ASH Clinical News December 2016 | Page 67

CLINICAL NEWS excluded if they evaluated a combination of PCCs and FFP or factor VIIa as a co-intervention .
The 13 studies included 2,114 patients ; all were adults who presented with warfarin-associated major bleeding or required urgent warfarin reversal for surgery or an invasive procedure .
In the 10 studies ( comprising 1,123 patients ) that reported on mortality , the study ’ s primary endpoint , more deaths occurred in patients treated with FFP than with PCCs ( 28.76 % [ n = 239 ] vs . 25.11 % [ n = 282 ]; p value not provided ). An a priori subgroup analysis also found that
PCCs significantly reduced all-cause mortality compared with FFPs ( OR = 0.57 ; 95 % CI 0.37-0.9 ; p = 0.02 ). In addition , 4F-PCCs were associated with reduced all-cause mortality , compared with FFP ( OR = 0.53 ; 95 % CI 0.34-0.83 ; p = 0.005 ); however , 3F-PCCs were not ( OR = 3.55 ; 95 % CI 0.12-105.82 ; p = 0.47 ).
Patients who received reversal with PCC also had a greater likelihood of achieving clinical hemostasis ( a secondary endpoint ) in the two studies that reported on this outcome : 77.2 percent of patients ( n = 149 / 193 ) who received PCC achieved hemostasis , compared with 64.5 percent
( n = 129 / 200 ) of those who received FFP ( OR = 2 ; 95 % CI 0.85-4.68 ; p = 0.11 ).
In the six studies that assessed the likelihood of achieving normalization of international normalized ratio ( INR ), Dr . Chai-Adisaksopha and authors found that 60.62 percent of PCC-treated patients ( n = 157 / 259 ) had rapid INR reduction , compared with 12.78 percent of FFP-treated patients ( n = 34 / 266 ), for an OR of 10.8 ( 95 % CI 6.12-19.07 ; p < 0.001 ). Further , the time to INR correction and the mean difference of INR correction was −6.5 hours in favor of PCC ( 95 % CI −9.7 to −3.24 ; p < 0.001 ).
Table 4 : All Adverse Reactions in ≥5.0 % and Grade 3 / 4 Adverse Reactions
in ≥ 1.0 % of Patients in the Rd Continuous or Rd18 Arms *
Grade 3 / 4 Adverse
All Adverse Reactions a
Reactions b
Rd
Rd
System organ class Continuous
Rd18
MPT
Continuous
Rd18
MPT
Preferred term
( N = 532 )
( N = 540 )
( N = 541 )
( N = 532 )
( N = 540 )
( N = 541 )
Musculoskeletal and connective tissue disorders
Back pain c
170 ( 32 ) 145 ( 26.9 ) 116 ( 21.4 )
37 ( 7 )
34 ( 6.3 )
28 ( 5.2 )
Muscle spasms f
109 ( 20.5 ) 102 ( 18.9 ) 61 ( 11.3 )
< 1 %
< 1 %
< 1 %
Arthralgia f
101 ( 19.0 ) 71 ( 13.1 )
66 ( 12.2 )
9 ( 1.7 )
8 ( 1.5 )
8 ( 1.5 )
Bone pain f
87 ( 16.4 )
77 ( 14.3 )
62 ( 11.5 )
16 ( 3.0 )
15 ( 2.8 )
14 ( 2.6 )
Pain in extremity f
79 ( 14.8 )
66 ( 12.2 )
