Younger women and women with STEMI ‘less likely’ to be prescribed evidence-based medicines

Results from a study funded by the British Heart Foundation and published in Journal of the American Heart Association have hit the headlines claiming that women who suffer heart attacks are not being offered the same treatment as men. [1]

The report from the SWEDEHEART study analysed data from 48,118 patients, 35.4% of whom were women, and all who were diagnosed with acute myocardial infarction. The primary endpoint of this analysis was all-cause mortality, however researchers also looked at the likelihood of patients receiving the recommended evidence-based pharmacological drugs.

This study revealed that, on the surface women had a better adjusted prognosis than men after an acute MI. However, scratch beneath the surface and a different picture emerges.

Younger women (aged under 60 years) and women with ST-elevation Myocardial Infarction (STEMI) had a worse prognosis, and were less likely to be prescribed evidence-based treatment than their male counterparts. Furthermore, this discrepancy in gender did not decrease over two decades. [1]

Women in the study were more likely to have previously been diagnosed with hypertension or type II diabetes, and were also more likely to develop prehospital cardiogenic shock or in-hospital heart failure.

Sub-group analyses showed that the estimated risk for developing prehospital cardiogenic shock was higher for women compared to men (OR 1.67, 95% Cl 1.30 to 2.16, P<0.001), and the risk in women with STEMI was also higher compared to the risk in men (OR 1.31, 95%Cl 1.16 to 1.48). [1]

Other findings show that women with STEMI were less likely to undergo coronary angiography than men, and after adjustment of traditional CV risk factors women were less likely to receive evidence-based treatments including beta-blockers, ACE inhibitors, statins and P2Y12 inhibitors.

The reasons for this are unclear and certainly warrant further investigation. It is common for women to present at a later stage in the disease than men for a variety of reasons. For example, as Professor Angela Maas, Professor Women’s Cardiac Health, Cardiology Department, Radboud University Medical Center, Nijmegen, The Netherlands told Cardio Debate: “We often think hypertension is asymptomatic, but it can actually give a lot of symptoms, especially in women who are middle aged,” adding that: “It is easy to discriminate between stress-related elevated blood pressure and severe developmental hypertension. Just ask questions about pregnancy [e.g., the presence of gestational diabetes] or the family history.” [2]

However the study authors suggest the presence of ‘systemic undertreatment’ in women. [1] Professor Juan Tamargo, Professor of Pharmacology, Universidad Complutense, Madrid, Spain has previously addressed this issue with Cardio Debate, saying: “We need to clarify to people that there is a problem and that there are some ways to improve it.” [3]

“There is the feeling that male physicians usually consider that women need less strict treatments; we don’t give the same advice to women as we do to men. There are lots of things (regarding gender differences and gender treatment bias) that should be included in position papers and clinical guidelines [to avoid undertreatment in women].” [3]

Patients should be prescribed evidence-based medicines regardless of their gender, and this should be a given. Hopefully this study will steer the conversation in the right direction, and encourage the medical community to address this serious issue.


  1. Redfors B, Angeras O, Ramunddal T, et al. Trends in gender differences in cardiac care and outcome after acute myocardial infarction in Western Sweden: A report from the Swedish Web System for Enhancement of Evidence-Baed Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). J Am Heart Assoc DOI: 10.1161/JAHA.115.001995

ATLANTIC: In-Ambulance vs. In-Cath Lab Administration of Ticagrelor in STEMI Patients Transferred For Primary PCI

Pre-hospital administration of ticagrelor in patients with acute ST-segment elevation myocardial infarction (STEMI) does not improve pre-percutaneous coronary intervention (PCI) coronary reperfusion, but it does appear safe and may prevent post-procedural acute stent thrombosis, according to results from the ATLANTIC trial presented Sept. 1 as part of ESC Congress 2014 and simultaneously published in the New England Journal of Medicine. External Link

The international, multi-center trial was based on 1,862 patients with ongoing STEMI of less than six hours duration who received ticagrelor treatment either in the ambulance or in the catheterization lab. Overall, the median time from randomization to angiography was 48 minutes and the median time difference between the two treatment strategies was 31 minutes. According to study investigators, the proportion of patients who did not have a 70 percent or greater resolution of ST-segment elevation before PCI and who did not have thrombolysis in myocardial infarction flow grade 3 in the infarct-related artery at initial angiography did not vary significantly between the two groups. The rates of major adverse cardiovascular events and of major bleeding also did not vary significantly.

