Atrial fibrillation and the use of oral bisphosphonates

Figures & data

Table 1 Creation of study cohorts according to oral bisphosphonate use

	MarketScan (US)a		Ingenix (US)a		THIN (UK)
	Users, N (%)	Nonusers, N (%)	Users, N (%)	Nonusers, N (%)	Users, N (%)	Nonusers, N (%)
Women aged 50–89 on index date between 01/01/2002 and 12/31/2005	565,370 (100%)	1,232,843 (100%)	251,680 (100%)	437,362 (100%)	35,744 (100%)	128,950 (100%)
Above, having at least two years of continuous enrollment before index date	213,234 (37.7%)	825,928 (67.0%)	84,834 (33.7%)	302,931 (69.3%)	34,125 (95.5%)	117,704 (91.3%)
Above, having at least one medical encounter and no bisphosphonate prescriptions during two years before index date	167,913 (29.7%)	769,871 (62.4%)	64,570 (25.7%)	269,068 (61.5%)	28,095 (78.6%)	113,230 (87.8%)
Above, having no diagnosis of AF, any cardiac dysrrhythmia, or antiarrhythmic prescriptions during two years before index date	151,488 (26.8%)	686,944 (55.7%)	53,049 (21.1%)	221,118 (50.6%)	24,666 (69.0%)	85,572 (66.4%)
Above, having no diagnosis of hyperthyroidism, hypothyroidism, alcoholism, or prescriptions of thyroxin, PTH or strontium during two years before index date	120,444 (21.3%)	544,005 (44.1%)	41,530 (16.5%)	175,009 (40.0%)	21,426 (59.9%)	76,589 (59.4%)
Above, having no oral glucocorticoid prescriptions in two years before index date	96,185 (17.0%)	448,140 (36.4%)	34,356 (13.7%)	148,544 (34.0%)	15,007 (42.0%)	72,207 (56.0%)
Above, with up to 4:1 matching of nonusers to users	95,228 (16.8%)	352,627 (28.6%)	33,907 (13.5)	122,196 (27.9%)	14,958 (41.8%)	54,847 (42.5%)

Note:

a Two rounds of matching were used.

Abbreviation: AF, atrial fibrillation.

