The PCI Gender Gap in Treating Calcified Lesions: A Paradigm Shift

Historically, why have women experienced worse percutaneous coronary intervention outcomes than men?

In general, our studies have shown us time and time again that both short and long-term mortality rates in women are higher after percutaneous coronary intervention (PCI), even in the contemporary era. The cause for this persistent finding is likely multifactorial and includes atypical presentations of coronary artery disease (CAD) with resulting delays in diagnosis, and invasive and noninvasive evidence-based treatment in female patients.

The new gender consensus statement in the Journal of the Society for Cardiovascular Angiography and Interventions (JSCAI) talks about how women are underdiagnosed and under-represented with underwhelming PCI outcomes. Can you elaborate on that?

Women have been historically underrepresented in cardiovascular clinical trials, often only accounting for 20%-25% of the study population, despite the fact that women do account for half of our patient population. With this under-representation, it follows that we do not have a good understanding of sex-based differences in drug or device outcomes. The SCAI Expert Consensus Statement on Sex-Specific Considerations in Myocardial Revascularization published in JSCAI earlier this year¹ highlights the gaps in knowledge regarding sex-specific management of CAD and should serve as a call to action for further research into this area. For example, the average coronary diameter, mean vessel area, and mean luminal area have been shown to be smaller in women than in men. However, there are no sex-specific recommendations for optical coherence tomography (OCT)- or intravascular ultrasound (IVUS)-guided thresholds for minimal luminal area cut-offs that should trigger intervention. When intervention is determined to be appropriate, there is little data to suggest what mode of revascularization is most appropriate for women. Indeed, a recent meta-analysis suggested that women with multivessel CAD and/or left main coronary artery disease may benefit more from treatment with CABG as compared to PCI.² That said, these data are limited by the fact that women comprised less than 25% of the study population for many of the included trials. As such, further research is needed to assess whether women with multivessel CAD should preferentially receive coronary artery bypass graft surgery over PCI.

What role does unconscious bias potentially play in the undertreatment of frail, elderly women with calcified disease?

I believe that unconscious bias may play a role in the undertreatment of female patients with CAD in two ways: (1) Women present more commonly than men with atypical symptoms (decreased exercise tolerance, fatigue, nausea, shortness of breath). Accordingly, providers may be less likely to look for CAD as a cause of their symptoms and defer cardiac work-up, even when indicated. (2) Since women have been shown to have smaller diameter and more tortuous arteries, there may be a concern that calcium modification could lead to a greater risk of perforation and so advanced techniques for optimal PCI may not be used as aggressively in female patients.

Intravascular lithotripsy data were included in the SCAI gender consensus statement. What impact could intravascular lithotripsy have on improving outcomes in women with calcified lesions?

Intravascular lithotripsy (IVL) has been shown to be both safe and effective in the treatment of calcified coronary artery disease, with low rates of device-related adverse events, as shown in the DISRUPT CAD study series.^3-6 Certainly, any device that may assuage operator concerns regarding complications when treating complex lesions could translate to an increase in use of calcium modification where indicated. Since we know that inadequate lesion preparation may lead to higher rates of in-stent restenosis and stent thrombosis, it follows that IVL could help lower suboptimal PCI rates in both men and women.

How do the coronary IVL in women-related data coming out of the SCAI 2022 meeting substantiate coronary IVL use as a first-line therapy for women with calcified lesions?

Small retrospective studies have suggested that women may be at an increased risk for procedural complications after atherectomy. Procedural complications are often related to vascular injury during plaque modification. As post-menopausal women have been shown to have increased arterial stiffness, less vessel compliance, and increased vascular fragility, it is not surprising that these factors, in conjunction with smaller coronary artery size, could lead to higher rates of coronary perforation and dissection during treatment of calcified plaque. The sex-specific analysis of the DISRUPT CAD series of studies presented at SCAI 2022 demonstrated that there was no difference in angiographic complications, successful stent delivery, and 30-day adverse cardiovascular events between men and women.⁷ These are certainly reassuring data, which suggest that the possible safety signals seen in women treated with atherectomy may not be present with IVL.

