Sex differences in cardiac arrest and STEMI

This month, I was honoured to be invited back on Dr. Jeannette Wolfe’s incredible podcast “seX and whY”. We chatted about a couple papers that looked at sex differences in the management and outcomes of cardiac arrest and STEMI. This is a brief summary of the papers we discussed. 

Sex differences in CPR

Blewer AL, McGovern SK, Schmicker RH, et al. Gender Disparities Among Adult Recipients of Bystander Cardiopulmonary Resuscitation in the Public. Circulation. Cardiovascular quality and outcomes. 2018; 11(8):e004710. PMID: 30354377

Methods: This is a retrospective look at a massive database of out of hospital cardiac arrest from the Resuscitation Outcomes Consortium (ROC). The goal was to look at the rate of bystander CPR (excluding police, health professionals, and EMS) in men and women. 

Results: Over a 4 year period, there were 19,000 arrests included in the database from 7 centres in the United States. 63% were male. (Sex is recorded as binary: male or female). 17% occured in public, with the remainder occurring in a private setting like the patient’s home. Overall, 37% of the cohort received bystander CPR (44% in public and 35% in private residences).

Males were more likely to get bystander CPR (38% vs 35%, p<0.01). This was only true in public settings. 

Males were more likely to survive than females (OR, 1.33; 95% CI, 1.21 -1.46; P<0.01). Patients receiving bystander CPR were also more likely to survive (OR, 2.03; 95% CI, 1.86 -2.22; P<0.01). They only present odds ratios, so it isn’t clear how big a difference in survival there was.

Thoughts: This is uncontrolled data, so there may be other explanations beneath the male/female dichotomy. Maybe males are more likely to arrest in places with more bystanders, like sporting events or casinos, so the chance of CPR is higher? It also isn’t clear whether the CPR was the cause of the gender gap in survival, or whether some other difference was at play. Women tend to be older and have more comorbidities when they have a cardiac arrest. However, they attempt to adjust for that, and the mortality gap is still there. Ultimately, a sex based mortality gap is clearly important and the difference in CPR rates might provide us with a possible solution. 

Perman SM, Shelton SK, Knoepke C, et al. Public Perceptions on Why Women Receive Less Bystander Cardiopulmonary Resuscitation Than Men in Out-of-Hospital Cardiac Arrest. Circulation. 2019; 139(8):1060-1068. PMID: 30779655

Women are less likely to get bystander CPR than men in the context of out of hospital cardiac arrest. This is an online survey looking at possible reasons. It is not a particularly representative survey, being primarily made up of caucasians with university degrees. The sample was 50/50 male and female. They came up with 3 big themes. I think the first was pretty predictable: performing CPR involves touching the chest and people are afraid of the potential sexual implications in women. The other two reasons surprised me. Women were seen as being weaker or more frail than men, and so bystanders might be worried about causing harm such as breaking ribs. Finally, there was a sense that women are less likely than men to have cardiac disease, so CPR might be the wrong treatment. These are just surveys speculating on why CPR isn’t performed. They weren’t looking at real cases of cardiac arrest and so do not necessarily get at the real reasons for a gender gap, but they provide a starting point for education aimed at dispelling these myths and increasing the rate of bystander CPR in the community.

Anatomical differences between males and females are rarely address in CPR courses. Every course I have attended has used the same dismembered, plastic, male torso to practice CPR. Another group has noticed this issue, and created the “womanikin” in the hopes of making bystanders more comfortable performing CPR on women.

Bottom Line

There are clearly sex differences in the rates of bystander CPR provided to women and men. The second paper reveals some possible reasons for the discrepancy, but doesn’t get at the more important question of what we should do about it. 

Personally, I think teaching CPR at a young age to normalize the practice is a good idea. Courses should specifically talk about the anatomical differences, and acknowledge that you may touch the patient’s breast, but that it is clearly appropriate in the context of a life saving medical intervention. Having clear and widely understood good Samaritan laws are also probably important. Being mentally prepared to perform scary and unusual procedures may also be important, so teaching lay rescuers to mentally practice as part of CPR courses might work. 