Table 2 Descriptions of the three study cohorts according to bisphosphonate use

	MarketScan (US)				Ingenix (US)				THIN (UK)
	ALN or RIS	ALN	RIS	Nonusers	ALN or RIS	ALN	RIS	Nonusers	ALN or RIS	ALN	RIS	Nonusers
Total, N	95,228	59,026	36,202	352,627	33,907	21,241	12,666	122,196	14,958	11,047	3,911	54,847
Age at index, median	64	63	65	64	60	60	60	60	72	72	73	71
Total PY of FU	144,991	92,582	52,409	599,349	45,881	28,848	17,033	198,017	28,613	21,508	7,105	120,167
AF cases, N	1,480	903	577	6,521	356	251	105	1,628	159	127	32	658
AF incidence/1,000 PY	10.2	9.8	11.0	10.9	7.8	8.7	6.2	8.2	5.6	5.9	4.5	5.5
AF cases (hospital)	328			1,580	208			1,064	11			40
AF cases (ECG)	913			4,099	212			1,053	10			55
Any dysrrhythmia, Na	5,965	3,676	2,289	23,181	1,577	1,000	577	6,682	515	401	114	1,849
Days of FU, median	519	539	487	603	441	441	442	574	746	777	677	895
# of all Rx, median	28	27	31	29	22	21	23	19	44	42	50	28
# of BIS Rx, median	5	5	4	NA	5	5	5	NA	9	9	8	NA
Weekly regimen, %	96.9	97.1	96.6	NA	97.3	97.5	96.8	NA	92.8	96.6	82.1	NA
Baseline medical history %*
Angina	2.4	2.3	2.7	2.7	1.9	1.7	2.0	2.0	2.3	2.2	2.4	2.1
CHF	2.3	2.1	2.5	2.7	1.4	1.3	1.4	2.1	1.0	0.9	1.3	0.7
Diabetes	9.8	9.4	10.6	14.7	8.6	8.5	8.9	14.4	4.4	4.2	5.0	6.4
Hospitalization	14.4	14.0	15.0	13.8	9.3	9.2	9.3	9.4	9.9	10.1	9.4	5.9
Hypertension	40.8	39.9	42.4	44.7	39.3	38.7	40.1	47.0	16.2	16.2	16.3	16.5
Osteoporosis	40.3	40.3	40.4	7.2	44.5	44.0	45.2	8.8	22.8	22.1	24.5	0.6
Other heart diseases	8.4	7.9	9.1	7.9	6.8	6.6	7.1	6.7	2.6	2.5	2.9	2.1
Renal disease	0.5	0.5	0.5	0.7	0.4	0.4	0.4	0.7	0.6	0.6	0.6	0.5
Stroke	3.9	3.7	4.3	3.8	2.1	2.0	2.2	2.1	0.8	0.8	0.9	0.7
Thrombosis	2.3	2.2	2.4	2.1	1.7	1.8	1.7	1.6	2.0	1.9	2.3	1.5
Baseline drug history, %*
ACE inhibitors	16.0	15.5	16.8	17.6	12.4	12.5	12.4	14.0	14.8	14.5	15.9	15.8
Anticoagulants	2.6	2.5	2.7	2.5	1.4	1.3	1.4	1.2	2.0	1.9	2.3	1.3
ARB	7.4	7.0	8.0	8.7	4.9	4.7	5.3	5.4	5.9	5.6	6.8	5.8
Beta-blockers	9.4	9.0	10.0	10.5	7.1	7.3	6.8	7.6	19.0	18.5	20.5	21.2
Ca^2+-channel blockers	15.8	15.2	16.8	18.2	11.5	11.5	11.5	12.5	17.1	16.6	18.7	16.6
Diuretics	25.6	24.7	27.1	31.3	19.8	19.7	20.0	23.5	33.1	32.6	34.6	33.1
Estrogens	31.4	31.6	31.1	26.4	31.7	31.1	32.8	25.6	18.4	18.9	17.1	11.9
Anti-ischemic drugs	4.2	4.0	4.6	4.9	2.2	2.2	2.2	2.3	8.6	8.4	9.2	7.0
Statins	29.4	28.5	30.8	28.0	22.9	22.7	23.3	19.9	15.6	14.8	17.9	15.7

Notes:

a Including atrial fibrillation, any other cardiac dysrrhythmia, or prescriptions for amiodarone;

* P-values all <0.001 with few exceptions.

Abbreviations: ACE, angiotensin converting enzyme; AF, atrial fibrillation; ALN, alendronate; ARB, angiotensin receptor blockers; BIS, bisphosphonate; CHF, congestive heart failure; FU, follow-up; NA, not applicable; PY, person-years; RIS, risedronate; Rx, prescriptions.

Figure 1A Graphical presentation of the overall cumulative incidence of AF, unadjusted for any covariates.

Abbreviations: AF, atrial fibrillation; I, Ingenix; M, MarketScan; T, THIN.

Figure 1B Graphical presentation of the overall cumulative incidence for all dysrrhythmias, unadjusted for any covariates.

Abbreviations: AF, atrial fibrillation; I, Ingenix; M, MarketScan; T, THIN.

Table 3 Hazard ratio (95% confidence interval) estimates for AF comparing bisphosphonate users to matched nonusers