However, the rates of definite stent thrombosis were lower in the pre-hospital group than the in-hospital group. “The observed preventive benefit is consistent with pharmacodynamics and ECG findings suggesting that the maximal effort of pre-hospital administration of ticagrelor occurs after the end of the procedure,” the investigators said.

Investigators did note limitations to the study based on the small sample size and the short intervals between administration of ticagrelor and reperfusion. “The time to PCI in our study was extremely short in both groups indicating excellent practice,” they said, “but this may have blunted the drug effect and may not reflect clinical practice.”

Major Bleed Risk Falls with Bivalirudin vs Heparin en Route to PCI for STEMI: EUROMAX.

The 30-day risk of death or major bleeding fell significantly in ST-elevation MI (STEMI) patients treated with bivalirudin (Angiomax, the Medicines Company) compared with heparin-based management, both initiated prior to arrival at a hospital for primary PCI, in a large randomized but open-label study[1].

The bivalirudin benefit for that composite end point in the European Ambulance Acute Coronary Syndrome Angiography(EUROMAX) trial was driven by a significant drop in major bleeding, the definition of which excluded bleeding related to CABG surgery.

The heparin-based strategy consisted of either unfractionated heparin (UFH) or the low-molecular-weight heparin enoxaparin(Lovenox, Sanofi). Both groups could receive a GP IIb/IIIa inhibitor provisionally.

EUROMAX was published today in the New England Journal of Medicine with lead author Dr Philippe Gabriel Steg (Hôpital Bichat, Paris, France) to coincide with his presentation of the trial here at TCT 2013 .

Dr Philippe Gabriel Steg

Bivalirudin’s 40% primary-end-point relative risk reduction included a >50% drop in risk for non-CABG major bleeding. On the other hand, the relative risk of stent thrombosis with bivalirudin was nearly threefold what was seen in the heparin group, although absolute rates were very low.

At a media briefing on the trial, Steg said the excess stent thromboses with bivalirudin were driven by events in the acute phase, within 24 hours of PCI. And, he observed, they didn’t translate into more reinfarctions or ischemia-driven revascularization.

Still, “acute stent thrombosis . . . while rarely fatal and not outweighing the advantages of bivalirudin, is the only troubling issue with bivalirudin in STEMI, and we do need strategies to reduce this complication,” according to Dr Gregg W Stone (New York-Presbyterian Hospital/Columbia University Medical Center New York, NY), the assigned discussant following Steg’s formal presentation of EUROMAX.


The trial’s findings are reminiscent of the HORIZONS AMI trial 30-day outcomes reported about six years ago and covered then by heartwire . That trial, Steg et al observe, preceded some important changes in STEMI management and PCI technique that likely affected bleeding risk, changes that were a part of EUROMAX. These included the expansion of radial-artery PCI access, newer antiplatelet agents, reduced GP-IIb/IIIa-inhibitor use, and progressively earlier initiation of IV anticoagulants.

In the >3600-patient HORIZONS AMI, anticoagulation wasn’t started early during transport. But both it and EUROMAX with its nearly 2200 patients saw a decreased bleeding risk and increased stent-thrombosis risk with bivalirudin compared with heparin. But in contrast to EUROMAX, the earlier trial also showed a reduced risk of cardiac death in bivalirudin patients.

The two studies taken together have more to say than either alone. “I think the results of EUROMAX will heavily impact clinical use of bivalirudin in Europe,” Steg said to heartwire . “The results are very consistent wih HORIZONS AMI, even to the point of the stent-thrombosis signal” and are “reassuring enough to embrace [bivalirudin] in the prehospital setting.” That is, he added, “If you want to. [The EUROMAX results] are not mind-blowing because we don’t see a mortality reduction. But they suggest that the benefits seen in HORIZONS AMI can be extended to the contemporary prehospital setting. “

At the media briefing, Dr Bernard Gersh (Mayo Clinic, Rochester, MN), who wasn’t involved in the trial, said, “It’s not that often that you see trials that really will change clinical practice, and I think this will.”

