Alendronate Use and Risk of Atrial Fibrillation
Alendronate Use and Risk of Atrial Fibrillation
Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008;168:826-831.
Data from the Group Health Atrial Fibrillation Study—an ongoing population-based, case-control study of women from a large integrated healthcare delivery system in Washington state—were examined to see whether alendronate use was associated with risk of incident atrial fibrillation (AF) in women in a clinical practice setting. The study identified 719 women who had AF between October 1, 2001, and December 31, 2004 (cases; mean age, 75 y), and matched them to 966 randomly selected women without AF (controls; mean age, 71 y). The participants were aged 30 to 84 years, and had at least four healthcare visits before their index date. For cases, this was the date the AF came to clinical attention; for controls, a random date was assigned. Women diagnosed with AF had no previous evidence of AF, and they were classified as having transitory, persistent/intermittent, or sustained AF. Cases and controls had never used another bisphosphonate.
More cases than controls had ever used alendronate (6.5% [n = 47] vs 4.1% [n = 40]; P = 0.03). After adjusting for matching variables, a diagnosis of osteoporosis, and any cardiovascular disease, the authors concluded that "the risk of incident AF was higher in women who were ever users of alendronate than in never users of bisphosphonates" (odds ratio, [OR], 1.86; 95% confidence interval [CI], 1.09-3.15). There was no evidence of a difference in risk according to the total grams of alendronate taken, or by the interval since the first prescription of the drug. Alendronate use was more strongly associated with AF that was sustained than with AF that was transitory or intermittent (sustained AF: OR, 5.75 [95% CI, 2.50-13.25]; transitory AF: OR, 1.93 [95% CI, 0.95-3.92]; and intermittent AF: OR, 1.25 [95% CI, 0.64-2.44]).
Concern about a possible relationship between bisphosphonates and cardiac arrhythmias surfaced when an unexpected and unexplained increase in the incidence of serious adverse events (SAEs) related to AF was observed in Black et al, one of two large randomized placebo-controlled trials (RCTs) with intravenous zoledronic acid in patients with osteoporosis. In that large study, the overall incidence of AF did not differ significantly between treated and placebo groups, and there was no relationship between the occurrence of SAE and the dosing of zoledronic acid, given once per year for 3 years. It is important to note that an SAE is an FDA-defined term that does not necessarily reflect the clinical seriousness of a condition. Most SAEs are recorded when the adverse experience results in hospitalization (such as due to rapid ventricular response or congestive heart failure) or occurs in a patient hospitalized for another reason (eg, exacerbation of chronic obstructive pulmonary disease). In the other large RCT with zoledronic acid, Lyles et al, in older patients who had recently experienced hip fracture, no differences in the incidence of AF or SAEs due to fibrillation were observed between treatment groups. In both studies, treatment substantially reduced the risk of fractures; in Lyles, treatment was associated with a 28% decrease in mortality. No other study with zoledronic acid has observed an association with cardiac arrhythmias, heart disease, or stroke.
In a letter accompanying the study by Black, he and other coauthors reported that a statistically insignificant "trend" toward an increased risk of AF SAEs was observed in the alendronate groups compared to placebo in the Fracture Intervention Trial with alendronate. Again, no increase in the incidence of AF was observed with treatment, and no other study with alendronate has been associated with a signal regarding cardiac safety outcomes. Additionally, a review of the entire risedronate clinical data set noted no effect of therapy on the frequency of SAEs regarding cardiac arrhythmias, AF, or stroke.
RCTs are designed primarily to evaluate efficacy of treatment and are not sufficient to exclude safety concerns that occur in a very small number of treated subjects. Because large observational studies can provide useful insight into concerns about safety, studies such as the one published by Heckbert and colleagues are welcomed. The Heckbert study observed that the frequency of taking or having previously used alendronate was modestly higher (6.5% vs 4.1%) in patients with AF compared to a control group without arrhythmia. Fewer than one sixteenth of the patients with AF had taken alendronate, and the difference existed only in patients who previously took alendronate—not those currently taking the drug. This is different than saying that the AF incidence is higher in patients who take alendronate than in those who do not.
Additionally, the Heckbert study involved fewer total patients (1,685) than either of the RCTs with zoledronic acid (Black, 7,765; Lyles, 2,127) and included only 87 patients who had received alendronate. In addition to the inherent limitations due to the nonrandomized, retrospective nature of the case-control study design, there were important differences between the two groups of subjects in this study; eg, the median age of the AF group was 4 years older than the control group.
This study, then, is a far weaker analysis than an RCT of the same size; conclusions about a causal link between bisphosphonate use and AF cannot be drawn. Interestingly, despite an overlap of senior authors, the paper by Heckbert did not cite a much larger case-control study from Denmark comparing 13,586 patients with AF to 68,054 controls (2,389 bisphosphonate users) in which no evidence was found linking bisphosphonate use to atrial arrhythmias. That study was a more valid and valuable assessment of the question at hand. In my opinion, the report by Heckbert is not a strong addition to our evidence regarding the cardiac safety of bisphosphonate therapy.
The news coverage of the Heckbert study focused only on the increased cardiac risk with alendronate treatment, not on bisphosphonates' very effective reduction of fracture risk in older adults with osteoporosis. This prompted many patients to discontinue their osteoporosis therapy and caused many physicians undue concern about alendronate safety. From this perspective, the conclusions of Heckbert may represent a risk to our patients. This is a good reminder to us all—including the epidemiologists who provide us with sophisticated analyses—to be aware of the important limitations of observational studies in determining the causality between a clinical marker and a clinical outcome and to put all new data in the proper and appropriate framework.
