Sex differences in outcomes after percutaneous coronary intervention or coronary artery bypass graft for left main disease: from the DELTA registries

Selected in Journal of the American Heart Association by M. Alasnag

The DELTA registry data provides real-world observational evidence that confirms what was reported in randomized trials: a higher rate of co-morbidities in women and better intermediate-term outcomes with CABG. 

Reviewer

Mirvat Alasnag

@mirvatalasnag

Interventional cardiologist / Cardiologist

Jeddah, Saudi Arabia

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My Comment

Why this study – the rationale/objective? 

Landmark trials form the basis for guideline recommendations. The current ESC revascularization guidelines elaborated in 2018 afford a class I for coronary artery bypass grafting (CABG) to treat left main (LM) disease. More distinction for percutaneous coronary interventions (PCI) is detailed by these guidelines and largely focused on the Syntax score whereby PCI with a Syntax score (SS) ≤ 22 is considered class 1, SS of 23-32 is class IIa and SS of >32 is class III.

Outcomes of more contemporary trials, namely, NOBLE, EXCEL at 3 years and SYNTAX at 5 years shaped these recommendations. Since then, SYNTAXES, EXCEL 5-year and PRECOMBAT 10-year outcomes have become available.

However, all these trials have underscored the variable outcomes of PCI in women making blanket recommendations inappropriate in my opinion. Gul et al performed one of the largest meta-analyses assessing both revascularization strategies for multivessel disease (including left main disease) and noted that women undergoing PCI have a 30 % higher hazard of long-term ischemic complications compared with CABG¹. The SYNTAX trial reported a higher 4-year mortality rate in women following PCI and similar mortality rates to men following CABG. Both the EXCEL and PRECOMBAT sub-analyses did not report worse outcomes with PCI^2-3.

As such, Moroni et al sought to mine the DELTA registry data to identify differences from a real-world cohort⁴. The DELTA (Drug‐Eluting Stents for Left Main Coronary Artery Disease) registries reported outcomes in two periods: 2002-2006 and 2006-2015 for patients with unprotected LM stenoses.

How was it executed? - the methodology

Pooled data from both registries were analyzed. The primary endpoint was defined as the composite of all‐cause death, myocardial infarction (MI), and cerebrovascular accidents (CVA). The secondary endpoints were all‐cause death, the composite of all‐cause death, and MI, Major adverse cardiovascular and cerebrovascular events (MACCE), target vessel revascularization (TVR,) and target lesion revascularization (TLR). Event rates with 95 % CIs and absolute rate differences at follow‐up were estimated using the Kaplan‐Meier method as time to first event. Predictors for in‐hospital events were estimated using multivariate binary regression analysis.

What is the main result?

The study included a total of 6,253 patients, 5,367 (86 %) underwent PCI, and 886 (14 %) underwent CABG.

Women constituted 27 % of the total. Women were older, with a mean age of 70 years in the PCI arm and 68 years in the CABG arm. While men had a mean age of 67 years in the PCI arm and 65 years in the CABG arm.

Women were more likely to have hypertension, hypercholesterolemia, diabetes, and chronic kidney disease (CKD). They were also more likely to present with an acute coronary syndrome although the rate of ST elevation MI was similar in both groups.

Interestingly, patients in the PCI arm of both men and women were higher risk, ie older, more risk factors, CKD, acute presentation, and prior revascularization compared with those in the CABG arm.

The procedural details were similar, including utilization of intravascular ultrasound (IVUS), 39 %.

In terms of outcomes:

• In‐hospital combined end point of death, MI, and CVA:
  • Men: 5.6 % following PCI & 29 % following CABG (AOR, 5.49; 95 % CI, 4.93–6.10; P<0.001)
  • Women: 7.9 % following PCI & 21.6 % following CABG (AOR, 2.67; 95 % CI, 2.03–3.11; P<0.001)
• In‐hospital MACCE:
  • Men: 5.7 % following PCI & 33.3 % following CABG (AOR, 6.77; 95 % CI, 6.11–7.50)
  • Women: 8 % following PCI & 22.6 % following CABG (AOR, 2.91; 95 % CI, 2.51–3.37)
• Primary & Secondary outcomes:
  • Overall: 14.4 % in the CABG arm & 13.3 % in the PCI arm (AHR, 0.96; 95 % CI, 0.78–1.18; P = 0.74).
  • Women: CABG was associated with lower risk of the primary end point (event rate 9.5 % vs 15.3 %; AHR, 0.53; 95% CI, 0.35–0.79, P<0.001) and all‐cause death (event rate 5.6 % vs 11.7 % AHR, 0.50; 95 % CI, 0.30–0.82). CABG was associated with lower risk of death or MI compared with PCI among women (6.8 % vs 14.1 %; AHR, 0.53; 95 % CI, 0.34–0.83; P = 0.005).
  • Men: The risk was comparable across different revascularization strategies (AHR, 1.18; 95% CI, 0.94–1.49; P = 0.161). There were no significant differences between CABG and PCI among men (14.9 % vs 12.1 %; AHR, 1.07; 95% CI, 0.90–1.27; P = 0.841).

Critical reading and the relevance for clinical practice

Sex-based analyses from the landmark LM trials noted two important findings:

1. Women had a higher set of risk factors and co-morbidities.
2. Attenuation of any significant interaction between sex and the chosen revascularization strategy was noted in EXCEL and SYNTAX trials over time. As such, sex is no longer factored into the Syntax II Score.

