Women More Often Than Men Report Lingering Angina After PCI, Raising More Questions

Residual chest pain after PCI is more common in women than in men, according to pooled data from two trials showing that female patients are nearly twice as likely after their procedures to report recurring angina during normal daily activities and at rest. Although the study found no difference in ‘hard’ endpoints between sexes after revascularization, quality of life continues to be the sticking point, raising important questions about what other factors may be at play.

“In women, the presence of chest pain after successful PCI with newer generation DES often does not indicate a failure of interventional treatment,” write lead author Marlies M. Kok, MD (Thoraxcentrum Twente, Enschede, the Netherlands), and colleagues. Instead, mechanisms other than epicardial obstruction, possibly microvascular disease, are more often responsible for the residual pain, they conclude.

The study, published online March 2, 2016, in JACC: Cardiovascular Interventions, pooled patient-level data from the TWENTE and DUTCH PEERS trials, in which stable angina or ACS patients were treated with either everolimus-eluting stents (EES) or zotorolimus-eluting stents (ZES). A total of 3,202 patients (27.2% women) were treated between 2008 and 2012. Patients in the two trials self-reported chest pain on a number system, ranging from 0 for no pain to 3 for chest pain with mild physical effort or while at rest.

At both 1- and 2-year follow-up, more women than men reported clinically relevant chest pain (self-reported score of 2 or 3).

Female gender was found to be an independent predictor of clinically relevant pain on multivariable analysis. Compared with men, women had a 1.7-fold increased risk of chest pain during normal daily activities and a 1.8-fold increased risk of pain at rest at 1-year follow up. The pattern held steady at 2 years.

However, clinical endpoints at 2 years—including the patient-oriented composite (all-cause death, any MI, or any coronary revascularization) and its individual components—were similar between men and women. Rates of ARC-defined definite stent thrombosis also were low and similar.

According to Kok and colleagues, women with ACS have been shown to have more ECG changes than men despite a lower prevalence of epicardial obstructions. This pattern, they say, suggests a higher prevalence of microvascular dysfunction, possibly due to oxidative stress in the presence of endothelial dysfunction, or from microvascular damage as a consequence of aging, arterial hypertension, and inflammatory processes. Hormonal changes also may play a role.

The study authors note that when comparing chest pain data from patients treated with contemporary metallic DES versus those treated with bioresorbable vascular scaffolds, “it is very important to take the proportion of female patients into account.” Furthermore, researchers should be stratifying for gender during randomization in studies that assess chest pain recurrence after PCI, they advise.

Looking Beyond Hard Endpoints

In an email to TCTMD, senior author Clemens von Birgelen, MD, PhD (Thoraxcentrum Twente), said the finding that women are continuing to have chest pain after PCI much more often than men “deserves more attention, not only in future research but also in daily clinical practice when informing patients about what they may expect from PCI.”

While the data are reassuring in that women derive the same benefits as men from PCI in terms of traditional clinical endpoints, he noted, they also clearly show that quality of life post-PCI differs.

“Chest pain may have a significant influence on the way patients live. And although women do not experience more adverse clinical events, they are more often limited by chest pain complaints, which pose a genuine burden and decrease quality of life,” von Birgelen said. “For my part, before I treat a female patient with [a] hemodynamically significant coronary lesion and partly atypical chest pain, I tend to inform her that after PCI her complaints may be gone, but that there is also a chance that some complaints may remain unaffected by PCI.”

More Questions Than Answers

In an editorial accompanying the study, Jennifer A. Tremmel, MD (Stanford University Medical Center, Stanford, CA), argues that the self-reported chest pain scale used in the study does not account for atypical symptoms or nonobstructed vessels.

 “Clearly, we need a better understanding of the nonobstructive causes of chest pain in patients following stent placement,” she writes.

As for the possibility that women have more microvascular obstruction than men, Tremmel says that following publication of the WISE study, which raised awareness of endothelial and microvascular dysfunction as alternative causes of stable angina in nonobstructive CAD, there has been “a sort of mental languor” among cardiologists whereby “angina, nonobstructive CAD, and woman equals [microvascular dysfunction].” In fact, Tremmel cites her own recent study, which found no difference in the incidence of microvascular dysfunction between men and women.

In response, von Birgelen noted that although microvascular dysfunction is likely a significant contributor to the residual complains observed, “we cannot exclude that in some cases the presence of myocardial bridging or noncardiac cause of chest pain (eg, musculoskeletal trigger points, irritation of nerves, and gastrointestinal or pulmonary disorders) might have played a role.”

Importantly, Tremmel also raises the question of how many patients had similar chest pain prior to their PCI that was unchanged with stenting. If this were the case for many of the women in the study, it suggests that the lesions that were stented may not be the cause of their angina. Since neither TWENTE nor DUTCH PEERS reported use of FFR or stress testing for determining whether a stent should be placed, the assumption is that visual estimates were generally used to guide treatment strategy. FFR, she said, may be even more relevant for women than men “to confirm hemodynamic significance before performing PCI, and if FFR is not significant, to consider an occult coronary abnormality as an alternative cause of their chest pain.”

von Birgelen countered that although no data on the frequency of FFR use were collected in the two trials, it has been a standard part of assessment of angiographically intermediate coronary lesions for many years and therefore “it is fair to assume that FFR was employed in many of the patients studied.” Broad use of FFR in both genders is justified and in women with atypical chest pain it may more often inspire changes to therapeutic strategy, he said, but there is also the probability of it resulting in false negatives that may misguide clinical decision making.

“However, further dedicated research on sex and gender issues is warranted—even required—and should include the evaluation of microvascular disease and the assessment of . . . whether gender-based treatment strategies may optimize both clinical prognosis and freedom from chest pain,” von Birgelen concluded.

Sources:  
1. Kok MM, van der Heijden LC, Sen H, et al. Gender difference in chest pain after implantation of newer generation coronary drug-eluting stents: a patient-level pooled analysis from TWENTE and DUTCH PEERS. J Am Coll Cardiol Intv. 2016;Epub ahead of print.
2. Tremmel JA. To define is to limit. Is that good or bad when it comes to chest pain? J Am Coll Cardiol Intv. 2016;Epub ahead of print. 

Disclosures:

• Kok and Tremmel report no relevant conflicts of interest. 
• von Birgelen reports consulting for Boston Scientific and Medtronic, receiving lecture fees from AstraZeneca, and receiving research grants to his institution from Abbott Vascular, Biotronik, Boston Scientific, Medtronic, and AstraZeneca. 

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