From the NAMS First to Know e-newsletter released June 24, 2008
For more, please visit http://www.menopause.org/news.aspx
Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008;168:826-831.
Data from the Group Health Atrial Fibrillation Study—an ongoing population-based, case-control study of women from a large integrated healthcare delivery system in Washington state—were examined to see whether alendronate use was associated with risk of incident atrial fibrillation (AF) in women in a clinical practice setting. The study identified 719 women who had AF between October 1, 2001, and December 31, 2004 (cases; mean age, 75 y), and matched them to 966 randomly selected women without AF (controls; mean age, 71 y). The participants were aged 30 to 84 years, and had at least four healthcare visits before their index date. For cases, this was the date the AF came to clinical attention; for controls, a random date was assigned. Women diagnosed with AF had no previous evidence of AF, and they were classified as having transitory, persistent/intermittent, or sustained AF. Cases and controls had never used another bisphosphonate.
More cases than controls had ever used alendronate (6.5% [n = 47] vs 4.1% [n = 40]; P = 0.03). After adjusting for matching variables, a diagnosis of osteoporosis, and any cardiovascular disease, the authors concluded that "the risk of incident AF was higher in women who were ever users of alendronate than in never users of bisphosphonates" (odds ratio, [OR], 1.86; 95% confidence interval [CI], 1.09-3.15). There was no evidence of a difference in risk according to the total grams of alendronate taken, or by the interval since the first prescription of the drug. Alendronate use was more strongly associated with AF that was sustained than with AF that was transitory or intermittent (sustained AF: OR, 5.75 [95% CI, 2.50-13.25]; transitory AF: OR, 1.93 [95% CI, 0.95-3.92]; and intermittent AF: OR, 1.25 [95% CI, 0.64-2.44]).
Concern about a possible relationship between bisphosphonates and cardiac arrhythmias surfaced when an unexpected and unexplained increase in the incidence of serious adverse events (SAEs) related to AF was observed in Black et al, one of two large randomized placebo-controlled trials (RCTs) with intravenous zoledronic acid in patients with osteoporosis. In that large study, the overall incidence of AF did not differ significantly between treated and placebo groups, and there was no relationship between the occurrence of SAE and the dosing of zoledronic acid, given once per year for 3 years. It is important to note that an SAE is an FDA-defined term that does not necessarily reflect the clinical seriousness of a condition. Most SAEs are recorded when the adverse experience results in hospitalization (such as due to rapid ventricular response or congestive heart failure) or occurs in a patient hospitalized for another reason (eg, exacerbation of chronic obstructive pulmonary disease). In the other large RCT with zoledronic acid, Lyles et al, in older patients who had recently experienced hip fracture, no differences in the incidence of AF or SAEs due to fibrillation were observed between treatment groups. In both studies, treatment substantially reduced the risk of fractures; in Lyles, treatment was associated with a 28% decrease in mortality. No other study with zoledronic acid has observed an association with cardiac arrhythmias, heart disease, or stroke.
In a letter accompanying the study by Black, he and other coauthors reported that a statistically insignificant "trend" toward an increased risk of AF SAEs was observed in the alendronate groups compared to placebo in the Fracture Intervention Trial with alendronate. Again, no increase in the incidence of AF was observed with treatment, and no other study with alendronate has been associated with a signal regarding cardiac safety outcomes. Additionally, a review of the entire risedronate clinical data set noted no effect of therapy on the frequency of SAEs regarding cardiac arrhythmias, AF, or stroke.
RCTs are designed primarily to evaluate efficacy of treatment and are not sufficient to exclude safety concerns that occur in a very small number of treated subjects. Because large observational studies can provide useful insight into concerns about safety, studies such as the one published by Heckbert and colleagues are welcomed. The Heckbert study observed that the frequency of taking or having previously used alendronate was modestly higher (6.5% vs 4.1%) in patients with AF compared to a control group without arrhythmia. Fewer than one sixteenth of the patients with AF had taken alendronate, and the difference existed only in patients who previously took alendronate—not those currently taking the drug. This is different than saying that the AF incidence is higher in patients who take alendronate than in those who do not.
Additionally, the Heckbert study involved fewer total patients (1,685) than either of the RCTs with zoledronic acid (Black, 7,765; Lyles, 2,127) and included only 87 patients who had received alendronate. In addition to the inherent limitations due to the nonrandomized, retrospective nature of the case-control study design, there were important differences between the two groups of subjects in this study; eg, the median age of the AF group was 4 years older than the control group.
This study, then, is a far weaker analysis than an RCT of the same size; conclusions about a causal link between bisphosphonate use and AF cannot be drawn. Interestingly, despite an overlap of senior authors, the paper by Heckbert did not cite a much larger case-control study from Denmark comparing 13,586 patients with AF to 68,054 controls (2,389 bisphosphonate users) in which no evidence was found linking bisphosphonate use to atrial arrhythmias. That study was a more valid and valuable assessment of the question at hand. In my opinion, the report by Heckbert is not a strong addition to our evidence regarding the cardiac safety of bisphosphonate therapy.
The news coverage of the Heckbert study focused only on the increased cardiac risk with alendronate treatment, not on bisphosphonates' very effective reduction of fracture risk in older adults with osteoporosis. This prompted many patients to discontinue their osteoporosis therapy and caused many physicians undue concern about alendronate safety. From this perspective, the conclusions of Heckbert may represent a risk to our patients. This is a good reminder to us all—including the epidemiologists who provide us with sophisticated analyses—to be aware of the important limitations of observational studies in determining the causality between a clinical marker and a clinical outcome and to put all new data in the proper and appropriate framework.
From the NAMS First to Know e-newsletter released June 24, 2008
For more, please visit http://www.menopause.org/news.aspx