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ENVOLVING THE FUTURE OF SINGLE PILL
COMBINATION IN ANTIHYPERTENSIVE
THERAPHY
Djanggan Sargowo
Shangri-La, Surabaya - Sabtu, 23 Juni 2012
1
Prevalence* of HTN (%)
HYPERTENSION IS A PREVALENT DISEASE
AFFECTING 1 BILLION PEOPLE TODAY
*Among persons aged 35–64 years old; age and sex adjusted
HTN = BP 140/90 mmHg or on treatment
Wolf-Maier et al. JAMA 2003;289:2363–9
2
CLASSIFICATION OF BLOOD PRESSURE IN US ADULTS:
JNC VII GUIDELINES
BP category
Normal
Systolic
(mmHg)
Diastolic
(mmHg)
<120
and
<80
Pre-hypertension
120–139
or
80–89
Hypertension,
stage 1
140–159
or
90–99
Hypertension,
stage 2
160
or
100
Chobanian et al. JAMA 2003;289:256072
3
JNC VII AND ESHESC SUMMARY :
Target Blood Pressure Goals
Type of hypertension
Uncomplicated
BP goal (mmHg)
<140/90
Complicated
Diabetes mellitus
<130/80
Kidney disease
<130/80
Chobanian et al. JAMA 2003;289:256072
Guidelines Committee. J Hypertens 2003;21:101153
4
JNC VII: ALGORITHM FOR TREATMENT
OF HYPERTENSION
Lifestyle modifications
Not at goal BP*
HTN without compelling
indications
HTN with compelling
indications
Drug(s) for the compelling
indications
Stage 1
Stage 2
Thiazide-type diuretics for
most. May consider ACE
inhibitor, ARB, β-blocker,
CCB, or combination
Two-drug combination for
most (usually including
thiazide-type diuretic)
Other antihypertensive
drugs (diuretics, ACE
inhibitor, ARB, β-blocker,
CCB) as needed
If not at goal, optimise dosages or add additional drugs until goal BP is achieved.
Consider consultation with hypertension specialist
*BP goal <140/90 mmHg or <130/80 mmHg for those
with diabetes or chronic kidney disease
Chobanian et al. JAMA 2003;289:2560–72
5
ESH–ESC: ALGORITHM FOR TREATMENT
OF HYPERTENSION
Consider: BP level before treatment
Absence or presence of TOD and risk factors
Choose between:
Single agent at low dose
2-drug combination at low dose
If goal BP not achieved
Previous agent
Switch to
at full dose
different agent
at low dose
Previous
combination
at full dose
Add a
third drug
at low dose
If goal BP not achieved
2–3 drug
combination
Full-dose
monotherapy
TOD = target organ damage
3-drug combination
at effective doses
ESH–ESC Guidelines. J Hypertens 2003;21:1779–86
6
APPROXIMATELY 73% OF EUROPEAN PATIENTS
WITH HYPERTENSION REMAIN UNTREATED
Patients (%)
100
Treated
Untreated
75
74
74
74
73
73
68
England
Sweden
Germany
Spain
Italy
80
60
40
20
0
Wolf-Maier et al. Hypertension 2004;43:10–17
7
Patients with BP control (%)
More than 60% of Patients do not Achieve BP goal of
<140/90 mmHg with monotherapy
BP < 140/90 mmHg
Dickerson et al. Lancet. 1999:353:2008–2013.
BP < 135/85 mmHg
8
ESH/ESC
JNC VII
Also Guidelines worldwide Acknowledge That Most
Patients Need Combination Therapy to Achieve BP Goals
Most patients with hypertension will require two or more
antihypertensive medications to achieve their BP goals
– When BP is > 20/10 mmHg above goal, consideration should
be given to initiating therapy with two drugs
•
Combination treatment should be considered as first choice
when there is high CV risk
– i.e., in individuals in whom BP is markedly above the
hypertension threshold (> 20/10 mmHg), or associated with
multiple risk factors sub-clinical organ damage, diabetes, renal
or CV disease
• Many patients will require more than one drug to achieve
adequate BP control
– Pathophysiological reasoning suggests that adding an ACE-I/ARB
to a CCB or a diuretic (or vice versa in the younger group) are
logical combinations
NICE
JSH
•
The Japanese Society of
Hypertension Committee for
Guidelines for the
Management of Hypertension
2009
• The use of two or three drugs in combination is often necessary
to achieve the target BP control
– A low dose of a diuretic should be included in this combination
Chobanian et al. JAMA. 2003;289:2560–2572; Mancia et al. Eur Heart J. 2007;28:1462–1536; http://www.nice.org.uk/
download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3–107.
