Supplement Table 1Incidence rate estimates of angioedema by antihypertensive treatment group and calendar year
Treatment group / Incidence rate per 1,000 person-years (95% confidence interval)
2008 / 2009 / 2010 / 2011 / Aggregate time period (2008-2011)
Overall / 2.11 (2.03-2.18) / 2.27 (2.19-2.35) / 2.30 (2.21-2.38) / 2.43 (2.34-2.52) / 2.28 (2.24-2.32)
Any Aliskiren / 2.89 (1.68-4.62) / 2.82 (1.74-4.31) / 2.75 (1.72-4.16) / 3.23 (2.11-4.73) / 2.58 (2.08-3.17)
Aliskiren monotherapy / 1.91 (0.23-6.91) / 2.74 (0.56-8.01) / 0.00 (NA) / 4.20 (0.87-12.27) / 1.71 (0.74-3.37)
AliskirenFDC / 0.00 (NA) / 1.88 (0.05-10.50) / 1.84 (0.22-6.63) / 1.43 (0.17-5.16) / 1.27 (0.41-2.96)
Aliskiren free-standing combination / 3.22 (1.80-5.30) / 2.92 (1.70-4.67) / 3.32 (2.03-5.12) / 3.53 (2.19-5.40) / 2.93 (2.31-3.66)
ACEIs / 2.69 (2.56-2.82) / 2.98 (2.84-3.12) / 2.85 (2.71-2.99) / 3.11 (2.95-3.27) / 2.94 (2.88-3.00)
ARBs / 1.39 (1.28-1.52) / 1.40 (1.28-1.53) / 1.58 (1.43-1.73) / 1.54 (1.39-1.70) / 1.47 (1.41-1.52)
BBs / 1.67 (1.51-1.84) / 1.76 (1.60-1.94) / 1.71 (1.54-1.90) / 1.97 (1.78-2.18) / 1.76 (1.68-1.83)
CCBs / 2.34 (2.05-2.67) / 2.42 (2.12-2.75) / 2.86 (2.52-3.23) / 2.64 (2.30-3.02) / 2.58 (2.44-2.72)
Diuretics / 1.94 (1.66-2.26) / 2.00 (1.72-2.33) / 1.94 (1.65-2.28) / 1.98 (1.66-2.33) / 1.98 (1.85-2.11)
All other / 2.47 (1.48-3.85) / 2.49 (1.47-3.93) / 3.00 (1.81-4.69) / 1.69 (0.77-3.22) / 2.08 (1.64-2.61)

ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; BB=beta blocker; CCB=calcium channel blocker; FDC=fixed-dose combination; NA=not applicable

Supplement Table 2 - Risk of angioedema by antihypertensive treatment group and by all covariates included in the adjusted case-control analysis
Independent variables / Adjusted Odds Ratio / 95% Confidence Interval / P-value
Lower limit / Upper limit
Index exposure: aliskiren monotherapy vs. beta-blockers / 0.99 / 0.45 / 2.20 / 0.98
Index exposure: aliskiren free-standing combination vs. beta-blockers / 2.51 / 1.47 / 4.30 / 0.0008
Index exposure: ACE-inhibitors vs. beta-blockers / 1.80 / 1.70 / 1.90 / <.0001
Index exposure: ARBs vs. beta-blockers / 0.81 / 0.75 / 0.86 / <.0001
Index exposure: calcium channel blockers vs. beta-blockers / 1.46 / 1.34 / 1.59 / <.0001
Index exposure: diuretics vs. beta-blockers / 1.02 / 0.93 / 1.12 / 0.6733
Index exposure: all other anti-hypertensive medications vs. beta-blockers / 1.19 / 0.90 / 1.58 / 0.2377
Male vs. female / 0.74 / 0.71 / 0.77 / <.0001
Geographic region: midwest vs. northeast / 1.144 / 1.09 / 1.21 / <.0001
Geographic region: south vs. northeast / 1.286 / 1.23 / 1.35 / <.0001
Geographic region: west vs. northeast / 0.974 / 0.91 / 1.05 / 0.50
CCI score: 1 vs. 0 / 1.208 / 1.15 / 1.27 / <.0001
CCI score: 2-3 vs. 0 / 1.420 / 1.35 / 1.50 / <.0001
CCI score: 4+ vs. 0 / 1.939 / 1.80 / 2.09 / <.0001
History of urticaria: yes vs. no / 4.963 / 4.62 / 5.33 / <.0001
History of allergic reactions: yes vs. no / 2.727 / 2.59 / 2.88 / <.0001
Concurrent NSAIDs: yes vs. no / 1.291 / 1.24 / 1.35 / <.0001
Concurrent estrogens: yes vs. no / 1.203 / 1.12 / 1.29 / <.0001
Concurrent anti-platelets: yes vs. no / 1.196 / 1.10 / 1.30 / <.0001
Concurrent statins: yes vs. no / 0.806 / 0.78 / 0.84 / <.0001
Supplement Table 3 Risk of angioedema by antihypertensive treatment group from the case-control analysis including multiple breakouts of aliskiren free-standing combinations
Antihypertensive drug index exposure / Crude
Odds Ratio / 95% Confidence Interval / P-value / Adjusted* Odds Ratio / 95% Confidence Interval / P-value
Aliskiren monotherapy vs. beta-blockers / 0.95 / 0.45-2.02 / 0.89 / 0.99 / 0.45-2.20 / 0.98
AliskirenFDC vs. beta-blockers / 0.86 / 0.33-2.22 / 0.75 / 1.06 / 0.40-2.76 / 0.91
AliskirenFSC overall vs beta-blockers / 3.29 / 2.45-4.41 / <.0001 / 3.29 / 2.42-4.48 / <.0001
AliskirenFSC with ACE inhibitors vs. beta-blockers / 6.13 / 3.64-10.30 / <.01 / 7.03 / 4.10-12.05 / <.01
AliskirenFSC with ARBs vs. beta-blockers / 2.12 / 1.25-3.58 / <.01 / 2.10 / 1.22-3.63 / <.01
AliskirenFSC with any other antihypertensive class vs. beta-blockers / 2.85 / 1.72-4.71 / <.01 / 2.51 / 1.47-4.30 / <.001
ACE-inhibitors vs. beta-blockers / 1.56 / 1.48-1.65 / <.01 / 1.80 / 1.70-1.90 / <.01
ARBs vs. beta-blockers / 0.80 / 0.75-0.86 / <.01 / 0.81 / 0.75-0.86 / <.01
Calcium channel blockers vs. beta-blockers / 1.48 / 1.37-1.61 / <.01 / 1.46 / 1.34-1.59 / <.01
Diuretics vs. beta-blockers / 1.06 / 0.97-1.16 / 0.19 / 1.02 / 0.93-1.12 / 0.67
All other anti-hypertensive medications vs. beta-blockers / 1.25 / 0.95-1.63 / 0.11 / 1.19 / 0.89-1.58 / 0.24

* Adjusted for gender, region, CCI, and history of specific conditions (urticaria and allergic reactions) and concurrent use of specific medications (NSAIDs, estrogens, anti-platelets, and statins), ACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker; FDC=fixed-dose combination