61 ( 11.3 )
8 ( 1.5 )
8 ( 1.5 )
7 ( 1.3 )
Musculoskeletal pain f
67 ( 12.6 )
59 ( 10.9 )
36 ( 6.7 )
< 1 %
< 1 %
< 1 %
Musculoskeletal chest pain f
60 ( 11.3 )
51 ( 9.4 )
39 ( 7.2 )
6 ( 1.1 )
< 1 %
< 1 %
Muscular weakness f
43 ( 8.1 )
35 ( 6.5 )
29 ( 5.4 )
< 1 %
8 ( 1.5 )
< 1 %
Neck pain f
40 ( 7.5 )
19 ( 3.5 )
10 ( 1.8 )
< 1 %
< 1 %
< 1 %
Infections and infestations
Bronchitis c
90 ( 16.9 )
59 ( 10.9 )
43 ( 7.9 )
9 ( 1.7 )
6 ( 1.1 )
3 ( 0.6 )
Nasopharyngitis f
80 ( 15 )
54 ( 10 )
33 ( 6.1 )
0 ( 0.0 )
0 ( 0.0 )
0 ( 0.0 )
Urinary tract infection f
76 ( 14.3 )
63 ( 11.7 )
41 ( 7.6 )
8 ( 1.5 )
8 ( 1.5 )
< 1 %
Upper respiratory tract infection c % f
69 ( 13.0 )
53 ( 9.8 )
31 ( 5.7 )
< 1 %
8 ( 1.5 )
< 1 %
Pneumonia c @
93 ( 17.5 )
87 ( 16.1 )
56 ( 10.4 ) 60 ( 11.3 )
57 ( 10.5 )
41 ( 7.6 )
Respiratory tract
infection %
35 ( 6.6 )
25 ( 4.6 )
21 ( 3.9 )
7 ( 1.3 )
4 ( 0.7 )
1 ( 0.2 )
Influenza f
33 ( 6.2 )
23 ( 4.3 )
15 ( 2.8 )
< 1 %
< 1 %
0 ( 0.0 )
Gastroenteritis f
32 ( 6.0 )
17 ( 3.1 )
13 ( 2.4 )
0 ( 0.0 )
< 1 %
< 1 %
Lower respiratory tract infection
29 ( 5.5 )
14 ( 2.6 )
16 ( 3.0 )
10 ( 1.9 )
3 ( 0.6 )
3 ( 0.6 )
Rhinitis f
29 ( 5.5 )
24 ( 4.4 )
14 ( 2.6 )
0 ( 0.0 )
0 ( 0.0 )
0 ( 0.0 )
Cellulitis c
< 5 %
< 5 %
< 5 %
8 ( 1.5 )
3 ( 0.6 )
2 ( 0.4 )
Sepsis c @
33 ( 6.2 )
26- ( 4.8 )
18 ( 3.3 )
26 ( 4.9 )
20 ( 3.7 )
13 ( 2.4 )
Nervous system disorders
Headache f
75 ( 14.1 )
52 ( 9.6 )
56 ( 10.4 )
< 1 %
< 1 %
< 1 %
Dysgeusia f
39 ( 7.3 )
45 ( 8.3 )
22 ( 4.1 )
< 1 %
0 ( 0.0 )
< 1 %
Blood and lymphatic system disorders d
Anemia
233 ( 43.8 ) 193 ( 35.7 ) 229 ( 42.3 ) 97 ( 18.2 )
85 ( 15.7 ) 102 ( 18.9 )
Neutropenia
186 ( 35.0 ) 178 ( 33 ) 328 ( 60.6 ) 148 ( 27.8 ) 143 ( 26.5 ) 243 ( 44.9 )
Thrombocytopenia
104 ( 19.5 ) 100 ( 18.5 ) 135 ( 25.0 ) 44 ( 8.3 )
43 ( 8.0 )
60 ( 11.1 )
Febrile neutropenia
7 ( 1.3 )
17 ( 3.1 )
15 ( 2.8 )
6 ( 1.1 )
16 ( 3.0 )
14 ( 2.6 )
Pancytopenia
5 ( 0.9 )
6 ( 1.1 )
7 ( 1.3 )
1 ( 0.2 )
3 ( 0.6 )
5 ( 0.9 )
Respiratory , thoracic and mediastinal disorders
Cough f
121 ( 22.7 ) 94 ( 17.4 )
68 ( 12.6 )
< 1 %
< 1 %
< 1 %
Dyspnea c , e
117 ( 22.0 ) 89 ( 16.5 ) 113 ( 20.9 ) 30 ( 5.6 )
22 ( 4.1 )
18 ( 3.3 )
Epistaxis f
32 ( 6.0 )
31 ( 5.7 )
17 ( 3.1 )
< 1 %
< 1 %
0 ( 0.0 )
Oropharyngeal pain f
30 ( 5.6 )
22 ( 4.1 )
14 ( 2.6 )
0 ( 0.0 )
0 ( 0.0 )
0 ( 0.0 )
Dyspnea exertional e
27 ( 5.1 )
29 ( 5.4 )
< 5 %
6 ( 1.1 )
2 ( 0.4 )
0 ( 0.0 )
Metabolism and nutrition disorders
Decreased
appetite
123 ( 23.1 ) 115 ( 21.3 ) 72 ( 13.3 )
14 ( 2.6 )
7 ( 1.3 )
5 ( 0.9 )
Hypokalemia %
91 ( 17.1 ) 62 ( 11.5 )
38 ( 7 )
35 ( 6.6 )
20 ( 3.7 )
11 ( 2.0 )
Hyperglycemia