9
MANAGEMENT OF HYPERTENSION: GUIDELINE
RECOMMENDATIONS FOR COMBINING THERAPIES
 Multiple antihypertensive agents are
needed to achieve BP goals
 European and US guidelines for
combining antihypertensive therapies
10
BENEFITS OF FIXED-DOSE COMBINATION
THERAPY
 Rationale for fixed-dose combinations
(FDCs): efficacy; tolerability;
compliance and persistence
 Beneficial impact of FDCs on
compliance and persistence, and costs
11
RATIONALE FOR THE USE OF FIXED-DOSE
COMBINATIONS: TOLERABILITY
FDC therapy may have an improved tolerability profile
compared with its single-mechanism components1,2
Low doses of two agents often result in fewer adverse
events than high doses of one agent1,2
– Physicians may accept less than optimal BP control to minimise
adverse events
Compound-specific adverse events can be attenuated,
e.g.1,2
– RAS blockers effectively blunt the metabolic effects of diuretics
– RAS blockers may attenuate the oedema that is caused by
calcium channel blockers (CCBs)
1Sica.
Drugs 2002;62:44362; 2Quan et al. Am J Cardiovasc Drugs 2006;6:10313
12
Single-Pill Combinations (SPC) significantly improve
Compliance/Treatment adherence (~25%)
30
p < 0.0001
Relative reduction in
non-compliance* (%)
26
p < 0.0001
24
20
10
0
Chronic disease
(9 studies)
Hypertension
(4 studies)
* With single-pill combination therapy vs free-drug regimens
Bangalore et al. Am J Med. 2007;120:713–719.
13
21% MORE PATIENTS ARE FULLY COMPLIANT WITH
FIXED-DOSE COMBINATION THERAPY THAN WITH FREECOMBINATION THERAPY
Patients fully compliant (%)
Cohort study of general practice research data (N=755)
100
Fixed-dose combination therapy
80
Co-administration of two pills
60
40
20
17%
21%
0
0
3
6
9
12
15
18
Months since start of therapy
21
24
27
Patients on free combination had a higher odds ratio (OR) of being
non-compliant than patients on FDC: OR 2.09 (95% CI: 1.69, 2.59)
Sturkenboom et al. J Hypertens 2005;23(Suppl 2):S236
14
15
Re-appraisal of ESH/ESC Guidelines suggests
4 Preferred Antihypertensive Drug Classes
2009
2007
Diuretics
Diuretics
β-blockers
ARB
ARB
ONTARGET®
ACCOMPLISH
HYVET
CCB
CCB
α-blockers
ACE-I
ACE-I
Most rational combinations
Combinations used as necessary
Mancia et al. Eur Heart J. 2007;28:1462–1536;
Mancia et al. J Hypertens. 2009;27:2121–2158.
16
CCB + ARB :
The Synergies of Counter-Regulation (2)
CCB
 Arteriodilation
 Peripheral oedema
 Effective in low-renin patients
 Reduces cardiac ischaemia
ARB
 Venodilation
 Attenuates peripheral oedema
 Effective in high-renin patients
 No effect on cardiac ischaemia
BP
Synergistic
BP reduction
Complementary
clinical benefits
17 et al. Expert Opin Pharmacother. 2006;7:575–581; Sica. Drugs. 2002;62:443–462;
Mistry
Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.