However, I think the best answer might simply be: we don’t know. Changing human behaviour is complex, and interventions often have unintended consequences. I would love to see studies which staged cardiac arrests, but altered a number of variables (including gender) to see what factors impact the likelihood of bystanders getting involved.

While we wait on those studies, I would love to hear from you. What do you think we should do to eliminate this gap, or to improve CPR rates overall?

Sex differences in DNR

Perman SM, Siry BJ, Ginde AA, et al. Sex Differences in “Do Not Attempt Resuscitation” Orders After Out-of-Hospital Cardiac Arrest and the Relationship to Critical Hospital Interventions. Clinical therapeutics. 2019; 41(6):1029-1037. PMID: 31047712

Methods: These authors note that in out of hospital cardiac arrest, survival to hospital admission is similar between men and women, but there is a gap in survival to discharge. We don’t know why. The authors look at one possible reason: differences in the rate of DNR orders between the sexes. This is a retrospective look at a large administrative database in which adult cardiac arrest patients were identified using ICD codes (which they think is about 85% accurate). The database was in California, where all DNR orders are recorded electronically. As prognosis after cardiac arrest is not accurate until 72 hours, the authors assumed that early DNR orders (within 24 hours) might be inappropriate. Their primary outcome of interest was the rate of DNR orders within 24 hours based on sex.

Results: In the 1 year study period, there were 6562 patients admitted to hospital through an emergency department after a cardiac arrest. 44% were female. Overall, 21% of patients had a DNR order put on their chart within 24 hours of admission. This was more common in females (23% vs 19%, p<0.01). They attempt to adjust for age, race, and comorbid conditions, and women were still more likely to have a DNR order (odds ratio = 1.23; 95% CI, 1.09-1.40; P = 0.001). Not surprisingly, patients with DNR orders had fewer investigations and procedures performed. 

Thoughts: In order to trust this data you have to trust the accuracy of the coding and the database, which is always somewhat questionable. The timing of the DNR is only coded by the day, so we don’t know if the DNR order was placed immediately (ie, the family clearly knew her wishes) or 23 hours later after some deliberation. We don’t know how many cardiac arrests were called in the field or were never started because a DNR was already in place. There are also a lot of confounders. Women were older than men and had somewhat more comorbidities (at least among what they measured). We also know nothing about the context of the arrests. Maybe women were more likely to have had prolonged asystolic arrests and men had shorter vfib arrests. Maybe the DNR orders were simply good medical judgement.

Assuming the difference is real, we can only speculate as to why. There are many potential reasons for the higher rate of DNR orders among women. This may simply be a biologic difference, as women are older and more comorbid at the time of their arrest (although they tried to adjust for that). Women are more likely to have out-lived their spouse, which could influence this decision. Financial considerations (the need to keep a pension going) often play into medical decisions in ways we don’t understand. I also wonder whether women are more comfortable talking about death and therefore more likely to have already discussed their end of life wishes. (My personal experiences with patients, family, and friends supports this hypothesis, but I don’t know of any science, so I may be biased). Perhaps it is as simple as women having more doctor visits in the preceding year, so it was more likely that end of life wishes had already been discussed? This data can tell us that a gap exists, but can’t answer the more important question of why.

Bottom Line

Women are more likely than men to have a DNR order placed on their chart in the first 24 hours after a cardiac arrest. The reason is unclear. (I would love to hear your opinions). It is also unclear whether this represents good or bad care. Are women less likely to end up in a nursing home with a poor quality of life, or are they missing out on years at home with a good neurologic outcome? Clearly, more research is needed.

Sex differences in STEMI

Huded CP, Johnson M, Kravitz K, et al. 4-Step Protocol for Disparities in STEMI Care and Outcomes in Women. Journal of the American College of Cardiology. 2018; 71(19):2122-2132. PMID: 29535061 [free full text]

Methods: Women are known to have longer door to balloon times and worse outcomes (including increased mortality) in STEMI. The Cleveland clinic wanted to reduce variability in STEMI treatment. They instituted a series of 4 key changes designed to improve outcomes. First, instead of waiting for a discussion between the ED physician and cardiology, the cath lab was activated directly by the ED. Second, they instituted a checklist that outlined important assessments and guideline recommended therapy. Third, they instituted a policy of immediate transfer to the cath lab (rather than waiting for word that the lab was ready). And finally, they strongly suggested a radial artery approach over the femoral artery for PCI. This study is a before and after study looking at those changes, and focusing on the differences in care between men and women.