62 ( 11.7 )
52 ( 9.6 )
19 ( 3.5 )
28 ( 5.3 )
23 ( 4.3 )
9 ( 1.7 )
Hypocalcemia
57 ( 10.7 )
56 ( 10.4 )
31 ( 5.7 )
23 ( 4.3 )
19 ( 3.5 )
8 ( 1.5 )
Dehydration %
25 ( 4.7 )
29 ( 5.4 )
17 ( 3.1 )
8 ( 1.5 )
13 ( 2.4 )
9 ( 1.7 )
Gout e
< 5 %
< 5 %
< 5 %
8 ( 1.5 )
0 ( 0.0 )
0 ( 0.0 )
Diabetes mellitus % e
< 5 %
< 5 %
< 5 %
8 ( 1.5 )
4 ( 0.7 )
2 ( 0.4 )
Hypophosphatemia e
< 5 %
< 5 %
< 5 %
7 ( 1.3 )
3 ( 0.6 )
1 ( 0.2 )
Hyponatremia % e
< 5 %
< 5 %
< 5 %
7 ( 1.3 )
13 ( 2.4 )
6 ( 1.1 )
Skin and subcutaneous tissue disorders
Rash
139 ( 26.1 ) 151 ( 28.0 ) 105 ( 19.4 ) 39 ( 7.3 )
38 ( 7.0 )
33 ( 6.1 )
Pruritus f
47 ( 8.8 )
49 ( 9.1 )
24 ( 4.4 )
< 1 %
< 1 %
< 1 % ( continued )
Table 4 : All Adverse Reactions in ≥5.0 % and Grade 3 / 4 Adverse Reactions
in ≥ 1.0 % of Patients in the Rd Continuous or Rd18 Arms *
Grade 3 / 4 Adverse
All Adverse Reactions a
Reactions b
Rd
Rd
System organ class Continuous
Rd18
MPT
Continuous
Rd18
MPT
Preferred term
( N = 532 )
( N = 540 )
( N = 541 )
( N = 532 )
( N = 540 )
( N = 541 )
Psychiatric disorders
Insomnia
147 ( 27.6 ) 127 ( 23.5 )
53 ( 9.8 )
4 ( 0.8 )
6 ( 1.1 )
0 ( 0.0 )
Depression
58 ( 10.9 )
46 ( 8.5 )
30 ( 5.5 )
10 ( 1.9 )
4 ( 0.7 )
1 ( 0.2 )
Vascular disorders Deep vein thrombosis c %
55 ( 10.3 )
39 ( 7.2 )
22 ( 4.1 )
30 ( 5.6 )
20 ( 3.7 )
15 ( 2.8 )
Hypotension c %
51 ( 9.6 )
35 ( 6.5 )
36 ( 6.7 )
11 ( 2.1 )
8 ( 1.5 )
6 ( 1.1 )
Injury , Poisoning , and Procedural Complications
Fall f
43 ( 8.1 )
25 ( 4.6 )
25 ( 4.6 )
< 1 %
6 ( 1.1 )
6 ( 1.1 )
Contusion f
33 ( 6.2 )
24 ( 4.4 )
15 ( 2.8 )
< 1 %
< 1 %
0 ( 0.0 )
Eye disorders Cataract
73 ( 13.7 )
31 ( 5.7 )
5 ( 0.9 )
31 ( 5.8 )
14 ( 2.6 )
3 ( 0.6 )
Cataract subcapsular e
< 5 %
< 5 %
< 5 %
7 ( 1.3 )
0 ( 0.0 )
0 ( 0.0 )
Investigations Weight decreased
72 ( 13.5 )
78 ( 14.4 )
48 ( 8.9 )
11 ( 2.1 )
4 ( 0.7 )
4 ( 0.7 )
Cardiac disorders Atrial fibrillation c
37 ( 7.0 )
25 ( 4.6 )
25 ( 4.6 )
13 ( 2.4 )
9 ( 1.7 )
6 ( 1.1 )
Myocardial infarction ( including acute ) c , e
< 5 %
< 5 %
< 5 %
10 ( 1.9 )
3 ( 0.6 )
5 ( 0.9 )
Renal and Urinary disorders
Renal failure ( including acute ) c @, f
49 ( 9.2 )
54 ( 10.0 )
37 ( 6.8 )
28 ( 5.3 )
33 ( 6.1 )
29 ( 5.4 )
Neoplasms benign , malignant and unspecified ( Incl cysts and polyps )
Squamous cell
carcinoma ce
< 5 %
< 5 %
< 5 %
8 ( 1.5 )
4 ( 0.7 )
0 ( 0.0 )
Basal cell carcinoma c e , f
< 5 %
< 5 %
< 5 %
< 1 %
< 1 %
0 ( 0.0 )
Note : System organ classes ( SOC ) and preferred terms ( PTs ) reflect coding of adverse
reactions using MedDRA . A subject with multiple occurrences of an adverse
reaction is counted only once under the applicable SOC / PT .