ARB
 RAS blockade
 CHF and renal
benefits
CCB
 RAS activation
 No renal or CHF
benefits
17
RATIONALE FOR A CCBARB COMBINATION
 The calcium channel blocker (CCB)angiotensin
receptor blocker (ARB) reduces BP by targeting
two key BP effector pathways
 Rationale for a CCBARB: tolerability and
efficacy
 Rationale for CCBARB therapy with
Amlodipine/Telmisartan
18
PERIPHERAL OEDEMA ASSOCIATED WITH CCBS
Fluid leakage
No venous
dilation
Arterial
dilation
Fluid leakage
Capillary bed
Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273
White et al. Clin Pharmacol Ther 1986;39:438
Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131
19
COMPLEMENTARY EFFECTS OF A CCB/ARB:
REDUCTION OF CCB-ASSOCIATED OEDEMA
Arterial
dilation
(CCB and
ARB)
Venous
dilation
(ARB)
Capillary bed
Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273
White et al. Clin Pharmacol Ther 1986;39:438; Gustaffson. J Cardiovasc Pharmacol
1987;10(Suppl. 1):S12131; Messerli et al. Am J Cardiol 2000;86:11827
20
Amlodipine – The longest half-life in class
Plasma elimination half-life (h)
35
> 30
30
25
19
20
15
12
10
5
0
5
Lercanidipine
7
Nifedipine
14
16
9
Nimodipine
Nisoldipine
Nicardipine
Felodipine
Lacidipine
Amlodipine
Based on available online product information.
21
Amlodipine - broadest CVP evidence and indication in class
PREVENT1
ASCOT-BPLA/CAFE3,4
825 CAD patients (≥ 30%); multicentre,
randomized, placebo-controlled
19,257 HTN patients; multicentre,
randomized, prospective study vs atenolol
CAMELOT2
1,991 CAD patients (≥ 20%); doubleblind, randomized study vs placebo and
enalapril 20 mg
ALLHAT5
18,102 HTN patients; multicentre,
randomized, prospective study vs lisinopril
INDICATION:
 Hypertension
 Coronary Artery Disease (CAD)



Chronic Stable Angina
Vasospastic Angina (Prinzmetal’s or Variant Angina)
Angiographically documented CAD without heart failure or an ejection fraction < 40%
1. Pitt et al. Circulation. 2000;102:1503–1510; 2. Nissen et al. JAMA. 2004;292:2217–2226; 3. Dahlof et al. Lancet.
2005;366:895–906; 4. Williams et al. Circulation. 2006;113:1213 –1225; 5. Leenen et al. Hypertension.2006;48:374–384.
22
Telmisartan has a Unique Pharmacology Profile in its
Class (ARB) …
Epro- LoVal- Cande- Olme- Irbe- Telmisartan sartan sartan sartan sartan sartan sartan
Highest receptor affinity
Receptor dissociation
half-life (min)
Plasma half-life (h)
Longest plasma half-life
Losartan
Valsartan
Candesartan
Olmesartan
Telmisartan
500
Most lipophilic
(high tissue penetration)
Cande- Epro- Val- Olme- LoIrbe- Telmisartan sartan sartan sartan sartan sartan sartan
23
Highest selective PPARγ activation
†
Active metabolite of losartan
PPARy fold activation
Volume of distribution (L)
500
Epro- Olme- EXP Cande- ValIrbe- Telmisartan sartan 3174† sartan sartan sartan sartan
Burnier, Brunner. Lancet. 2000;355:637–645; Brunner. J Hum Hypertens. 2002;16(Suppl 2):S13–S16; Kakuta et al. Int J Clin Pharmacol Res. 2005;25:
41–46; Wienen et al. Br J Pharmacol. 1993;110:245–252; Song, White. Formulary. 2001;36:487–499; Asmar. Int J Clin Pract.
2006;60:315–320; Israili. J Hum Hypertens. 2000;14(Suppl 1):S73–S86; Benson et al. Hypertension. 2004;43:993–1002.
23
… is the Most Studied Amongst ARBs in Mortality and
Morbidity Endpoint Trials …
51,878
Number of patients
44,264
19,335
12,565
1,405
Eprosartan
MOSES1
4,449
Olmesartan
ROADMAP2
6,405
Irbesartan
Candesartan
Losartan
Valsartan
IRMA II3
SCOPE6
RENAAL8
Val-HeFT12
TRANSCEND®16
IDNT4
CHARM7
ELITE II9
NAVIGATOR13
PRoFESS®16
OPTIMAAL10
VALIANT14
ONTARGET®16
LIFE11
VALUE15
I-Preserve5
1. Schrader et al. Stroke. 2005;36:1218–1226; 2. http://www.roadmapstudy.org/resident.aspx; 3. Parving et al. N Engl J Med. 2001;345:870–878; 4. Lewis et al. N Engl J Med. 2001;345:851–860; 5.