Database	MarketScan (US)			Ingenix (US)			THIN (UK)
Index drug	ALN or RIS	ALN	RIS	ALN or RIS	ALN	RIS	ALN or RIS	ALN	RIS
Unadjusted	0.92 (0.87–0.98)	0.91 (0.84–0.98)	0.94 (0.85–1.03)	0.96 (0.85–1.09)	1.06 (0.91–1.24)	0.78 (0.62–0.97)	0.93 (0.78–1.12)	0.99 (0.80–1.21)	0.92 (0.87–0.98)
Adjusted	0.92 (0.85–0.99)a	0.93 (0.85–1.02)	0.90 (0.80–1.01)	1.00 (0.87–1.16)	1.12 (0.94–1.34)	0.79 (0.62–1.03)	0.97 (0.79–1.20)	1.02 (0.81–1.28)	0.86 (0.54–1.37)
BIS Rx ≥ 2	0.86 (0.79–0.93)a	0.89 (0.80–0.98)a	0.82 (0.72–0.93)a	0.96 (0.82–1.13)	1.09 (0.90–1.33)	0.71 (0.52–0.95)a	0.98 (0.79–1.23)	1.03 (0.80–1.31)	0.88 (0.54–1.44)
Age
≥70	0.95 (0.88–1.04)	0.96 (0.86–1.06)	0.93 (0.81–1.06)	1.01 (0.84–1.20)	1.17 (0.95–1.44)	0.71 (0.51–0.99)	1.07 (0.86–1.33)b	1.14 (0.89–1.45)b	0.88 (0.55–1.43)
<70	0.85 (0.74–0.98)	0.87 (0.74–1.03)	0.83 (0.67–1.03)	1.03 (0.80–1.32)	1.05 (0.79–1.39)	0.93 (0.64–1.35)	0.33 (0.13–0.82)b	0.35 (0.15–0.83)b	0.67 (0.18–2.48)
Heart disease
Yes	0.94 (0.81–1.09)	0.92 (0.76–1.11)	0.97 (0.78–1.22)	0.97 (0.69–1.36)	1.10 (0.71–1.69)	0.75 (0.43–1.32)	0.51 (0.24–1.08)	0.37 (0.16–0.88)b	2.04 (0.32–12.80)
No	0.91 (0.84–0.99)	0.94 (0.84–1.04)	0.87 (0.76–1.00)	1.01 (0.86–1.18)	1.12 (0.93–1.36)	0.80 (0.60–1.06)	1.03 (0.83–1.28)	1.12 (0.88–1.42)b	0.84 (0.53–1.35)
Vascular disease
Yes	1.75 (1.55–1.97)b	1.69 (1.44–1.98)b	1.83 (1.52–2.20)b	1.98 (1.45–2.71)b	2.30 (1.58–3.34)b	1.39 (0.77–2.51)b	1.09 (0.70–1.71)	1.06 (0.64–1.73)	1.10 (0.36–3.34)
No	0.74 (0.68–0.80)b	0.77 (0.69–0.85)b	0.70 (0.61–0.80)b	0.91 (0.78–1.06)b	1.04 (0.86–1.26)b	0.71 (0.54–0.94)b	0.95 (0.76–1.19)	1.01 (0.78–1.30)	0.82 (0.50–1.34)
Blood pressure drugs
Yes	1.00 (0.92–1.09)b	1.03 (0.92–1.16)	0.96 (0.84–1.10)b	1.04 (0.86–1.25)	1.18 (0.94–1.47)	0.77 (0.55–1.09)	1.01 (0.79–1.30)	1.07 (0.81–1.41)	0.88 (0.51–1.51)
No	0.78 (0.69–0.88)b	0.77 (0.66–0.90)	0.80 (0.65–0.97)b	0.97 (0.79–1.20)	1.05 (0.81–1.36)	0.85 (0.59–1.22)	0.87 (0.62–1.21)	0.93 (0.64–1.34)	0.66 (0.30–1.44)
Fracture
Yes	1.05 (0.84–1.31)	1.20 (0.90–1.60)	0.93 (0.47–1.84)	1.41 (0.90–2.21)	1.74 (1.00–3.05)	0.85 (0.60–1.21)	0.82 (0.45–1.50)	0.93 (0.47–1.84)	1.00 (0.47–2.15)
No	0.90 (0.81–1.11)	0.90 (0.81–0.99)	0.98 (0.75–1.27)	0.95 (0.81–1.11)	1.06 (0.88–1.28)	0.90 (0.80–1.02)	0.94 (0.74–1.19)	0.98 (0.75–1.27)	0.76 (0.58–1.00)
Follow-up (days) since index
<90	0.94 (0.83–1.07)	0.95 (0.80–1.12)	0.93 (0.76–1.14)	1.33 (1.02–1.75)	1.37 (0.99–1.91)	1.24 (0.77–1.99)	1.00 (0.57–1.77)	1.11 (0.59–2.08)	0.67 (0.17–2.65)
90–179	0.86 (0.73–1.01)	0.83 (0.67–1.03)	0.90 (0.70–1.16)	1.23 (0.92–1.66)	1.33 (0.92–1.94)	1.05 (0.65–1.71)	0.87 (0.50–1.49)	0.95 (0.53–1.71)	0.54 (0.12–2.42)
180–364	0.93 (0.81–1.07)	0.92 (0.77–1.10)	0.94 (0.75–1.17)	0.77 (0.59–1.02)	0.95 (0.69–1.31)	0.45 (0.25–0.81)	0.88 (0.59–1.30)	0.83 (0.53–1.30)	1.07 (0.44–2.64)
≥365	0.92 (0.82–1.04)	0.97 (0.84–1.13)	0.84 (0.69–1.03)	0.89 (0.70–1.12)	1.02 (0.77–1.37)	0.68 (0.44–1.04)	1.04 (0.79–1.37)	1.12 (0.82–1.53)	0.90 (0.50–1.64)
# of BIS prescriptions
1	1.13 (1.01–1.28)	1.11 (0.95–1.30)	1.16 (0.97–1.40)	1.47 (1.16–1.86)	1.62 (1.21–2.19)	1.20 (0.80–1.80)	1.05 (0.64–1.74)	1.12 (0.64–1.96)	0.80 (0.25–2.56)
2–10	0.83 (0.76–0.91)	0.83 (0.74–0.94)	0.83 (0.72–0.96)	0.88 (0.73–1.07)	0.97 (0.77–1.22)	0.73 (0.52–1.03)	0.85 (0.65–1.12)	0.93 (0.69–1.26)	0.58 (0.29–1.15)
≥11	0.91 (0.73–1.13)	1.08 (0.83–1.40)	0.61 (0.41–0.92)	0.78 (0.52–1.16)	1.10 (0.69–1.74)	0.29 (0.11–0.75)	1.23 (0.82–1.83)	1.26 (0.80–2.00)	1.31 (0.57–2.98)
Per 1 more	0.98 (0.97–0.99)c	0.99 (0.98–1.00)	0.97 (0.95–0.99)c	0.99 (0.97–1.00)	1.00 (0.98–1.02)	0.96 (0.93–0.99)c	1.00 (0.99–1.02)	1.00 (0.98–1.02)	1.02 (0.99–1.06)