The Role of Prehospital Diagnosis and Treatment

Gersh also said, “I’ve never seen really anything that suggests that prehospital administration [of anticoagulants] and [STEMI] diagnosis is not beneficial.”

But whether they are achievable in the field varies by country, even within Europe. Interviewed, Steg pointed out that at most participating centers, there were no physicians in the ambulances. It does take some expertise to interpret the ECGs, unless the tracings can be transmitted to a center for remote reading. But, he said, “It’s been shown in other trials if you have good trained paramedics, they do just as well if not better than physicians.”

Also speaking at the briefing as a EUROMAX observer, Dr Philippe Généreux (NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY) said prehospital STEMI diagnosis and treatment initiation could make the most difference in countries like Canada, “where there aren’t cath labs on every corner” and it might take 45 to 60 minutes for an ambulance to reach a PCI center.

Prospects for prehospital management in the US seem more remote, observers agreed. Dr James B Hermiller, Jr (St Vincent Hospital/The Heart Center of Indiana, Indianapolis,) said at the briefing, “The barrier to this in the US is very great. It’s difficult just to  get ECGs in the field, let alone administer anticoagulants, but we need to get there because this is very important.”

The Open-Label Randomization

EUROMAX randomized patients at centers in nine European countries presenting within 12 hours of onset of symptoms from electrocardiographically defined STEMI, on an open-label basis, to the bivalirudin or heparin strategies. Treatment was initiated in the ambulance or at a non-PCI hospital with subsequent transport to a PCI center.

For the 1089 patients who received bivalirudin, the drug was started as a 0.75-mg/kg bolus followed by an infusion of 1.75 mg/kg/h continued for at least four hours after PCI. The 1109 control patients received UFH at either 100 IU/g or 60 IU/kg with a GP IIb/IIIa inhibitor or were allowed to have enoxaparin at 0.5 mg/kg. Adjuvant GP IIb/IIIa inhibitors were allowed at physicians’ discretion. All patients received aspirin plus a P2Y12 inhibitor.

Relative Risk (95% CI) for Outcomes, Bivalirudin vs Heparin Strategies for STEMI Initiated During Emergency Transport to Primary PCI

End points

RR (95% CI)


30-day death from any cause or non-CABG major bleedinga

0.60 (0.43–0.82)


30-day death from any cause, reinfarction, or non-CABG major bleeding

0.72 (0.54–0.96)


Non-CABG major bleeding

0.43 (0.28–0.66)


Major bleeding (TIMI definition)

0.62 (0.32–1.20)


Severe or life-threatening bleeding (GUSTO definition)

0.61 (0.22–1.68)


Definite stent thrombosisb

2.89 (1.14–7.29)


a. Primary end point 
b. Academic Research Consortium criteria

No significant differences were seen at 30 days for the composite of death, reinfarction, ischemia-driven revascularization, or stroke, or for any stroke or ischemic stroke. A committee blinded to treatment assignment adjudicated bleeding episodes and clinical events.

As discussant, Stone pointed out that PCI via the radial artery, rather than the femoral artery, was done in only 6% of cases in HORIZONS AMI but in 47% of EUROMAX patients. Some predicted that the greater proportion of radial procedures would lead to a much lower major bleeding rate and make it hard for bivalirudin to show an effect. A EUROMAX subgroup analysis found, however, that the benefits of bivalirudin over the heparin-based strategy were consistent for different kinds of patients, including whether their PCI was by the radial or femoral routes.

“Therefore, bivalirudin is beneficial regardless of the access site, and this is because most bleeding in the STEMI and ACS setting is not access-site related,” he said. It’s the non–access-site bleeds to pose the greater threat to later outcomes. So, he said, “the advantages of bivalirudin are present in patients undergoing radial as well as femoral intervention, and radialists should pay attention to this.”

Stone said EUROMAX raises the question of whether using cangrelor (the Medicines Company) as part of the accompanying antiplatelet therapy might help prevent stent thrombosis with bivalirudin, and that’s being addressed in HORIZONS-AMI-2, which is starting soon.

