this meta-analysis because despite its limitations, it is a known outcome measure reported in the literature on this topic. It should be noted however, that our economic analysis paper did not for this reason use MACCE, and instead used the incidence of myocardial infarction, stroke, repeat coronary artery bypass graft and repeat percutaneous coronary intervention to calculate the medium and long-term quality of life following these interventions [1].
1. Rao C, Aziz O, Panesar SS, Jones C, Morris S, Darzi A, et al. Cost effectiveness analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. Bmj 2007;334(7594):621.
Competing interests: None declared

Minimally invasive left mammary artery or percutaneous coronary stenting for isolated lesion of the left anterior descending coronary artery 1 April 2007

Robert F Bonvini,
fellow of interventional cardiology
1211 geneva,
Marc Righini, Pierre Fontana
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Re: Minimally invasive left mammary artery or percutaneous coronary stenting for isolated lesion of the left anterior descending coronary artery

To the Editor:
In the March 24th issue of the Journal, Aziz et al1 concluded in their meta-analysis that the minimally invasive left internal thoracic artery by-pass (MIDCAB) was superior to percutaneous coronary intervention (PCI) with stent implantation for isolated lesion of the left anterior descending coronary artery (LAD). However, several comments concerning their meta-analysis before definitively stating that MIDCAB is superior to PCI should be made. In the discussion section, the authors state that: �emergence of new technologies such as drug eluting stents (DES) offer the potential to improve the outcome of PCI, although recent evidence does not show that their use translate to a reduction in total mortality�. We agree that DES do not reduce mortality compared to bare metal stents (BMS), especially considering all the recently published data concerning long-term DES safety.2 However, it is also clearly demonstrated that DES significantly reduce in-stent restenosis (ISR) leading to target vessel revascularisation (TVR) and long-term angina symptoms3-4, which were part of the selected endpoints evaluated in the Aziz meta-analysis.
Only one study (Hong SJ et al.)5 compared MIDCAB to DES implantation in the proximal LAD. Of interest, in this particular study, the mid-term (i.e. 6 months) MACE rate (death, myocardial infarction (MI), clinically driven TVR), and angina symptoms (CCS class III/IV) were not different between the surgical and the PCI group. All the other studies, even the most recent ones (Kim et al., Reeves et al.)6-7, included in the Aziz meta-analysis evaluated MIDCAB vs. BMS. From our point of view, it is not surprising that MIDCAB is better than BMS concerning the TVR rate and recurrence of angina (see Fig. 1 of the Aziz meta-analysis). However, no surgical benefits are further observed if one considers hard end-points such as death, MI and stroke.
We think that the major limitation of the Aziz meta-analysis is that the majority of the included studies compared MIDCAB to PCI utilizing BMS. Nowadays, current practice favours the implantation of DES on lesions of such a prognostic vessel (i.e. proximal LAD). In conclusion, Aziz et al. showed that MIDCAB is superior to PCI utilizing BMS when considering endpoints like repeat revascularisation and recurrence of angina. Since DES reduce both endpoints when compared to BMS, the real benefit of MIDCAB over PCI, if any, is nowadays probably reduced.
1) Aziz O, Rao C, Panesar SS, Jones C, Morris S, Darzi A, Athanasiou T. Meta-analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. BMJ. 2007 Mar 24;334(7594):617.
2) Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med. 2007 Mar 8;356(10):998-1008.
3) Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE; SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003 Oct 2;349(14):1315-23.
4) Holmes DR Jr, Leon MB, Moses JW, Popma JJ, Cutlip D, Fitzgerald PJ, Brown C, Fischell T, Wong SC, Midei M, Snead D, Kuntz RE.Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation. 2004 Feb 10;109(5):634-40.
5) Hong SJ, Lim DS, Seo HS, Kim YH, Shim WJ, Park CG, Oh DJ, Ro YM. Percutaneous coronary intervention with drug-eluting stent implantation vs. minimally invasive direct coronary artery bypass (MIDCAB) in patients with left anterior descending coronary artery stenosis. Catheter Cardiovasc Interv. 2005 Jan;64(1):75-81.
6) Kim JW, Lim DS, Sun K, Shim WJ, Rho YM. Stenting or MIDCAB using ministernotomy for revascularization of proximal left anterior descending artery? Int J Cardiol. 2005 Mar 30;99(3):437-41.
7) Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, Samani NJ, Roberts JA, Jacklin P, Seehra HK, Culliford LA, Keenan DJ, Rowlands DJ, Clarke B, Stanbridge R, Foale R. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery. Health Technol Assess. 2004 Apr;8(16):1-43.
Competing interests: None declared

Re: Minimally invasive left mammary artery or percutaneous coronary stenting for isolated lesion of the left anterior descending coronary artery 2 April 2007

Thanos Athanasiou,
Consultant Cardiothoracic Surgeon
Department of Biosurgery & Surgical Technology, Imperial College, St Mary's Hospital, W2 1NY,
Omer Aziz
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Re: Re: Minimally invasive left mammary artery or percutaneous coronary stenting for isolated lesion of the left anterior descending coronary artery

It is clear that longer and more complete angiographic follow-up is required to determine the role of drug-eluting stents in left anterior descending coronary artery revascularization. Recent non-randomised comparative evidence does however shed some light on the mid-term (>18 month follow-up) comparison between drug-eluting transluminal stenting and minimally invasive internal thoracic artery bypass, suggesting improved outcome with minimally invasive surgery [1]. Although this and other evidence does seem to favour surgery [2], we appreciate the need for longer follow-up of this patient group and eagerly await this evidence on drug-eluting stents. These comments have been clearly addressed in our paper [3].
1. Ben-Gal Y, Mohr R, Braunstein R, Finkelstein A, Hansson N, Hendler A, et al. Revascularization of left anterior descending artery with drug- eluting stents: comparison with minimally invasive direct coronary artery bypass surgery. Ann Thorac Surg 2006;82(6):2067-71.
2. Herz I, Moshkovitz Y, Hendler A, Adam SZ, Uretzky G, Ben-Gal Y, et al. Revascularization of left anterior descending artery with drug-eluting stents: comparison with off-pump surgery. Ann Thorac Surg 2005;79(1):88- 92.
3. Aziz O, Rao C, Panesar SS, Jones C, Morris S, Darzi A, et al. Meta -analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. Bmj 2007;334(7594):617.
Competing interests: None declared