Notes:

a P < 0.05 for likelihood ratio test;

b P < 0.05 for test of interaction or effect modification;

c P < 0.05 for trend test, with number of bisphosphonate prescriptions as a continuous variable. Model adjusted variables: history of angina, congestive heart failure, diabetes, any hospitalizations, hypertension, myocardial infarction, osteoporosis, renal diseases, stroke, thrombosis, prescriptions for ACE inhibitors, angiotensin receptor blockers, anticoagulants, beta-blockers, calcium channel blockers, medications for cardiac ischemia, estrogens, diuretics, statins, and total number of all prescriptions.

Abbreviations: AF, atrial fibrillation; ALN, alendronate; BIS, bisphosphonate; HR, hazard ratio; NA, not applicable; RIS, risedronate; Rx, prescription.

Table 4 Hazard ratio (95% confidence interval) for a) hospitalized AF cases and b) ECG confirmed AF cases

MarketScan	Ingenix	THIN
a)
0.89 (0.77–1.03)	0.96 (0.80–1.16)	0.96 (0.37–2.51)
b)
0.92 (0.84–1.00)	0.94 (0.78–1.13)	0.64 (0.28–1.46)

Abbreviations: AF, atrial fibrillation; ECG, electrocardiogram.

Table 5 Hazard ratio (95% confidence interval) estimates for any dysrrhythmia comparing bisphosphonate users to matched nonusers