Carson et al. J Card Fail. 2005;11:576–585; 6. Papademetriou et al. J Am Coll Cardiol. 2004;44:1175–1180; 7. www.atacand.com; 8. Brenner et al. N Engl J Med. 2001;345:861–869; 9. Pitt et al.
Lancet. 2000;355:1582–1587; 10. Dickstein et al. Lancet. 2002;360:752–760; 11. Dahlof et al. Lancet. 2002;359:955–1003; 12. Cohn et al. N Engl J Med. 2001;345:1667–1675; 13.
www.novartis.com; 14. Pfeffer et al. N Engl J Med. 2003;349:1893–1906; 15. Julius et al. Lancet. 2004;363:2022–2031; 15. www.ontarget-micardis.com.
24
Telmisartan
24
… with the broadest CV prevention indication in class (based
on the ONTARGET trial program)
Patients Based on the Data From The ONTARGET® Trial Program
LoEpro- Irbe- Olme- Val- Cande- Telmisartan sartan sartan sartan sartan sartan sartan
Hypertension
✔
Treatment of renal disease
✔
✔
Prevention of stroke in LVH
✔
✔
✔
✔
✔
✔
✔
CV high risk
✔
Atherothrombotic CV disease such as:
✔
✔
✔
✔
✔
Coronary heart disease
Peripheral vascular disease
Stroke
Type 2 diabetes with target organ damage
Heart failure or LV dysfunction
Product information provided by EMA (http://www.emea.europa.eu) and eMC (http://emc.medicines.org.uk).
✔
✔
25
Telmisartan + Amlodipine® key
topics
BP efficacy of Telmisartan + Amlodipine
BP efficacy of Telmisartan + Amlodipine in added risk patients
Safety & Tolerability of Telmisartan + Amlodipine
26
Telmisartan + Amlodipine : Provides consistent BP
Reductions across hypertension severities
Moderate HTN1
Mild HTN1
140 – <150
150 – <160
160 – <170
170 – <180
180 – <190
190– <200
(n = 39)
(n = 34)
(n = 31)
(n = 13)
(n = 305)
(n = 71 )
Mean SBP reductions from
baseline (mmHg)
Baseline SBP =
Severe HTN2
T80/A10
1Littlejohn
27
2Neutel
et al. J Clin Hypertens. 2009;11:207–213;
et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
27
Are you hungry
or
sleepy ????
Sciences
28
Telmisartan + Amlodipine :
80% of Maximum Effect within 2 Weeks
Mean SBP reduction (mmHg)
Mean SBP (mmHg)
Baseline
80%*
– 37.9 mmHg
Week 2
– 47.5 mmHg
Week 8
A5 and T80/A5 for the first 2 weeks, then forced-titration to A10 and T80/A10, respectively;
baseline BP = 185.4/103.2 mmHg
Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
29
Telmisartan + Amlodipine :
83% at goal for a full 24 hour (< 130/80 mmHg)
p < 0.0001
100
Patients achieving 24-h
ABPM goal* (%)
82.7
80
60
40
37.9
20
0
A10
T80/A10
(n = 58)
(n = 52)
Littlejohn et al. J Hypertens. 2008;26(suppl 1):S494; White et al. Blood Press Monit. 2010: In press.
30
Telmisartan + Amlodipine key
topics
BP efficacy of Telmisartan + Amlodipine in added risk patients
Safety & Tolerability of Temisartan + Amlodipine
31
Telmisartan + Amlodipine : Consistently High BP
reductions in added-risk Hypertensive Patients
Mean SBP reductions from
baseline (mmHg)
Diabetes
n = 320
n = 62
Obesity
(BMI ≥ 30 kg/m2)
n = 189
n = 175
Mild-moderate HTN: SBP ≥150 – <180 mmHg1*
*Mean baseline BP = 160,7/90,5 mmHg; **Mean baseline BP = 185.4/103.2 mmHg
***Diabetes, obesity (BMI  30kg/m2), and HTN
1TEAMSTA
2TEAMSTA
diabetes study (data on file; Boehringer Ingelheim)
severe HTN study (data on file, Boehringer Ingelheim)
Metabolic syndrome***
n = 189
n = 36
severe HTN: SBP ≥180 – <200 mmHg2**
T80/A10
32
Telmisartan + Amlodipine key topics
Safety & Tolerability of Telmisartan + Amlodipine
33
Renal Hyperfiltration Induced by
Amlodipine is reduced by Telmisartan
Amlodipine
L-type Ca
channels
Amlodipine + Telmisartan
L-type Ca
channels
Increased
Decreased
Glomerular pressure
and filtration
Glomerular pressure
and filtration
Peti-Peterdi; Abstract ESC 2010 (submitted).