a All treatment-emergent adverse reactions in at least 5.0 % of subjects in the
Rd Continuous or Rd18 Arms and at least a 2.0 % higher frequency (%) in either the
Rd Continuous or Rd18 Arms compared to the MPT Arm .
b All grade 3 or 4 treatment-emergent adverse reactions in at least 1.0 % of subjects in
the Rd Continuous or Rd18 Arms and at least a 1.0 % higher frequency (%) in either
the Rd Continuous or Rd18 Arms compared to the MPT Arm .
c
Serious treatment-emergent adverse reactions in at least 1.0 % of subjects in the
Rd Continuous or Rd18 Arms and at least a 1.0 % higher frequency (%) in either the
Rd Continuous or Rd18 Arms compared to the MPT Arm .
d Preferred terms for the blood and lymphatic system disorders SOC were included by
medical judgment as known adverse reactions for Rd Continuous / Rd18 , and have also
been reported as serious .
e Footnote “ a ” not applicable
f
Footnote “ b ” not applicable .
@ - adverse reactions in which at least one resulted in a fatal outcome
%
- adverse reactions in which at least one was considered to be life threatening ( if the
outcome of the reaction was death , it is included with death cases )
* PTs for combined adverse reaction terms :
Abdominal Pain : Abdominal pain , abdominal pain upper , abdominal pain lower ,
gastrointestinal pain
Pneumonias : Pneumonia , lobar pneumonia , pneumonia pneumococcal ,
bronchopneumonia , pneumocystis jiroveci pneumonia , pneumonia legionella , pneumonia
staphylococcal , pneumonia klebsiella , atypical pneumonia , pneumonia bacterial ,
pneumonia escherichia , pneumonia streptococcal , pneumonia viral
Sepsis : Sepsis , septic shock , urosepsis , escherichia sepsis , neutropenic sepsis ,
pneumococcal sepsis , staphylococcal sepsis , bacterial sepsis , meningococcal sepsis ,
enterococcal sepsis , klebsiella sepsis , pseudomonal sepsis
Rash : Rash , rash pruritic , rash erythematous , rash maculo-papular , rash generalised ,
rash papular , exfoliative rash , rash follicular , rash macular , drug rash with eosinophilia
and systemic symptoms , erythema multiforme , rash pustular
Deep Vein Thrombosis : Deep vein thrombosis , venous thrombosis limb , venous
thrombosis
After At Least One Prior Therapy for MM Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID / dexamethasone ( 353 patients ) or placebo / dexamethasone ( 350 patients ).
In the REVLIMID / dexamethasone treatment group , 269 patients ( 76 %) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients ( 57 %) in the placebo / dexamethasone treatment group . Of these patients who had one dose interruption with or