Database	MarketScan (US)			Ingenix (US)			THIN (UK)
Index drug	ALN or RIS	ALN	RIS	ALN or RIS	ALN	RIS	ALN or RIS	ALN	RIS
Unadjusted	1.05 (1.02–1.08)	1.04 (1.00–1.08)	1.07 (1.02–1.13)	1.03 (0.97–1.09)	1.02 (0.95–1.10)	1.03 (0.94–1.14)	1.16 (1.05–1.29)	1.17 (1.04–1.31)	1.13 (0.91–1.40)
Adjusted	1.01 (0.98–1.05)	1.01 (0.97–1.06)	1.01 (0.96–1.07)	1.06 (0.99–1.13)	1.07 (0.99–1.17)	1.02 (0.91–1.15)	1.12 (0.99–1.26)	1.13 (0.99–1.29)	1.10 (0.85–1.42)
Adjusted, define anti-arrhythmics rx	1.03 (1.00–1.07)a	1.03 (0.99–1.08)	1.03 (0.98–1.09)	1.10 (1.03–1.17)a	1.13 (1.05–1.22)a	1.04 (0.94–1.15)	1.08 (0.98–1.19)	1.10 (0.99–1.23)	1.01 (0.82–1.24)
BIS Rx ≥ 2	0.96 (0.92–1.00)a	0.96 (0.92–1.01)	0.95 (0.90–1.02)	1.02 (0.95–1.10)	1.04 (0.95–1.14)	0.98 (0.86–1.11)	1.11 (0.98–1.25)	1.12 (0.97–1.29)	1.08 (0.82–1.42)
Age
≥70	0.98 (0.94–1.03)b	0.99 (0.93–1.05)	0.98 (0.91–1.05)	1.08 (0.98–1.19)	1.12 (0.99–1.25)	0.99 (0.84–1.17)	1.08 (0.94–1.24)	1.11 (0.95–1.30)	0.99 (0.73–1.35)
<70	1.05 (1.00–1.11)b	1.05 (0.98–1.12)	1.07 (0.98–1.16)	1.05 (0.96–1.14)	1.04 (0.93–1.16)	1.05 (0.91–1.20)	1.19 (0.99–1.43)	1.16 (0.94–1.43)	1.33 (0.90–1.95)
Heart disease
Yes	0.96 (0.89–1.04)	0.99 (0.90–1.09)	0.92 (0.82–1.03)	1.02 (0.85–1.22)	0.97 (0.77–1.22)	1.10 (0.83–1.47)	0.80 (0.52–1.22)	0.71 (0.44–1.15)	1.23 (0.51–2.98)
No	1.03 (0.99–1.07)	1.02 (0.97–1.07)	1.04 (0.98–1.11)	1.07 (0.99–1.15)	1.09 (0.99–1.19)	1.01 (0.89–1.14)	1.15 (1.02–1.30)	1.17 (1.02–1.35)	1.11 (0.85–1.45)
Vascular disease
Yes	1.38 (1.29–1.49)b	1.38 (1.26–1.52)b	1.38 (1.23–1.54)b	1.44 (1.19–1.74)b	1.60 (1.27–2.03)b	1.18 (0.85–1.63)	1.17 (0.89–1.53)	1.07 (0.78–1.46)	1.60 (0.91–2.83)
No	0.94 (0.90–0.98)b	0.94 (0.90–0.99)b	0.93 (0.88–0.99)b	1.03 (0.96–1.10)b	1.04 (0.95–1.13)b	1.00 (0.89–1.13)	1.11 (0.98–1.26)	1.14 (0.99–1.31)	1.03 (0.78–1.36)
Blood pressure drugs
Yes	1.02 (0.97–1.06)	1.02 (0.97–1.08)	1.00 (0.93–1.08)	1.13 (1.03–1.24)	1.17 (1.04–1.31)	1.06 (0.90–1.23)	1.10 (0.94–1.28)	1.10 (0.93–1.31)	1.08 (0.78–1.49)
No	1.01 (0.96–1.07)	1.00 (0.94–1.07)	1.03 (0.95–1.12)	1.01 (0.92–1.10)	1.01 (0.90–1.13)	0.99 (0.85–1.16)	1.11 (0.94–1.31)	1.13 (0.94–1.36)	1.05 (0.73–1.52)
Fracture
Yes	1.06 (0.94–1.19)	1.12 (0.96–1.30)	0.96 (0.80–1.17)	1.28 (0.99–1.65)	1.31 (0.96–1.80)	1.22 (0.79–1.88)	0.92 (0.63–1.35)	0.91 (0.58–1.41)	0.85 (0.38–1.89)
No	1.01 (0.98–1.05)	1.01 (0.96–1.06)	1.02 (0.96–1.08)	1.04 (0.97–1.12)	1.06 (0.97–1.15)	1.01 (0.90–1.14)	1.14 (1.01–1.30)	1.17 (1.01–1.35)	1.10 (0.83–1.46)
Follow-up (days) since index
<90	1.01 (0.94–1.08)	1.06 (0.97–1.15)	0.94 (0.84–1.05)	1.04 (0.90–1.20)	1.05 (0.88–1.25)	1.01 (0.80–1.28)	0.95 (0.69–1.30)	1.03 (0.72–1.46)	0.72 (0.34–1.54)
90–179	0.94 (0.87–1.02)	0.97 (0.88–1.07)	0.89 (0.78–1.01)	1.17 (1.01–1.35)	1.19 (0.99–1.44)	1.12 (0.88–1.42)	1.36 (1.01–1.81)	1.27 (0.90–1.79)	1.70 (0.98–2.95)
180–364	1.05 (0.99–1.12)	1.02 (0.94–1.11)	1.11 (1.00–1.23)	1.05 (0.93–1.19)	1.06 (0.91–1.23)	1.04 (0.85–1.27)	1.12 (0.90–1.39)	1.16 (0.91–1.48)	1.00 (0.62–1.60)
≥365	1.03 (0.97–1.09)	1.01 (0.94–1.08)	1.06 (0.97–1.16)	1.03 (0.93–1.14)	1.05 (0.92–1.20)	0.97 (0.81–1.16)	1.10 (0.94–1.29)	1.11 (0.93–1.32)	1.09 (0.78–1.54)
# of BIS prescriptions
1	1.24 (1.17–1.32)	1.25 (1.16–1.35)	1.23 (1.12–1.35)	1.30 (1.16–1.47)	1.33 (1.14–1.54)	1.25 (1.03–1.53)	1.38 (1.05–1.80)	1.37 (1.01–1.86)	1.32 (0.72–2.41)
2–10	0.94 (0.90–0.98)	0.94 (0.89–1.00)	0.93 (0.87–1.00)	1.01 (0.93–1.10)	1.00 (0.90–1.12)	1.02 (0.89–1.18)	1.07 (0.92–1.24)	1.08 (0.91–1.28)	1.05 (0.76–1.45)
≥11	0.93 (0.84–1.04)	0.92 (0.81–1.04)	0.96 (0.81–1.14)	0.90 (0.75–1.09)	1.09 (0.88–1.37)	0.60 (0.43–0.85)	1.14 (0.90–1.44)	1.12 (0.86–1.47)	1.26 (0.78–2.02)
Each 1 more	0.99 (0.99–1.00)c	0.99 (0.99–1.00)c	0.99 (0.99–1.00)	1.00 (0.99–1.00)	1.00 (0.99–1.01)	0.99 (0.98–1.01)	1.00 (0.99–1.01)	1.00 (0.99–1.01)	1.01 (0.99–1.03)