34
Telmisartan + Amlodipine : Up to 90% less edema
compared to Amlodipine 10mg
p < 0.0001
p < 0.0001
20
Patients with peripheral
oedema (%)
17.8
15
–90%
–71%
10
5.2
5
1.7
0
A10
T40–80+A5
T40–80+A5–A10
(n = 124)
(n = 264)
(n = 543)
Littlejohn et al. J Clin Hypertens. 2009;11:207–213.
35
Why Telmisartan + Amlodipine,
because it
• Combines the best in class compounds –
unique PK/PD evidence – in a single-pill
combination
• Provides powerful and ‘smart’ BP
reductions and high 24h BP control
including patients with added-risk such as
diabetes and obese
• Has a safety & tolerability profile similar to36
37
38
About 50% of hypertensive patients remain uncontrolled
(NHANES) -> similar results from EUROSPIRE
Percentage of population
100
90
Failed to achieve BP control*
71
75
73
71
68
63
54 **
50
50 **
**
25
0
1976–
1980
1988–
1991
1991–
1994
1999–
2000
2001–
2002
2003–
2004
2005–
2006
2007–
2008
Year
* BP control defined as BP < 140/90 mmHg; BP < 130/80 mmHg for patients with diabetes or CKD; includes treated and
untreated patients, except ** (only treated patients)
Chobanian et al. Hypertension. 2003;42:1206–1252; Ong et al. Hypertension. 2007;49:69–75;
Ostchega et al. NCHS Data Brief. 2008;3:1–38; Egan et al. JAMA. 2010;303:2043–2050.
39
RATIONALE FOR THE USE OF FIXED-DOSE COMBINATIONS:
COMPLIANCE AND PERSISTENCE
 A single, once-daily pill simplifies the treatment
regimen compared with agents given as separate
pills
– Increases convenience for patients
– Reduces the pill burden
 Increased convenience and lower pill burden likely
to improve compliance to and persistence with
antihypertensive medications
– Overcomes a major barrier to effective BP control
 Likely to cost less than the individual components
prescribed separately
Neutel. In: Oparil and Weber, eds. Hypertension. Companion to Brenner & Rector’s The Kidney. 2nd
ed. Philadelphia: Elsevier Saunders, 2005. p. 5229
40
CCB + ARB :
The Synergies of Counter-Regulation (1)
CCB
 Arteriodilation
 Peripheral oedema
 Effective in low-renin patients
 Reduces cardiac ischaemia
BP
Synergistic
BP reduction
Complementary
clinical benefits
41 et al. Expert Opin Pharmacother. 2006;7:575–581;
Mistry
Sica. Drugs. 2002;62:443–462; Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.
CCB
 RAS activation
 No renal or CHF
benefits
41
THE CCBARB TARGETS TWO KEY BP
EFFECTOR PATHWAYS (1)
Sympathetic nervous system (SNS)
 SNS activity → noradrenaline binds to α1-adrenergic
receptors on vascular smooth muscle → vasoconstriction1
 SNS also stimulates renin secretion from the kidney,
thereby activating the RAS2
 CCBs inhibit SNS-induced vasoconstriction by blocking
influx of calcium ions (needed for contraction) through
voltage-gated calcium channels → vasodilation3,4
 Other effects of CCBs: natriuresis; inhibition of aldosterone
release; interference with angiotensin II-mediated
vasoconstriction4
1Grassi.
