How Long Does It Take For Metoprolol To Lower Heart Rate

Pharmacotherapy. Writer manuscript; bachelor in PMC 2014 Dec 1.

Published in final edited form as:

PMCID: PMC3797244

NIHMSID: NIHMS484713

Take a chance of Emergent Bradycardia Associated with Initiation of Immediate- or Wearisome-Release Metoprolol

Jaekyu Shin

¹Department Clinical Pharmacy, San Francisco, CA

^vUniversity of California, San Francisco, CA

Marco Gonzales

^twoMedi-Cal Pharmacy Benefits Division, San Francisco, CA

³California Department of Health Care Services, San Francisco, CA

Marker J Pletcher

⁴Departments of Epidemiology & Statistics and Medicine, San Francisco, CA

⁵University of California, San Francisco, CA

Supplementary Materials

Supp Data S1.

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Supp Table S1.

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Supp Table S2.

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Supp Tabular array S3.

GUID: C32C1394-BF96-408E-BDD1-A78E21F1DEC5

Abstruse

Objectives

To guess and compare the take a chance of emergent bradycardia associated with initiation of immediate-release (IR) and deadening-release (SR) formulations of metoprolol.

Design

Retrospective assay of administrative claims information.

Data Source

Country of California Medicaid program (Medi-Cal) claims database.

Patients

A total of 31,574 adults initiating metoprolol betwixt May i, 2004, and November 1, 2009, without a chemist's shop claim for a beta blocker within the previous 6 months of metoprolol initiation; patients with a principal or secondary diagnosis of symptomatic bradycardia, pacemaker, or implantable cardioverter-defibrillator placement before metoprolol initiation were excluded.

Measurements and Master Results

The study outcome was the time to commencement occurrence of emergent bradycardia, measured at an emergency section visit or hospitalization due to diagnosis of symptomatic bradycardia, after metoprolol initiation. We calculated the incidence and compared the risk of emergent bradycardia by using a proportional hazards model that included the metoprolol conception with adjustment for total daily metoprolol dose and the apply of other medications as time-varying covariates, too as demographics and comorbidities. Among 31,574 patients initiating metoprolol, 18,516 (58.six%) initiated the IR formulation. The incidence of emergent bradycardia was 19.1 per 1000 person-years overall simply was nearly twice as mutual in patients using the IR versus the SR formulation (24.i per 1000 person-years in the IR grouping vs. 12.nine per thousand person-years in the SR grouping; unadjusted hazard ratio [HR] i.81; 95% CI one.28-2.56). Adjustment for other medications also associated with symptomatic bradycardia (cytochrome P450 2D6 inhibitors, class I or III antiarrhythmics, and atrioventricular node–blocking agents), metoprolol dose, and other participant characteristics somewhat adulterate the clan (adjusted Hour 1.48, 95% CI one.03-two.13).

Conclusion

The take a chance of emergent bradycardia associated with metoprolol initiation was higher with the IR formulation than the SR conception, although the accented run a risk was low.

Keywords: metoprolol, oral, conception, bradycardia

Metoprolol is the most widely prescribed oral beta blocker in the United States. In 2008, its prescription volume exceeded 68 one thousand thousand, making it the tertiary most widely prescribed drug.¹ It has various indications including hypertension, angina, and myocardial infarction.

Bradycardia is a potentially serious adverse effect of metoprolol. Its incidence in large clinical trials is low, ranging from 0.8-9%.^2,3 Despite widespread utilize of the drug, however, the incidence in clinical practice outside of controlled experimental settings is unknown. Metoprolol reduces heart rate by antagonizing beta₁ receptors in the center. Importantly, the caste of heart rate reduction positively correlates with the blood concentrations of metoprolol.^4-vi Thus, patients with elevated metoprolol blood concentrations may accept an increased risk of bradycardia.