Notes:

a P < 0.05 for likelihood ratio test;

b P < 0.05 for test of interaction or effect modification;

c P < 0.05 for trend test, with number of bisphosphonate prescriptions as a continuous variable. Model adjusted variables: history of angina, congestive heart failure, diabetes, any hospitalizations, hypertension, myocardial infarction, osteoporosis, renal diseases, stroke, thrombosis, prescriptions for ACE inhibitors, angiotensin receptor blockers, anticoagulants, beta-blockers, calcium channel blockers, medications for cardiac ischemia, estrogens, diuretics, statins, and total number of all prescriptions.

Abbreviations: ALN, alendronate; BIS, bisphosphonate; HR, hazard ratio; NA, not applicable; RIS, risedronate; Rx, prescription.

Table 6 Hazard ratio (95% confidence interval) estimates comparing bisphosphonate users (alendronate and risedronate) to nonusers, restricted to patients of 80 years of age or older at the index date

	P-value	Hazard ratio	Lower	Upper
MarketScan, AF	0.10	1.10	0.98	1.25
Ingenix, AF	0.69	1.05	0.82	1.35
THIN, AF	0.81	0.96	0.72	1.29
MarketScan, all dysrrhythmias	0.42	1.03	0.96	1.10
Ingenix, all dysrrhythmia	0.13	1.12	0.97	1.31
THIN, all dysrrhythmia	0.21	1.15	0.93	1.42

Abbreviation: AF, atrial fibrillation.