J Hypertens 2001;19:1713–16; 2Mancia and Grassi. http://www.sns-web.org/pages/advances/11/article.asp; 3Robertson and Robertson. In: Hardman
JG, Limbard JG, editors-in chief. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. 1996. p. 759–79
4Prisant. In: Oparil S, Weber MA, editors. Hypertension: Companion to Brenner & Rector’s The Kidney. 2nd ed. 2005. p. 683–704
42
THE CCBARB TARGETS TWO KEY BP
EFFECTOR PATHWAYS (2)
Renin angiotensin system (RAS)
 Release of renin catalyses conversion of
angiotensinogen into angiotensin I, which is
converted by ACE to angiotensin II →
– Vasoconstriction; increased aldosterone and sodium/water
retention; SNS activation
 ARBs block the effects of angiotensin II by binding to
AT1 receptors
– Arterial and venous dilation
– Reduced SNS activity
– Reduced secretion of aldosterone and increased secretion of
sodium and water
Mistry et al. Expert Opin Pharmacother 2006:7:575–81
43
Clinical Evidence With ARBs AFTER ONTARGET®
CV high risk
ONTARGET® trial programme
Heart failure
VALIANT
CHARM
Val-HeFT
ELITE II
Hypertension
MI and
stroke
LIFE
VALUE
Microalbuminuria
Atherosclerosis and
LVH
Endothelial
dysfunction
Remodelling
Ventricular dilation/
cognitive dysfunction
Macroproteinuria
Nephrotic
proteinuria
Risk factors:
hypertension, diabetes, obesity,
smoking, age
Dzau et al. Circulation. 2006;114:2850–2870; Dzau, Braunwald. Am Heart J. 1991;121:1244–1263;
Yusuf et al. Lancet. 2004;364:937–952; The ONTARGET Investigators. N Engl J Med. 2008;358:1547–1559.
.
ESRD
CHF/
secondary stroke
Cardio/
cerebrovascular
death
44
Telmisartan : Numerically better than Valsartan
Agent
Baseline BP
Telmisartan+Amlodipine
(all doses)1
153/102 mmHg
0
T40/A5
T40/A10
T80/A5
T80/A10
0
-5
Agent
Baseline BP
Valsartan with:2
5 mg amlodipine
10 mg amlodipine
153/99 mmHg
157/99 mmHg
V160/A5
V160A10
V320/A10
-16.2
-15.9
mmHg †
mmHg †
-5
-10
-15
-10
-15
-13.2
-15.5
-20
V320/A5
-19.3
-20
-19.6
-22.2
-25
* Indirect
SBP
-23.9
-25
SBP
comparisons: study design varied; †Placebo-corrected values
1.TWYNSTA™ [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc, 2009;
2. Exforge [prescribing information]. East Hanover, CJ: Novartis Pharmaceuticals Corporation, 2009.
45
Telmisartan + Amlodipine : up
to 87% of added-risk
hypertensive patients archive BP goal
BP goal rate (<140/90 mmHg)
after 8 weeks (%)
100
More moderate systolic HTN (baseline
BP 160.7/90.5 mmHg)2
More mild systolic HTN (baseline BP
153.2/101.7 mmHg)1
87,0
80
84,6
81,7
71,4
68,2
68,2
60
40
20
(n = 23)
(n = 320)
(n = 71)
(n = 198)
(n = 13)
(n = 198)
0
Diabetes
Obese
BMI ≥ 30kg/m2
* Presence of diabetes, obesity (BMI  30kg/m2), and HTN
1Factorial
design study (data on file; Boehringer Ingelheim Pharmaceuticals, Inc);
diabetes study (data on file, Boehringer Ingelheim)
2TEAMSTA
Metabolic
syndrome*
T80/A10
46
Telmisartan + Amlodipine : Comparable Safety & Tolerability
Profile of 80/5-10 and 40/5-10 combinations
100
Patients per 100 patient years
90
T40/A5-101,2
(n=1814)
T80/A5-101,2
(n=1008)
3,0
3,9
80
70
60
50
40
30
20
13,2 12,5
6,7
10
0
Drug related
AEs
AE = Adverse events
1. Neldam et al. ESH 2010 poster presentation (P-95)
2. Neldam et al. ESH 2010 poster presentation (P-90)
6,4
Peripheral
edema
2,4
AEs leading to
premature
discontinuation
3,4
Serious AEs
47