Two oral formulations of metoprolol are available: immediate release (IR; metoprolol tartrate) and boring release (SR; metoprolol succinate). Considering of the dissimilar release kinetics, the IR conception is normally administered twice a day versus once a day for the SR formation. In clinical practise, they are interchanged based on a full daily dose. For case, the IR formulation 50 mg twice daily is normally interchanged with the SR 100 mg once daily. Yet, the two formulations take different pharmacokinetics, which may produce different pharmacodynamics including the degree of heart rate reduction.^7-ix

Thus, the objective of the written report was to estimate and compare the adventure of emergent bradycardia, measured at emergency department visits or hospitalizations due to bradycardia, associated with initiation of the two formulations of metoprolol (IR and SR) used in routine clinical do.

Methods

Study Design and Data Source

In this retrospective analysis of authoritative claims information, we used the Land of California Medicaid program (Medi-Cal) claims database. Medi-Cal, which had over 8 1000000 beneficiaries for at least one calendar month between 2007 and 2008, provides insurance for persons with low income or disabilities in the Land of California. The Medi-Cal claims database contains inpatient and outpatient administrative and pharmacy claims data including age, sexual activity, race-ethnicity, first and last dates of Medi-Cal enrollment, merits types, dates of service, procedures, primary and secondary diagnoses, emergency department visits, drugs dispensed, national drug code numbers, units dispensed, and the number of days of a drug supply.

The study was approved by the Committee for the Protection of Human Subjects and the Information and Research Committee in the Department of Health Care Services in the State of California too as the Commission for Human Research at the University of California San Francisco.

Study Sample

Patients aged ≥ 18 years old who were continuously enrolled in the Medi-Cal program for at least six months and had an oral metoprolol claim between May ane, 2004, and November 1, 2009, were included. Patients were a priori excluded if they were a Medicare beneficiary; had a beta blocker merits half-dozen months before the first metoprolol claim; had a diagnosis of symptomatic bradycardia or pacemaker placement at least 6 months before the first metoprolol merits; had a diagnosis of hypothyroidism, hyperthyroidism, or ventricular fibrillation, or implantable cardioverter-defibrillator placement at least 6 months earlier the first metoprolol merits and the concluding day of metoprolol therapy; or had a thyroid hormone or antithyroid drug claim thirty days earlier the first metoprolol claim and 30 days after the terminal day of metoprolol therapy. The last twenty-four hours of metoprolol therapy was calculated by adding the number of days of the supply of the last metoprolol claim to the date of the last metoprolol claim. Diagnoses of symptomatic bradycardia, hypothyroidism, hyperthyroidism, ventricular fibrillation, and placement, revision, or bank check-upwards of the pacemaker or implantable cardioverter-defibrillator were identified with the International Classification of Diseases, Ninth Revision (ICD-9) codes (run across Supplement for listing of specific ICD-ix codes used in the analysis). Apply of a thyroid hormone and antithyroid drug was identified by searching for a chemist's claim on the corresponding drugs (meet Supplement). Patients with a total daily metoprolol dose of either < six.25 mg or > 450 mg were besides excluded because the 25 mg tablet of metoprolol is the lowest forcefulness available, and the current maximum approved daily dose of metoprolol is 450 mg.¹⁰ The follow-up time began at the time of the first metoprolol merits.

Study Event

The study outcome was the time to first occurrence of an emergency department visit or hospitalization due to symptomatic bradycardia equally a primary diagnosis identified past ICD-9 codes (sinus node dysfunction, 427.81; sinus bradycardia, 427.89; atrioventricular cake, 426.10).

Metoprolol Employ

The metoprolol formulation (IR versus SR) was the principal predictor of the study event. To account for the effect of metoprolol dose on the study outcome, we adjusted for total daily metoprolol dose calculated according to the post-obit formula: total daily dose = tablet force dispensed × number of tablets dispensed ÷ number of days of supply.

Total daily metoprolol doses at the time of the study outcome or censoring were likewise grouped into four ranges based on the distribution of the total daily dose in the study sample: ≤ 37.5 mg/day, > 37.5 mg/twenty-four hours and ≤ 75 mg/day, > 75 mg/day and ≤ 125 mg/24-hour interval, and > 125 mg/day.