The DELTA registry data provides real-world observational evidence that confirms what was reported in randomized trials: a higher rate of co-morbidities in women and better intermediate-term outcomes with CABG.

Unlike the other trials, the DELTA registry recorded persistent divergence of outcomes favoring CABG in the long term. There are glaring differences most notable is the use of 1^st generation drug-eluting stents (DES) in the DELTA registries. A sub-analysis of the more recent DES demonstrated attenuation of the benefit of CABG. The development of better DES technology can partially explain the different results obtained by the DELTA trial. Another plausible explanation is refinement of the PCI technique itself with better proximal optimization and uptake of IVUS which was 39 % in DELTA and 76 % in the EXCEL trial. Of course, the observational nature of the data adds bias.

What further confounds interpretation of sex differences extracted from multinational trials is the obvious ethnic differences and not only differences in practice. Recently, the geographic differences in outcomes of the EXCEL trial were published⁵. Investigators reported a higher rate of ischemia-driven revascularization in the North American cohort and the higher all-cause death at 30 days in the European cohort. However, the long-term outcomes of those with an intermediate or low Syntax Score remained similar across all regions particularly with the longer follow up.

This brings us to the sex analysis of the landmark trials mentioned above. The early results of the PRECOMBAT trial demonstrated similar outcomes in women undergoing PCI which persisted during a longer follow-up period⁶. Sotomi et al clearly illustrated the heterogeneity of the treatment effect in the various trials assessing outcomes in women only. Outcomes remained consistent in men. In the Western cohort evaluated in SYNTAX, CABG was preferred with a HR of 2.213; 95 % confidence interval, 1.242–3.943; P = 0.007. In an Asian cohort of women, PRECOMBAT and BEST, the treatment effect was neutral for both revascularization strategies (PRECOMBAT Pinteraction = 0.469 & BEST Pinteraction = 0.472; I2 = 58 %).

Although the DELTA sub-analysis adds to the body of evidence, it does not completely clarify the interaction of sex and outcomes. Other factors beyond anatomy, co-morbidities, and DES platform need to be ascertained. Understanding geographic and ethnic differences specific to different populations and perhaps the adopted PCI techniques in different regions may serve to inform guidelines better.

References

1. Gul B, Shah T, Head SJ, Chieffo A, Hu X, Li F, Brackett A, Gesick C, Bisarya PK, Lansky A. Revascularization options for females with multivessel coronary artery disease: a meta‐analysis of randomized controlled trials. JACC Cardiovasc Interv. 2020; 13:1009–1010.
2. Sotomi Y, Onuma Y, Cavalcante R, Ahn J‐M, Lee CW, van Klaveren D, de Winter RJ, Wykrzykowska JJ, Farooq V, Morice M‐C, et al. Geographical difference of the interaction of sex with treatment strategy in patients with multivessel disease and left main disease: a meta‐analysis from SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery), PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus‐Eluting Stent in Patients With Left Main Coronary Artery Disease), and BEST (Bypass Surgery and Everolimus‐Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease) randomized controlled trials. Circ Cardiovasc Interv. 2017; 10:e005027. doi: 10.1161/CIRCINTERVENTIONS.117.005027.
3. Serruys PW, Cavalcante R, Collet C, Kappetein AP, Sabik JF, Banning AP, Taggart DP, Sabaté M, Pomar J, Boonstra PW, et al. Outcomes after coronary stenting or bypass surgery for men and women with unprotected left main disease: The EXCEL trial. JACC Cardiovasc Interv. 2018; 11:1234–1243. doi: 10.1016/j.jcin.2018.03.051.
4. Moroni F, Beneduce A, Giustino G, Briede I, Park SJ, Daemen J, Claude Morice M, Nakamura S, Meliga E, Cerrato E, Makkar RR, D'Ascenzo F, Lucarelli C, Capranzano P, Tchetche D, Templin C, Kirtane A, Buzman P, Alfieri O, Valgimigli M, Mehran R, Colombo A, Montorfano M, Chieffo A; DELTA, DELTA 2 Investigators* *. Sex Differences in Outcomes After Percutaneous Coronary Intervention or Coronary Artery Bypass Graft for Left Main Disease: From the DELTA Registries. J Am Heart Assoc. 2022 Mar;11(5):e022320. doi: 10.1161/JAHA.121.022320. Epub 2022 Feb 22.
5. Myat A, Hildick-Smith D, de Belder AJ, Trivedi U, Crowley A, Morice MC, Kandzari DE, Lembo NJ, Brown WM III, Serruys PW, Kappetein AP, Sabik JF III, Stone G. Geographical variations in left main coronary artery revascularisation: a prespecified analysis of the EXCEL trial. EuroIntervention. 2022 Jan 28;17(13):1081-1090. doi: 10.4244/EIJ-D-21-00338.
6. Sotomi Y, Onuma Y, Cavalcante R, Ahn J‐M, Lee CW, van Klaveren D, de Winter RJ, Wykrzykowska JJ, Farooq V, Morice M‐C, et al. Geographical difference of the interaction of sex with treatment strategy in patients with multivessel disease and left main disease: a meta‐analysis from SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery), PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus‐Eluting Stent in Patients With Left Main Coronary Artery Disease), and BEST (Bypass Surgery and Everolimus‐Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease) randomized controlled trials. Circ Cardiovasc Interv. 2017; 10:e005027. doi: 10.1161/CIRCINTERVENTIONS.117.005027.