Are the results of the analyses presented at the Transcatheter Cardiovascular Therapeutics (TCT) 2021 and SCAI 2022 meetings are strong enough to change the historical paradigm of a risk for worse safety outcomes in women with calcified lesions versus men?

First, it is important to note that the single-arm design of the DISRUPT CAD studies does not allow for comparisons of IVL with other calcium modification techniques and additionally, only 23% of patients in these studies were female. As such, it is difficult to say that we have definitive data that IVL will improve outcomes in female PCI patients with calcified lesion(s). That being said, I do believe that the DISRUPT CAD safety data could lead to an uptick in IVL use in female patients in particular, which could certainly contribute to not only lower rates of procedural complications, but also to the performance of more optimal PCI in female patients, with resulting better long-term clinical outcomes.   

What are the other key initiatives that the interventional cardiology community is working on to narrow gender disparities of PCI outcomes in calcified lesions?

Part of the reason for gender disparities in PCI outcomes is that women remain severely underrepresented in cardiac device trials and this fact has been recognized by the medical community and industry. SCAI-WIN (Women in Innovations), as well as other groups, such as Women as One and ACC-WIC (Women in Cardiology), are actively working with industry as well as regulatory agencies on ways to increase female representation in these trials through initiatives supporting increased female representation in study leadership, and programs aimed at understanding and then alleviating barriers to female enrollment in trials. 

This article is sponsored by Shockwave Medical. Dr. Baron is a paid consultant for Shockwave Medical. See Important Safety Information on the next page.

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References

1. Lansky A, Baron SJ, Grines CL, et al. SCAI expert consensus statement on sex-specific considerations in myocardial revascularization. JSCAI. 2022 Feb;1(2):100016. https://doi.org/10.1016/j.jscai.2021.100016

2. S Gul B, Shah T, Head SJ, et al. Revascularization options for females with multivessel coronary artery disease: a meta-analysis of randomized controlled trials. JACC Cardiovasc Interv. 2020 Apr 27; 13(8): 1009-1010. doi: 10.1016/j.jcin.2019.12.036

3. Brinton TJ, Ali ZA, Hill JM, et al. Feasibility of Shockwave coronary intravascular lithotripsy for the treatment of calcified coronary stenoses. Circulation. 2019 Feb 5; 139(6): 834-836. doi: 10.1161/CIRCULATIONAHA.118.036531

4. Ali ZA, Nef H, Escaned J, et al. Safety and effectiveness of coronary intravascular lithotripsy for treatment of severely calcified coronary stenoses: the Disrupt CAD II study. Circ Cardiovasc Interv. 2019 Oct; 12(10): e008434. doi: 10.1161/CIRCINTERVENTIONS.119.008434

5. Hill JM, Kereiakes DJ, Shlofmitz RA, et al; Disrupt CAD III investigators. Intravascular lithotripsy for treatment of severely calcified coronary artery disease. J Am Coll Cardiol. 2020 Dec 1; 76(22): 2635-2646. doi: 10.1016/j.jacc.2020.09.603

6. Saito S, Yamazaki S, Takahashi A, et al; Disrupt CAD IV investigators. Intravascular lithotripsy for vessel preparation in severely calcified coronary arteries prior to stent placement - primary outcomes from the Japanese Disrupt CAD IV study. Circ J. 2021 May 25; 85(6): 826-833. doi: 10.1253/circj.CJ-20-1174

7. Hussain Y, Kearney KE, Abbott JD, et al. Sex-specific outcomes after coronary intravascular lithotripsy: a patient-level analysis of the Disrupt CAD studies. JSCAI. 2022 Jan; 1(1): 100011. https://doi.org/10.1016/j.jscai.2021.100011