Potential Confounders

The historic period at the time of the first metoprolol claim was calculated. Race-ethnicity was categorized as Caucasian, Hispanic, African-American, Asian, other, and unknown according to the race-ethnicity information in the database. Comorbidity data on hypertension, diabetes mellitus, coronary avenue affliction, heart failure, and atrial fibrillation were obtained past searching for principal and secondary diagnoses with the corresponding ICD-ix codes and claims on drugs for the handling of comorbidities before the first metoprolol merits and xxx days after the last solar day of metoprolol therapy. Total daily metoprolol dose was also considered as a potential confounder.

Use of non-metoprolol drugs—an atrioventricular (AV) node–blocking agent, a Vaughan Williams classes I and Three antiarrhythmics, a cytochrome P450 (CYP) 2D6 inhibitor, a cholinergic agent for Alzheimer'southward disease, a drug that increases heart rate, or an ophthalmic beta blocker—was defined as whatsoever respective drug claim between 30 days earlier the first metoprolol merits and 30 days after the last 24-hour interval of metoprolol therapy. Non-metoprolol oral beta blockers were included in AV node–blocking agents. The listing of CYP2D6 inhibitors, which can increase metoprolol blood concentrations, was obtained from the Indiana University Clinical Pharmacology P450 Drug Interaction Table.^5,11-14 The supplement contains the list of the drugs used in this study.

Statistical Assay

Nosotros described patients initiating metoprolol by formulation type (SR and IR). The unpaired t-test, Wilcoxon rank sum test, and Chi-squared examination were used every bit advisable. Nosotros analyzed cumulative incidence, incidence rates (per one thousand person-years), and fourth dimension to consequence for the study upshot. Time to outcome was estimated by the Kaplan-Meier method and compared betwixt the SR and IR groups past the log-rank exam. Patients were censored at the time of the first occurrence of one of the following: they disjoined the Medi-Cal program; they did not have a claim on the same formulation of metoprolol within five days after the refill due date; or November 1, 2009 (the stop date of the study). The Cochran-Armitage examination was used to check a significant trend between the study consequence and the total daily metoprolol dose ranges. A Cox proportional hazard regression assay was performed to model the study outcome equally a dependent variable with metoprolol formulation as an independent variable, with adjustments for potential confounders. In this model, full daily metoprolol doses and the use of non-metoprolol drugs were treated as time-varying covariates. Because of the small number of study outcomes, the backward elimination method was likewise used to select a model. Interactions between the metoprolol formulation and potential confounders were tested in a full model. The linearity of total daily metoprolol doses was checked by adding a quadratic term. The proportional hazards assumption was checked past adding to a full model an interaction term between each explanatory variable and time. As an exploratory analysis, cumulative risk ratios were computed by days afterward metoprolol initiation.

Four sets of sensitivity analyses were conducted. Outset, equally an alternating method for adjustment, we synthetic a propensity score including baseline covariates (historic period, sex activity, race-ethnicity, and comorbidities) using logistic regression and used this score in lieu of the baseline covariates in the Cox model. Second, syncope was included every bit part of the report upshot considering it can be caused by symptomatic bradycardia. In this analysis, patients with a main or secondary diagnosis of syncope, hypotension, or seizure and/or with a chemist's merits on drugs used for syncope or seizure before the get-go claim on metoprolol were excluded. In addition to the confounders of the emergent bradycardia, apply of diuretics, vasodilators, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, direct renin inhibitors, and drugs used for the treatment of syncope were considered equally potential confounders (meet Supplement for a full list of the drugs). A Cox proportional hazard regression assay was performed to model the start occurrence of emergent bradycardia or syncope as a dependent variable with metoprolol formulation as an independent variable, with adjustments for potential confounders. Third, a multivariable Cox proportional hazards regression analysis was performed but in patients without a diagnosis of middle failure because centre failure was significantly more prevalent in the IR group than in the SR group, and heart failure may exist associated with symptomatic bradycardia.¹⁵ Finally, a multivariable logistic regression analysis limited to patients who had the study outcome during the first month of metoprolol therapy and had the beginning metoprolol claim with at least 30 days of a supply was performed. In this analysis, metoprolol formulation was included in a multivariable logistic regression model that used the cumulative incidence of an emergency department visit or hospitalization due to bradycardia during the showtime month equally a dichotomous outcome, and with adjustments for potential confounders. SAS statistical software, version 9.i (SAS Institute Inc., Cary, NC) was used for all analyses. A p value of less than 0.05 was considered to indicate a statistically significant difference.