Results: They include 1272 patients, 68% of whom are men. As expected, the women are older, with more comorbidities. Door to balloon time was 8 minutes longer for women in the before group (112 minutes vs 104 minutes). After the intervention, door to balloon times improved in both groups, and were no longer statistically different (91 versus 89 minutes).

Before the intervention, 97% of men received all guideline recommended treatments (dual antiplatelets and an anticoagulant) before the end of PCI as compared to 93% of women. After the intervention, it was still 97% in men, but increased to 98% in women.

In the before group, women had a higher rate of stroke, vascular complications, bleeding, transfusions, and in hospital mortality than men. There were no significant differences in the after group, although the point estimate for in hospital mortality was still higher for women.

Some thoughts: Demonstrating a decrease in physician variance is a big deal. It is very hard to change physician practice, so these authors deserve a lot of credit, and we should try to learn as much as we can from their process.

That being said, the results are complicated and a little hard to make sense of. There is no doubt that outcomes improved over time here, and that the gap between men and women decreased. However, it isn’t clear what accounts for those changes. With any before and after study, simple improvement in care over time and the Hawthorne effect have to be considered. How exactly does the protocol account for the change in adverse events? If you focus only on strokes, it may make sense, because the heparin rate was higher with the intervention, so we might expect strokes to go down (although the overall change in heparin use was only 5%, so you would have to believe that heparin had almost a 100% relative risk reduction to achieve the 3% decrease in strokes). However, it wasn’t just the thrombotic events that improved. Bleeding also decreased. How can this protocol, that increased the use of anticoagulation and dual antiplatelet therapy, decrease both bleeding and clotting? That doesn’t really make sense to me. I think that likely suggests some other confounder hidden in the before/after study design that accounts for some of the changes seen, although the simultaneous change from femoral to radial access complicates the data.

We have to remember that guideline based care is not the same as evidence based care. Although dual antiplatelet therapy and heparin are strongly recommended, neither decrease mortality, and the decrease in thrombotic events with these agents is closely balanced by an increase in bleeding events. (Magee 2008; Squizzato 2011) Thus, I think it would be wrong to infer that any changes in mortality were the result of increases in guideline based care.

It isn’t clear to me whether these studies should be dividing patients based on sex or gender (or both). This critique applies to all the studies discussed today, which exclusively focused on sex (and did so as a dichotomized variable). That is fine if the observed differences are primarily genetic, but I think social, environmental, and behavioral differences tied to gender would be at least as important. 

Finally, minimizing treatment differences between men and women makes sense, unless there is a difference in the underlying disease that requires a different approach to treatment. Women have STEMIs at an older age, are more likely to have negative caths, and have higher mortality. That makes me wonder about underlying physiologic differences. Maybe our focus should be on determining those differences, and asking whether women might need a different approach to treatment than men? At this point, it’s hard to know, and so until that research is done, it makes sense to eliminate gender based treatment differences if possible.

Bottom line

In this study, which echoes prior data, women have worse outcomes from STEMI. They were able to decrease (but not eliminate) the gap by instituting a 4 step protocol. I think there is clearly value in checklists and protocols in reducing variability in medicine, but I worry that we sometimes get carried away with such protocols, and mandate practices that might be more appropriate for individual decisions on a patient by patient basis.

Summary

Overall, these 4 papers represent my favourite kind of medical research. Although they have significant methodological flaws, and don’t provide us with any clear answers, they made me stop and think. I am not sure how these papers should impact my clinical practice, but they will force me to reflect further on potential sex and gender based differences in emergency medical care.

You can find the first of three podcasts on seX and whY here.

Other References

Magee KD, Campbell SG, Moher D, Rowe BH. Heparin versus placebo for acute coronary syndromes. The Cochrane database of systematic reviews. 2008; [pubmed]

Squizzato A, Keller T, Romualdi E, Middeldorp S. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. The Cochrane database of systematic reviews. 2011; [pubmed]