Bivalirudin During Transport for PCI in STEMI Lowers Bleeding, But Increases Stent Thrombi.

The direct thrombin inhibitor bivalirudin — when given to patients with ST-segment elevation myocardial infarction (STEMI) during transport for percutaneous coronary intervention (PCI) — is associated with lower rates of major bleeding after PCI. However, risks for early stent thrombosis are increased sixfold, according to a New England Journal of Medicine study. The drug’s maker participated in the study.

 Some 2200 patients with STEMI being transported to facilities for PCI were randomized en route to begin antithrombotic treatment with either bivalirudin or with heparin and optional glycoprotein inhibitors. By 30 days, the composite outcome of death or major bleeding was lower with bivalirudin (5.1% vs. 8.5%). However, the risk for stent thrombosis within 24 hours was higher with bivalirudin (1.1% vs. 0.2%).

An editorialist observes that the “clearest findings” after two bivalirudin trials are that the drug increases stent thrombosis while reducing bleeding complications. He writes that it’s “critical that clinicians weigh the relative importance of these events before selecting an antithrombotic strategy for their patients.”

Source: NEJM

Randomized Trial of Preventive Angioplasty in Myocardial Infarction.

Patients with acute ST-segment elevation myocardial infarction (STEMI) are effectively treated with emergency angioplasty, hereafter called percutaneous coronary intervention (PCI), to restore blood flow to the coronary artery that is judged to be causing the myocardial infarction (infarct artery, also known as culprit artery).1-5 These patients may have major stenoses in coronary arteries that were not responsible for the myocardial infarction,6 but the value of performing PCI in such arteries for the prevention of future cardiac events is not known.

Some physicians have taken the view that stenoses in noninfarct arteries may cause serious adverse cardiac events that could be avoided by performing preventive PCI during the initial procedure.7-12Others have suggested that medical therapy with antiplatelet, lipid-lowering, and blood-pressure–lowering drugs is sufficient and that the risks of preventive PCI outweigh the benefits.2-4,13-17

The aim of our single-blind, randomized study, called the Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial, was to determine whether performing preventive PCI as part of the procedure to treat the infarct artery would reduce the combined incidence of death from cardiac causes, nonfatal myocardial infarction, or refractory angina.


The results of this trial show that in patients with acute STEMI, the use of preventive PCI to treat noninfarct coronary-artery stenoses immediately after PCI in the infarct artery conferred a substantial advantage over not performing this additional procedure. The combined rate of cardiac death, nonfatal myocardial infarction, or refractory angina was reduced by 65%, an absolute risk reduction of 14 percentage points over 23 months. The effect was similar in magnitude and remained highly significant when the analysis was limited to cardiac death and nonfatal myocardial infarction.

In this trial, all decisions regarding the treatment of patients, other than the random assignments to the two study groups, were left to the discretion of the clinicians involved. The rates of use of drug-eluting stents and medical therapy were similar in the two groups. In the group receiving no preventive PCI, ischemia testing was performed in about one third of patients: 44 tests in asymptomatic patients (usually ≤6 weeks after the myocardial infarction) and 37 tests in patients with chest pain. In the preventive-PCI group, ischemia testing was performed in about one sixth of patients: 8 tests in asymptomatic patients and 31 tests in patients with chest pain. Although such testing was not a prespecified trial outcome, these findings suggest that preventive PCI may lead to less ischemia testing and that when such testing is performed, it tends to be in patients with symptoms.

Although refractory angina is a more subjective outcome than myocardial infarction or cardiac death, it was included as a component of the primary outcome because it is a serious symptomatic condition that warrants prevention. We sought to reduce bias in the assessment of this outcome by requiring that the diagnosis be confirmed with objective evidence of ischemia. The benefit of preventive PCI was also evident when the less subjective outcomes of cardiac death and nonfatal myocardial infarction were considered alone.

We decided against using revascularization as a primary outcome, since subsequent revascularization procedures could be prompted by the identification of stenosis in a noninfarct artery in the group receiving no preventive PCI during the initial procedure. This factor would also tend to underestimate the effect of preventive PCI on primary-outcome events by reducing the treatment difference between the two study groups. However, revascularization was retained as a secondary outcome to record the number of subsequent procedures in each group.