Results

A total of 31,574 patients were included in the analysis. Of these patients, xiii,058 (41.four%) were in the SR group and 18,516 (58.6%) were in the IR grouping (Table 1). Of note, the IR group had a significant higher proportion of patients with a diagnosis of middle failure and atrial fibrillation as well as of the use of an AV node–blocking agent and class I or III antiarrhythmic agent than the SR group. The study sample was enrolled in Medi-Cal for a median of 28 months (range 7-67 months). The SR grouping had a significantly longer enrollment than the IR group (median 28 months vs. 25 months, P < 0.001).

Table 1

Baseline Demographic and Clinical Characteristics of the Study Patients

Characteristic	All Patients (north=31,574)	Metoprolol SR Group (n=13,058)	Metoprolol IR Group (north=eighteen,516)	P-value
Proportion of all patients		41.4%	58.6%
Age (yrs), mean ± SD	56.ane ± 12.7	56.iv ± 12.8	55.nine ± 12.vii	0.001
Male	46.2%	43.0%	48.4%	<0.001
Race-ethnicity				<0.001
Caucasian	34.7%	39.4%	31.5%
Hispanic	27.0%	21.vi%	30.8%
African-American	fifteen.0%	11.vii%	17.3%
Asian	8.vii%	10.6%	vii.iv%
Other	9.0%	11.1%	vii.5%
Unknown	5.7%	5.vii%	five.7%
Comorbidities
Hypertension	88.0%	88.0%	88.0%	0.94
Diabetes mellitus	39.2%	35.5%	41.8v	<0.001
Coronary artery affliction	32.0%	xxx.i%	33.3%	<0.001
Center failure	fifteen.7%	12.7%	17.eight%	<0.001
Atrial fibrillation	half dozen.seven%	5.one%	7.7%	<0.001
Use of not-metoprolol drugs
AV node–blocking agenta	17.5%	14.7%	19.5%	<0.001
Non-metoprolol oral beta blockerb	iii.2%	3.i%	iii.2%	0.65
Class I or III antiarrhythmicc	ane.7%	1.iv%	one.9%	0.005
CYP2D6 inhibitord	42.6%	45.1%	40.viii%	<0.001
Cholinergic agent for Alzheimer's	ane.4%	1.7%	1.two%	<0.001
diseaseeast
Drug that increases heart charge per unitf	three.iv%	4.8%	2.4%	<0.001
Ophthalmic beta blockeryard	1.1%	1.2%	1.ane%	0.40

The duration of the metoprolol therapy was relatively short (median 58 days; range ane-1825 days). The SR group had a slightly longer duration than the IR group (median sixty days [range two-1710 days] vs. median 52 days [range 1-1825 days], P<0.001). At the fourth dimension of the censoring or study outcome, both groups had a median total daily metoprolol dose of 50 mg (range 6.25-400 mg in the SR grouping vs. 6.25-450 mg in the IR group, P<0.001) for a median of 30 days (range 0-1100 days in the SR grouping vs. 1-1418 days in the IR group, P<0.001).

The study issue developed in 154 patients (Tabular array ii). Emergency section visits for emergent bradycardia were three times as common as hospitalizations for the same condition. The SR grouping had a significantly lower incidence of emergent bradycardia than the IR grouping (12.nine per 1000 person-years in the SR group vs. 24.ane per grand person-years in the IR group, P=0.0037). This difference was primarily due to the departure in emergency department visits (P=0.0013).

