Immediate Oral Beta-Blockers in STEMI

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Context:

Prior to 2005, standard practice in treatment of STEMI in many emergency departments included giving IV beta-blockers (typically metoprolol 5 mg IV q 5 minutes up to 3 doses, unless contraindicated by hypotension or bradycardia). Patients were then admitted and given oral beta-blockers.

In 2005, the COMMIT trial (aka 2nd Chinese Cardiac Study/CCS-2) was published in Lancet: 45,852 patients were randomized to receive either placebo or metoprolol (15 mg IV in the emergency department followed by 50 mg PO q 6 hours for 48 hours, followed by 200 mg extended release metoprolol daily for 4 weeks). There was no difference between the treatment and control groups for the primary outcome (composite of death, reinfarction, or cardiac arrest) (odds ratio [OR] 0.96, 95% CI 0.90-1.01) or for death alone (OR 0.99, 95% CI 0.92-1.05). However, there was a significant increase in the risk of cardiogenic shock in patients receiving metoprolol (OR 1.30, 95% CI 1.19-1.41).

The result for our emergency department (and many others) was that we stopped giving immediate metoprolol to STEMI patients (though they still received oral metoprolol once admitted). The AHA/ACC STEMI guidelines changed as well, though not so drastically as our practice. The wording in 2004 was that “oral beta-blocker therapy should be administered promptly to those patients without a contraindication,” compared to the current wording: “oral beta blockers should be initiated in the first 24 hours in patients with STEMI.” The guidelines remained unchanged with regards to IV beta-blockers, which they state “it is reasonable to administer…promptly to STEMI patients without contraindications.”



Methods:

This observational study used data collected prospectively in the Austrian Myocardial Infarction Network from June 1, 2006 to December 31, 2010. The use of bisoprolol (2.5 mg orally) was recommended by protocol to be given by the emergency physician either out-of-hospital or in the ED within 30 minutes of confirmation of an acute STEMI. If bisoprolol was not given within 30 minutes, the protocol recommended it be given 24 hours after the first ECG. The decision to give bisoprolol immediately was made by the physician on duty. Contraindications included:

1) Systolic blood pressure (SBP) < 100 mmHg

2) Bradycardia (HR < 60 bpm)

3) 2nd or 3rd degree AV block

4) Clinical signs of heart failure (bilateral rales, cyanosis).

All patient eligible for percutaneous intervention (PCI) also received aspirin, clopidogrel, bivalirudin, and abciximab. Patients receiving rtPA were given aspirin, clopidogrel, and unfractionated heparin.

The primary outcome was all-cause mortality greater than 48 hours after presentation: only patients who survived the first 48 hours were included in the survival analyses. Secondary outcomes included cardiovascular death at 30 days and 1 year. Mortality was also assessed for two predefined subgroups: elderly patients aged > 70 years and patients with ≥ 2 COMMIT shock index criteria (age > 70, symptoms > 12 hours, SBP < 120 mmHg, and HR > 110 bpm). Follow-up data on mortality was obtained from the Statistical Department of the Austrian government that collects data on the cause of death in all patients who die in a hospital in Austria.



Results:

664 patients with STEMI were analyzed: 343 (52%) received immediate β-blocker therapy while 321 (48%) received delayed β-blocker therapy. The average age was 64, with 70% male. The two groups were similar with respect to age, gender, previous medical history, time from onset of pain to first ECG, time from first ECG to PCI, and reperfusion strategy. The delayed β-blocker group had significantly lower initial mean SBP (129 vs. 146 mmHg, p < 0.001), lower initial mean diastolic blood pressure (77 vs. 85 mmHg, p < 0.001), and lower initial mean heart rate (75 vs. 82 bpm, p <0.001).

24 patients died within the first 48 hours (immediate β-blocker group: 5, delayed β-blocker group: 19), all related to the MI. For the remaining 640 patients, survival analysis revealed an overall mortality of 19.2% in the delayed β-blocker group vs. 10.7% in the immediate β-blocker group (p = 0.0022, RR = 0.56, NNT 11.7). Thirty-day and one-year cardiovascular mortality were lower in the immediate β-blocker group than the delayed β-blocker group, as were 30-day and one-year all-cause mortality (Table 1). The use of immediate β-blocker was not associated with an increase in all-cause mortality in either those with an increased risk for cardiogenic shock, or those over 70 years of age.