In our study, 13 patients did not receive their assigned treatment. In the group receiving no preventive PCI, 2 patients underwent PCI in a noninfarct artery (1 for unknown reasons and 1 because the operator treated what turned out to be a noninfarct right coronary artery and then had to treat the infarct circumflex artery). In the preventive-PCI group, 11 patients underwent PCI only in the infarct artery because the preventive PCI could not be completed owing to insufficient time (because of competing emergency PCIs) in 3 patients, failure of the noninfarct-artery PCI in 5 patients, and other complications in 3 patients. These deviations from the assigned treatment mean that the intention-to-treat analysis, adopted to ensure comparability of the two study groups, will tend to underestimate the benefit of preventive PCI. However, the results of the as-treated analysis were consistent with those of the intention-to-treat analysis.

In two other randomized trials, investigators have specifically assessed the value of preventive PCI in patients with acute STEMI undergoing PCI in the infarct artery. In one study, 69 patients were randomly assigned (in a 3:1 ratio) to preventive PCI (52 patients) or no preventive PCI (17 patients).20 At 1 year, in the preventive-PCI group, there were nonsignificant reductions in the rates of repeat revascularization (17% and 35%, respectively) and cardiac death or myocardial infarction (4% and 6%, respectively). In the other trial, 214 patients were randomly assigned to one of three groups: no preventive PCI (84 patients), immediate preventive PCI (65 patients), and staged preventive PCI performed during a second procedure about 40 days later (65 patients).7 At 2.5 years, the rate of repeat revascularization was less frequent in the immediate– and staged–preventive PCI groups combined, as compared with the group receiving no preventive PCI (11% and 33%, respectively), and there was a nonsignificant decrease in the rate of cardiac death (5% and 12%, respectively). These studies were limited by a lack of statistical power and a reliance on repeat revascularization as an outcome, which, as indicated above, may be subject to bias. However, the results of these studies are consistent with those of our study.

Current guidelines on the management of STEMI recommend infarct-artery-only PCI in patients with multivessel disease, owing to a lack of evidence with respect to the value of preventive PCI.2-5 This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia. The results of this trial help resolve the uncertainty by making clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction. However, our findings do not address the question of immediate versus delayed (staged) preventive PCI, which would need to be clarified in a separate trial.

Several questions remain. First, are the benefits of preventive PCI applicable to patients with non-STEMI?21 Such patients tend to be difficult to study because, unlike those with STEMI (in whom the infarct artery is invariably identifiable), there is often uncertainty over which artery is the culprit. Second, do the benefits extend to coronary-artery stenoses of less than 50%? There is uncertainty over the level of stenosis at which the risks of PCI outweigh the benefits. Third, would a physiological measure of blood flow, such as fractional flow reserve,22,23 offer an advantage over angiographic visual assessment in guiding preventive PCI? Further research is needed to answer these questions.

In conclusion, in this randomized trial, we found that in patients undergoing emergency infarct-artery PCI for acute STEMI, preventive PCI of stenoses in noninfarct arteries reduced the risk of subsequent adverse cardiovascular events, as compared with PCI limited to the infarct artery.


Source: NEJM




Consider Immediate Trip to Cath Lab for Comatose Cardiac Arrest Survivors Without STEMI.

Acute coronary occlusions were common in comatose cardiac arrest survivors without ST-segment elevation myocardial infarction.
Immediate cardiac catheterization for cardiac arrest survivors with acute ST-segment-elevation myocardial infarction (STEMI) is standard practice, but whether it is beneficial in postarrest patients without STEMI is unclear. Investigators retrospectively analyzed data from 269 comatose adult patients at six U.S. medical centers who were treated with therapeutic hypothermia after cardiac arrest due to ventricular arrhythmia without evidence of STEMI on electrocardiogram (ECG).