Tabular array 2

Incidence of Emergent Bradycardia by Metoprolol Formulation^a

Metoprolol Conception Group	Emergency department visits			Hospitalizations			Total events
	No. of Patients	% of Patientsb	No./1000 person-years	No. of Patients	% of Patientsb	No./1000 person-years	No. of Patients	% of Patientsb	No./1000 person-years
SR (n=13,058)	32	0.25	nine.0	fourteen	0.xi	3.9	46	0.35	12.9
IR (north=18,516)	87	0.47	19.4	21	0.11	4.7	108	0.58	24.1
Both SR and IR (n=31,574)	119	0.38	xiv.8	35	0.11	4.3	154	0.49	19.ane

The Kaplan-Meier assay showed a meaning difference in the study outcome between the groups (Effigy 1). In both the unadjusted and adjusted proportional hazards regression analyses, the metoprolol conception was significantly associated with the risk of the written report consequence (Tabular array iii). The utilise of the IR formulation was associated with a 48% increment in the hazard of the study upshot compared with the utilise of the SR formulation in a fully adapted model (60 minutes = 1.48; 95%CI: 1.03-two.13), which is somewhat adulterate from the unadjusted estimate (Hr = ane.81; 95%CI: 1.28-2.56). We establish no pregnant interaction between potential confounders and conception, and no deviations from the proportional hazards assumption.

Kaplan-Meier estimates of the risk of emergent bradycardia by oral metoprolol formulation (log-rank P= 0.0006).

Abbreviations: SR, slow-release; IR, immediate-release.

Table 3

Unadjusted and adjusted hazard ratios of emergent bradycardia between the two metoprolol formulations.

Metoprolol Formulation Grouping	Hazard Ratio (95% CI)
	Unadjusted	Adjusted
		Model 1a	Model iib	Model 3c
SR	1 (Reference)	one (Reference)	1 (Reference)	1 (Reference)
IR	1.81 (1.28-2.56)	i.63 (1.13-two.36)	1.51 (one.04-2.18)	1.48 (ane.03-ii.13)

The incidence of emergent bradycardia significantly increased as full daily metoprolol doses at the time of an event or censoring increased (Figure ii). Even so, there was no significant interaction between metoprolol dose range and formulation in a fully adjusted model (p=0.51).

Incidence of emergent bradycardic events by total metoprolol daily dose range (*trend P= 0.02).

Abbreviations: SR, slow-release; IR, immediate-release.

During the get-go 60 days subsequently metoprolol initiation, the use of the IR formulation was associated with a 70% increased hazard of emergent bradycardia compared with that of the SR formulation (Table 4; Hr 1.70; 95% CI i.06-2.71). After this period, the take a chance deviation betwixt the formulations was attenuated.

Table iv

Occurrence of emergent bradycardia by number of days after metoprolol initiation.

Days later metoprolol initiation	No. (%) of events			Cumulative Take a chance Ratio* (95% CI)
	All Patients (n=31,574)	Metoprolol SR Group (northward=13,058)	Metoprolol IR Group (n=xviii,516)
0-fifteen	50 (0.16)	13 (0.10)	37 (0.twenty)	1.86 (0.95-iii.65)
15-xxx	30 (0.ten)	viii (0.06)	22 (0.12)	one.81 (1.06-three.08)
30-60	21 (0.07)	half-dozen (0.05)	15 (0.08)	1.70 (1.06-2.71)
lx-xc	fourteen (0.04)	7 (0.05)	7 (0.04)	1.42 (0.93-2.xviii)
90-365	31 (0.10)	10 (0.08)	21 (0.11)	ane.39 (0.96-2.01)
>365	8 (0.03)	2 (0.02)	6 (0.03)	1.48 (1.03-two.13)