Table 1. 30-day and 1-year cardiovascular (CV) and all-cause mortality

Delayed βBL

Immediate βBL

P -value

30-day CV mortality

4.34%

0.89%

0.0058

1-year CV mortality

8.14%

1.88%

0.0003

Total CV mortality

13.41%

5.17%

0.0002

30-day all-cause mortality

4.66%

0.89%

0.0033

1-year all-cause mortality

9.79%

3.23%

0.0006

Total all-cause mortality

19.19%

10.73%

0.0022



Commentary:

If we believe this study, we need to give 12 STEMI patients 2.5 mf of oral bisoprolol (equivalent to 25 mg metoprolol) to save one life over the next 4.4 years, or 26 patients to save one life in the next month (these numbers would be even lower if we included deaths in the first 48 hours). Compare this with a NNT of 42 for aspirin (ISIS-2) and 50 for PCI (vs. thrombolysis) (Wang 2009) to prevent one death at one month.

It seems biologically implausible that giving a small dose of an oral blocker 24 hours earlier in STEMI could result in such a large reduction in mortality. This is especially true considering the large mortality difference seen in the first 48 hours (5 in the immediate group vs. 19 in the delayed group). The authors themselves note “The assumption is that patients dying within the first 48 hrs have died independently of immediate or delayed β-blocker treatment, e.g., death occurred prior to a sufficient β-blocker effect,” but go on to attribute the large mortality reduction seen to treatment effect. It would seem more plausible, given the observational non-randomized nature of the study, that a prognostic imbalance existed between the two groups at the beginning of the study that would explain the difference in outcomes (rather than an effect of the treatment), including:

· Reported: the only reported differences were SBP, diastolic blood pressure, and heart rate, which were all lower in the control group. While decreased SBP has been shown to increase mortality in STEMI, lower heart rates have been shown to be protective (Gale 2008).

· Not reported: location of MI (anterior STEMI has been shown to predict increased mortality compare to other locations [Stone 2008])

· Not reported - hx of CHF has been shown to increase mortality (Gale 2008).

· Hidden: the proportion of patients with ≥ 2 shock index criteria was significantly imbalanced: 79 (26.2%) patients in the delayed β-blocker group vs. 54 (16.0%) in the immediate β-blocker group (p = 0.0016). And that’s in patients who survived the first 48 hours!!!

· Hidden: there was in increase in both the incidence of hypotension (17 vs. 5, p = 0.008) and bradycardia (41 vs. 14, p < 0.001) in the delayed treatment group. It seems unlikely that withholding beta-blockers for 24 hours would result in an increase in these complications during that same time period. It is more likely that a prognostic imbalance put the control group at increased risk of both of these.



Bottom Line:

Despite a large reduction in mortality (19.19% vs. 10.73%) with immediate vs. delayed oral beta-blocker administration in STEMI, it seems unlikely that this difference was due to treatment effect, and more plausible that the difference was due to prognostic imbalance. As the authors state, a randomized-controlled trial to assess the efficacy of immediate beta-blockers would be helpful to resolve this issue. Randomization attempts to balance both known and unknown confounders between treatment groups, so that any difference in outcome can be attributed to treatment effect.



EBM Teaching Point:

The authors used a survival analysis, and presented Kaplan-Meier curves of the results for mortality over time. If we take the total all-cause mortality for the delayed beta-blocker group as an example, we see 41 deaths out of 302 participants. If we use these numbers to calculate a percent, we do not arrive at the 19.19% probability of death reported. This is because all of the patients could not be followed for the same duration. Imagine a patient enrolled on day 1 of the study (June 1, 2006), who is followed for approximately 4.5 years (the last point plotted on the Kaplan-Meier curve): we know whether or not that patient died over a 4.5-year period. Now imagine a patient enrolled on the last day of the study (December 31, 2010). If we followed this patient for 4.5 years, we would still be watching for the outcome (and would continue doing so until July of 2015!). Instead, the authors took the follow-up data they had until the point at which they stopped looking at outcomes. Entering this data into statistical software will yield a survival analysis and Kaplan-Meier curve, which is used to compute an estimate of survival probability.



Posted on June 1, 2013 and filed under Cardiology.