Of 269 patients, 45% received early cardiac catheterization (either at hospital admission or during hypothermia treatment), 15% received catheterization later during hospitalization, and 39% did not receive catheterization. The early-catheterization group was more likely to be in shock on admission and to receive mechanical support (usually with an intraaortic balloon pump), aspirin, antithrombin agents, and glycoprotein IIb/IIIa inhibitors than patients who received later or no catheterization. Acute coronary occlusion was present in 26% of the early-catheterization group and 29% of the late-catheterization group.

Overall hospital mortality rate was 43.5%. Patients who received early catheterization were significantly more likely to survive than those who received late or no catheterization (66% vs. 49%) and to have good neurologic outcome (61% vs. 45%). Differences in outcomes were even more striking when the early-catheterization group was compared to the no-catheterization group.


Given that the post-resuscitation electrocardiogram may be unreliable and ST-elevation is insensitive for predicting acute coronary occlusion, it is reasonable to consider immediate cardiac catheterization for comatose survivors of arrhythmia-induced cardiac arrest, even in the absence of STEMI.

Source: NEJM

If Possible, STEMI Patients Should Go Straight to a Cath Lab.

Within a system designed to reduce time to reperfusion, mortality was lower in patients transported directly to a PCI-capable center than in those transferred from a non–PCI-capable center.

In the city of Ottawa, emergency medical system providers trained in electrocardiogram interpretation can triage patients with ST-segment-elevation myocardial infarction (STEMI) directly to a center with percutaneous coronary intervention (PCI) capability. In a registry study, investigators compared outcomes in 822 patients transported directly to a PCI-capable hospital with those in 567 patients transported initially to a non–PCI-capable hospital, then transferred for primary PCI.

The median door-to-balloon time was significantly shorter in patients transported directly for PCI (66 minutes) than in those transferred for PCI (117 minutes). At 180 days, all-cause mortality was lower in directly transported patients than in those first taken to a non–PCI-capable hospital (5.0% vs. 11.5%; P<0.001). After multivariable adjustment, direct transfer was associated with about a 50% reduction in mortality risk (odds ratio, 0.52; P=0.01).

Comment: This study strengthens evidence that standardized geographic protocols designed to reduce time to reperfusion for ST-segment-elevation myocardial infarction reduce mortality. The importance of prehospital STEMI diagnosis and systems for rapid transport and treatment are now reflected in guideline recommendations (JW Cardiol Jan 6 2010), and implementation of these practices should be a public-health priority.

Source: Journal Watch Cardiology

Evidence-Based Therapies for ST-Segment-Elevation Myocardial Infarction Improve Survival

A national registry in Sweden captures comprehensive data on the evolution of STEMI treatment and outcomes.

Several reports have described trends in therapy and outcomes in patients with myocardial infarction (MI), but few have included unrestricted populations. This study focuses on trends in evidence-based therapies and mortality in 61,238 patients who had a first-time diagnosis of ST-segment-elevation MI (STEMI) at acute cardiac care hospitals throughout Sweden from 1996 through 2007.

Over the study period, the mean age of the STEMI patients decreased from 71 to 69; rates of baseline hypertension and cigarette use increased; and the proportions taking statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), or both at admission increased. The rate of fibrinolysis declined from 66% in 1996–1997 to 7% in 2006–2007, with concomitant increases in the rates of angiography (from 12% to 93%) and primary percutaneous coronary intervention (from 12% to 61%). Rates of guideline-recommended medication use, including aspirin, clopidogrel, beta-blockers, ACE inhibitors or ARBs, and statins, increased significantly over time, and hospital-to-hospital variability in the use of all of these medications except ACE inhibitors or ARBs narrowed. Mortality at 1 year, standardized for differences in baseline patient characteristics, decreased substantially, from 19.0% in 1996 to 11.2% in 2007.

Comment: This study in an unselected Swedish population revealed a marked decline in mortality concurrent with the adoption of evidence-based therapies for STEMI. Although the observational analysis cannot rule out unmeasured factors that might have played a role in producing these gratifying improvements in outcome, better treatment must have been an important contributor. The fact that 8 in 100 patients treated in 1996 who died may have been alive at 1 year had they been treated in 2007 strongly supports systematic efforts to continually improve delivery of the right therapies to the right STEMI patients at the right time.

Source: Journal Watch Cardiology