The results of the sensitivity analyses were not qualitatively dissimilar from the main results. In a model adjusting for propensity scores, the use of the IR formulation was associated with a 50% higher gamble than that of the SR formulation (Hr ane.50; 95% CI: 1.04-2.16). When syncope was included equally office of the study outcome, a total of 28,285 patients (57.8% in the IR group, 42.2% in the SR group) were included in the analysis, with 268 patients who had emergent bradycardia or syncope (eTable 1). In this analysis, the utilise of the IR formulation was associated with a twoscore% increased chance of emergent bradycardia or syncope compared with the utilize of the SR formulation (eTable 2; HR ane.twoscore; 95% CI: 1.07-1.83). When the analysis was limited to patients without a diagnosis of heart failure or to patients with the first metoprolol claim with at least 30 days of supply, the results were unchanged (patients without centre failure: Hour 1.62, 95% CI 1.04-ii.53; patients with at least xxx days of supply: OR 1.82, 95% CI 1.06-3.14).

Discussion

To our noesis, this is the starting time comparative effectiveness study estimating accented and relative risks of emergent bradycardia associated with initiation of ii oral metoprolol formulations (IR and SR) used in routine clinical practice. In this retrospective assay of Medi Cal claims information, nosotros constitute that the overall absolute risk of emergent bradycardia associated with metoprolol therapy in routine clinical exercise was low (19.1 per 1000 person-years), but that there is a 48% increase in that risk with use of the IR formulation compared with the SR formulation. Of annotation, the difference in risk of the emergent bradycardia betwixt the IR and SR formulations was larger during the first 60 days subsequently metoprolol initiation compared with the later period (HR 1.70 vs. 1.48), suggesting that patients newly starting the IR formulation should exist more advisedly monitored during the first lx days of the IR initiation.

Although the incidence rate of agin drug events is usually higher in clinical practice than that in a clinical trial, our incidence charge per unit (xix.one per thou person-years) was lower than that of the previous quantitative overview of 9 large, randomized, clinical trials in patients with heart failure (38 per 1000 person-years).^xvi The fact that some of these clinical trials did not require an emergency section visit or hospitalization as role of their definitions of adverse bradycardia may help explain why the charge per unit in that report is higher than the rate we institute. The trials also used different beta blockers such equally carvedilol and bisoprolol. Finally, the characteristics of our study sample, which was relatively young and had fewer structural heart diseases, could accept contributed to the lower incidence rate. Overall, our data suggest that emergent bradycardia associated with the use of metoprolol, the well-nigh prescribed beta blocker in the Usa, may not be common in clinical practice.

Our results are in contrast to those of a randomized trial reporting no significant departure in the degree of heart rate reduction between the 2 metoprolol formulations in 100 patients with hypertension.¹⁷ Since it had a small sample size and excluded patients at a loftier risk of metoprolol-related bradycardia such equally those with eye failure, however, our written report may have better assessed the risk of bradycardia between the metoprolol formulations.

In our study, there was a significant trend between total daily metoprolol dose and the incidence of emergent bradycardia (Figure 2). At the same daily dose, the metoprolol IR formulation produced a 2.four-2.viii fold higher tiptop blood concentration than the SR formulation.^7-9 Since the degree of heart rate reduction by metoprolol is positively correlated with metoprolol blood concentrations, the IR formulation would decrease centre charge per unit to a greater degree than the SR formulation at the fourth dimension of acme concentration.^5,half-dozen Indeed, the administration of the metoprolol IR formulation of l mg twice a day reduced heart rate past 19.i% from the baseline compared with 13.4% with the SR conception of 100 mg daily.^seven Thus, the divergence in blood concentrations between the formulations at the same daily dose may have atomic number 82 to a meaning deviation in the risk of emergent bradycardia in our report. Because only 8.iii% of the report population received a full daily metoprolol dose of >125 mg/day at the time of the study upshot or censoring, however, we were not able to fully assess dose-response relationship at higher metoprolol doses (>125 mg/mean solar day).

