Effect of Beta-Blocker Dose on Survival After Acute Myocardial Infarction
Key result
Higher beta-blocker doses approximating those used in prior randomized clinical trials (>50% target dose) were not associated with increased survival compared to lower doses (>12.5% to 25% target dose, HR 0.799).
Why the study?
Beta-blocker doses used in clinical practice after acute MI are often substantially lower than those used in randomized trials establishing their efficacy, and the association of dose with survival is unclear.
Does higher dose beta-blocker therapy improve survival compared to lower doses in patients after acute myocardial infarction?
Key Points
- To evaluate the association of discharge beta-blocker dose with 2-year survival following acute myocardial infarction, testing the hypothesis that higher doses improve survival.
- Multicenter study (NCT00430612) enrolling 7,057 consecutive patients with acute myocardial infarction (6,682 discharged alive with follow-up, median 2.1 years).
- Discharge beta-blocker dose was indexed to randomized clinical trial target doses: >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of target dose.
- Primary endpoint was time-to-death right-censored at 2 years, evaluated using multivariable adjustment and propensity score analyses.
- Compared with the >50% target dose, adjusted hazard ratios for 2-year mortality were 0.862 (95% CI: 0.677 to 1.098) for >0% to 12.5%, 0.799 (95% CI: 0.635 to 1.005) for >12.5% to 25%, and 0.963 (95% CI: 0.765 to 1.213) for >25% to 50% of target dose.
Study Design
Type
Cohort (n=7,057)
Multicenter
Yes
Structured PICO
Does higher dose beta-blocker therapy improve survival compared to lower doses in patients after acute myocardial infarction?
P
Population
6,682 patients discharged alive after an acute myocardial infarction from a multicenter registry, followed for a median of 2.1 years to assess the association of discharge beta-blocker dose with survival.
E
Exposure
Beta-blocker therapy prescribed at hospital discharge (most commonly metoprolol or carvedilol), grouped by proportion of clinical trial target dose: >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of target dose.
C
Comparator
No beta-blocker therapy, as well as cross-comparisons between the different beta-blocker dose groups (using the >50% target dose group as the reference standard).
O
Outcome
Time to all-cause mortality with survival right-censored at 2 years.hard clinical
Main Result
Hazard Ratio: 0.799 (95% CI 0.635–1.005)
Limitations
- Observational registry design with nonrandomized beta-blocker dose assignment.
- Baseline differences and potential unmeasured confounders (e.g., extent of coronary artery disease, follow-up heart rate) among treatment groups.
- The specific clinical rationale for individual dosing regimens was unknown.
- Multiple different beta-blockers were used and indexed to historical target doses.
- Observational registry design subject to unmeasured confounding and non-uniform distribution of risk factors
- Multiple different beta-blockers were used
- Specific rationale for individual dosing regimens chosen by physicians is unknown
- Dose changes over time occurred and were only partially accounted for (survival indexed to discharge dose)
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“I thought that was terrible quality of care. We set out on a mission to show if you treat patients with the doses that were used in the clinical trials, they will do better. We expected to see patients treated with the lower doses to have worse survival. We were shocked to discover they survived just as well, and possibly even better.”
“It's not 100% clear, but if there is a benefit, we only found it in that one dosing group.”
RTRicky TurgeonPharmacist researcher, University of British Columbia
“When we get newer therapies, we need to not forget about the old therapies and understand how these all interplay and interact together. With all of the new interventions that are coming out for these patients, and with increasing complexity with the different antithrombotics and other therapies, we need to really not look at this as a sort of grocery list of therapies that we could use, but really see which combination is optimal for patients.”
Implication
In patients surviving an acute myocardial infarction, higher beta-blocker doses approximating those used in randomized clinical trials were not associated with better survival compared with lower doses.
Abstract
Background Beta-blocker therapy after acute myocardial infarction (MI) improves survival. Beta-blocker doses used in clinical practice are often substantially lower than those used in the randomized trials establishing their efficacy. Objective This study evaluated the association of beta-blocker dose with survival after acute MI, hypothesizing that higher dose beta-blocker therapy will be associated with increased survival. Methods A multicenter registry enrolled 7,057 consecutive patients with acute MI. Discharge beta-blocker dose was indexed to the target beta-blocker doses used in randomized clinical trials, grouped as >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of target dose. Follow-up vital status was assessed, with the primary endpoint of time-to-death right-censored at 2 years. Multivariable and propensity score analyses were used to account for group differences. Results Of 6,682 with follow-up (median 2.1 years), 91.5% were discharged on beta-blocker (mean dose 38.1%). Lower mortality was observed with all beta-blocker doses (p < 0.0002) versus no beta-blocker therapy. After multivariable adjustment, hazard ratios (HRs) for 2-year mortality compared with the >50% dose were 0.862 (95% confidence interval [CI]: 0.677 to 1.098), 0.799 (95% CI: 0.635 to 1.005), and 0.963 (95% CI: 0.765 to 1.213) for the >0% to 12.5%, >12.5% to 25%, and >25% to 50% of target dose, respectively. Multivariable analysis with an extended set of covariates and propensity score analysis also demonstrated that higher doses were not associated with better outcome. Conclusions These data do not demonstrate increased survival in patients treated with beta-blocker doses approximating those used in prior randomized clinical trials compared with lower doses. These findings provide the rationale to re-engage in research to establish appropriate beta-blocker dosing following MI to derive optimal benefit from this therapy. (The PACE-MI Registry Study - Outcomes of Beta-blocker Therapy After Myocardial Infarction [OBTAIN]: NCT00430612)
Discussion
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Cite This Study
Goldberger et al. (2015) conducted a cohort in Acute Myocardial Infarction (n=7,057). Beta-blocker therapy (>12.5% to 25% of target dose) vs. >50% of target beta-blocker dose was evaluated on Time to all-cause mortality right-censored at 2 years (HR 0.799, 95% CI 0.635 to 1.005). Higher beta-blocker doses approximating those used in prior randomized clinical trials (>50% target dose) were not associated with increased survival compared to lower doses (>12.5% to 25% target dose, HR 0.799).