Our information take important clinical implications. The metoprolol SR formulation has more than convenient dosing and is the only metoprolol formulation approved for the treatment of centre failure. Since our data also propose that the SR conception may be safer than the IR formulation, the SR formulation may be preferable particularly for patients at a loftier risk of emergent bradycardia, such as those with heart failure who are also taking a CYP2D6 inhibitor or an AV node–blocking agent (eTable 3). For patients who are uninsured or need improve heart rate control, the IR formulation is less costly and provides higher blood concentrations. Given the increased risk of emergent bradycardia with the IR formulation, center rate should exist monitored closely for patients who have a depression resting heart rate, particularly during the get-go sixty days after the SR formulation is switched to the IR conception.

Our study has several limitations. Offset, our study relies on administrative claims data. Claims data do not provide information on potential clinical predictors of emergent bradycardia episodes such as heart charge per unit, CYP2D6 genotypes, over-the-counter medication use, and the patients' drug adherence. Thus, our data collection did not account for many important factors that may impact on the study results. In addition, population is relatively young, which could take influenced our study results. Given the divergence in the indications of the 2 formulations, confounding by indication may have influenced our study results. In detail, confounders associated with an increased risk of emergent bradycardia, such as middle failure, were significantly more prevalent in the IR group than in the SR group. We were unable to rebalance the groups with our statistical methods. Instead, we attempted to control for misreckoning past using both standard adjustment methods and propensity scores equally well equally by limiting the assay to patients without heart failure, simply the sparse covariate data in this dataset limits this arroyo to some degree. It is possible that an unmeasured confounder could account for our findings, simply to do so, the confounder would take to be very strongly associated with both the predictor and the outcome. Adapting prior methods for use in our written report, we guess that for a common confounder (overall prevalence of 50%), the association between the confounder and both the exposure and the illness must still be quite strong (odds ratio of iv for each)¹⁸; this could occur, for example, if the confounder is nowadays in 64% of the IR grouping and 30% of the SR group, and the outcome rate (proportion with an event) is about 0.008 vs. 0.002 when the confounder is present vs. absent-minded. If the confounder is less mutual (overall prevalence of 10%), the associations would have to be stronger (odds ratios of 6 for each). Although we allowed merely 5 days between metoprolol refill dates, this may be too long given the brusque half life of metoprolol (6-8 hours).

In our sensitivity analysis, by limiting to patients with at least thirty days of supply of the first metoprolol claim, however, our results were unchanged. Inaccurate coding of administrative claims can effect in misclassification of diagnoses and report outcomes.¹⁹ Our study could have missed shortness of breath and lightheadedness due to bradycardia. This inaccurate coding may take contributed to the reduced rates of bradycardia in our study compared to those in other studies.¹⁶ When syncope was included as part of the report outcome, however, the results were not substantially dissimilar from those excluding syncope.

2d, we excluded pacemaker implantation as office of the study outcome because it was difficult to distinguish between elective and urgent pacemaker implantation by using ICD-9 codes. This exclusion may accept resulted in underestimation of the study outcome. Third, we observed only a brusque median duration of metoprolol therapy, which may have led to the underestimation of the report upshot. Finally, comorbidities identified by the use of drugs may not accept been accurate considering some drugs take multiple indications. For example, amiodarone is indicated for both atrial fibrillation and ventricular fibrillation.

Conclusion

The utilise of the metoprolol IR conception instead of the SR formulation was associated with an increased risk of serious bradycardic events requiring emergency care or hospitalization, although the absolute gamble was low.

Supplementary Material

Supp Information S1

Supp Table S1

Supp Tabular array S2

Supp Table S3

Acknowledgments

This work was supported by the National Institutes of Health (NIH)/National Center for Research Resources University of California San Francisco–Clinical and Translational Science Institute grant (UL1 RR024131). Its contents are solely the responsibility of the authors and do not necessarily stand for the official views of the NIH.

Footnotes

Presented as a poster at the almanac coming together of the American College of Clinical Chemist's, Hollywood, Florida, Oct 21-24, 2012.

References

two. Hjalmarson A, Goldstein Southward, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-beingness in patients with heart failure: the Metoprolol CR/Forty Randomized Intervention Trial in congestive middle failure (MERIT-HF). MERIT-HF Written report Group. JAMA. 2000;283(10):1295–1302. [PubMed] [Google Scholar]

3. Poole-Wilson PA, Swedberg Yard, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362(9377):vii–13. [PubMed] [Google Scholar]

4. Nozawa T, Taguchi Thousand, Tahara Thousand, et al. Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparing with bisoprolol. J Cardiovasc Pharmacol. 2005;46(5):713–720. [PubMed] [Google Scholar]

5. Hemeryck A, Lefebvre RA, De Vriendt C, Belpaire FM. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in good for you volunteers. Clin Pharmacol Ther. 2000;67(3):283–291. [PubMed] [Google Scholar]

6. Koytchev R, Alken RG, Vlahov V, et al. Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol. Eur J Clin Pharmacol. 1998;54(half-dozen):469–474. [PubMed] [Google Scholar]

seven. Sandberg A, Blomqvist I, Jonsson UE, Lundborg P. Pharmacokinetic and pharmacodynamic backdrop of a new controlled-release conception of metoprolol: a comparison with conventional tablets. Eur J Clin Pharmacol. 1988;(33):S9–14. [PubMed] [Google Scholar]

8. Lucker P, Moore G, Wieselgren I, Olofsson B, Bergstrand R. Pharmacokinetic and pharmacodynamic comparing of metoprolol CR/ZOK in one case daily with conventional tablets once daily and in divided doses. J Clin Pharmacol. 1990;30(two Suppl):S17–27. [PubMed] [Google Scholar]

ix. Parker RB, Soberman JE. Furnishings of paroxetine on the pharmacokinetics and pharmacodynamics of firsthand-release and extended-release metoprolol. Pharmacotherapy Jul. 2011;31(7):630–641. [PubMed] [Google Scholar]

11. Goryachkina M, Burbello A, Boldueva South, Babak Due south, Bergman U, Bertilsson L. Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI) Eur J Clin Pharmacol. 2008;64(3):275–282. [PubMed] [Google Scholar]

12. Sharma A, Pibarot P, Pilote Southward, et al. Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during practise testing in healthy premenopausal women. J Pharmacol Exp Ther. 2005;313(3):1172–1181. [PubMed] [Google Scholar]

14. Ahern TP, Pedersen L, Cronin-Fenton DP, Sorensen HT, Lash TL. No increase in breast cancer recurrence with concurrent employ of tamoxifen and some CYP2D6-inhibiting medications. Cancer Epidemiol, Biomarkers Prevent. 2009;18(9):2562–2564. [PMC free commodity] [PubMed] [Google Scholar]

15. Barrett TW, Abraham RL, Jenkins CA, Russ S, Storrow AB, Darbar D. Risk factors for bradycardia requiring pacemaker implantation in patients with atrial fibrillation. Am J Cardiol. 2012;110(ix):1315–1321. [PMC free article] [PubMed] [Google Scholar]

16. Ko DT, Hebert PR, Coffey CS, et al. Agin furnishings of beta-blocker therapy for patients with heart failure: a quantitative overview of randomized trials. Arch Intern Med. 2004;164(13):1389–1394. [PubMed] [Google Scholar]

17. Carruthers G, Shearer R, Taylor W, Moore M. A comparison of a controlled release (CR/ZOK) formulation of metoprolol, one time daily, with conventional metoprolol tablets, twice daily, in balmy to moderate hypertension. J Clin Pharmacol. 1990;30(2 Suppl):S61–65. [PubMed] [Google Scholar]

18. Greenland Southward. Basic methods for sensitivity analysis of biases. Int J Epidemiol. 1996;25(6):1107–1116. [PubMed] [Google Scholar]

19. Sarrazin MS, Rosenthal GE. Finding pure and simple truths with authoritative data. JAMA. 2012;307(13):1433–1435. [PubMed] [Google Scholar]

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797244/

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