Transcript Document

Cardiovascular New Drug Update
C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS
Professor of Clinical Pharmacy and
Outcome Sciences
South Carolina College of Pharmacy
Professor of Family Medicine
Medical University of South Carolina
Charleston, South Carolina
[email protected]
Disclosure
• I am a consultant for Merck in the area of
outcomes research.
• I served on a formulary advisory board for
BMS and Pfizer for apixaban – Eliquis
FDA approved on 12-28-2012.
FDA Safety Update on Statins
• March 2, 2012 Monitoring Liver Enzymes
• Labels have been revised to remove the need
for routine periodic monitoring of liver
enzymes in patients taking statins. The labels
now recommend that liver enzyme tests
should be performed before starting statin
therapy and as clinically indicated thereafter.
FDA has concluded that serious liver injury
with statins is rare.
FDA Safety Update on Statins
• March 2, 2012 Adverse Event Information:
• Rare post-marketing reports of cognitive
impairment (e.g., memory loss, forgetfulness,
amnesia, memory impairment, confusion)
associated with statin use. These reported
symptoms are generally not serious and
reversible upon statin discontinuation, with
variable times to symptom onset (1 day to
years) and symptom resolution (median of 3
weeks).
FDA Safety Update on Statins
• March 2, 2012 Increases in glycosylated hemoglobin
(HbA1c) and fasting plasma glucose
• FDA’s review of the results from the Justification for the Use of Statins
in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin
(JUPITER) reported a 27% increase in investigator-reported diabetes
mellitus in rosuvastatin-treated patients compared to placebo-treated
patients. High-dose atorvastatin had also been associated with
worsening glycemic control in the Pravastatin or Atorvastatin Evaluation
and Infection Therapy – Thrombolysis In Myocardial Infarction 22
(PROVE-IT TIMI 22) sub study.
• FDA also reviewed the published medical literature. A meta-analysis by
Sattar et al. which included 13 statin trials with 91,140 participants,
reported that statin therapy was associated with a 9% increased risk for
incident diabetes (Absolute risk is about 1 in 100-150 patients)
• FDA continues to believe that the cardiovascular benefits of statins
outweigh these small increased risks.
• Cause and effect has not been established
Citalopram hydrobromide (Celexa)
FDA Safety Alert
• Patients at particular risk for developing
prolongation of the QT interval include
those with underlying heart conditions and
those who are predisposed to low levels of
potassium and magnesium in the blood.
• Studies have not shown a benefit in the
treatment of depression at doses higher
than 40 mg per day.
• Citalopram and sertraline are the
recommended agents of choice for
patients with depression and CVD
according to the AHA/APA
• Circulation 2008;118:1768-75
Citalopram hydrobromide (Celexa)
FDA Safety Alert
Additional Recommendations: 3-28-2012
• Citalopram is not recommended for use in patients with congenital
long QT syndrome, bradycardia, hypokalemia, or
hypomagnesaemia, recent acute myocardial infarction, or
uncompensated heart failure.
• Citalopram use is also not recommended in patients who are
taking other drugs that prolong the QT interval.
• The maximum recommended dose of citalopram is 20 mg per day
for patients with hepatic impairment, patients who are older than 60
years of age, patients who are CYP 2C19 poor metabolizers, or
patients who are taking concomitant cimetidine (Tagamet) or
another CYP2C19 inhibitor, because these factors lead to
increased blood levels of citalopram, increasing the risk of QT
interval prolongation and Torsade de Pointes.
Aliskiren (Tekturna) Safety Update
• December 20, 2011 - Novartis announced that following the
seventh interim review of data from the ALTITUDE study
with Rasilez®/Tekturna® (aliskiren), a decision to terminate
the trial has been taken on the recommendation of the
independent Data Monitoring Committee (DMC) overseeing
the trial. The trial involved 8606 patients with type 2
diabetes and renal impairment who are at high risk of
cardiovascular and renal events
• The DMC concluded that patients were unlikely to benefit
from treatment added on top of standard anti-hypertensives
(ACEI or ARB), and identified higher adverse events in
patients receiving Rasilez/Tekturna in addition to standard
of care in the trial. Specifically, in the trial arm in which
Rasilez/Tekturna was added to the standard of care there
was an increased incidence after 18-24 months of non-fatal
stroke, renal complications, hyperkalemia and hypotension
in this high-risk study population.
Aliskiren (Tekturna) Safety
Update Continued…
• As a precautionary measure, Novartis will
no longer promote Rasilez / Tekturnabased medicines for use in combination
with a therapy in the ACE or ARB classes.
Novartis is having discussions with the FDA
about these findings and the FDA has not
taken any specific action to date.
Aliskiren-containing Medications: Drug
Safety Communication - New Warning
and Contraindication
• 4/20/2012 RECOMMENDATION: Concomitant
use of aliskiren with ARBs or ACEIs in patients
with diabetes is contraindicated because of
the risk of renal impairment, hypotension, and
hyperkalemia. Avoid use of aliskiren with
ARBs or ACEIs in patients with renal
impairment where GFR < 60 mL/min. Patients
should not stop taking aliskiren without talking
to your healthcare professional. Stopping
aliskiren suddenly can cause problems if your
high blood pressure (hypertension) is not
treated.
Generic Clopidogrel is here
FDA Approvals May 17, 2012
• Brand Plavix
– clopidogrel bisulfate
$185.49/30
• Apotex Inc
• Aurobindo Pharma
• Generic wholesale
Ltd
cost
• Dr Reddys Labs Ltd
• $3.48 - $6.00/30
• Gate Pharma
WAC as of
• Mylan Pharma Inc
10/16/2012
• Roxane
• Sun Pharma Global
• Teva
• Torrent Pharma Ltd
Generic Atorvastatin–
The price is falling!
• May 29. 2012 we now have 5 new manufacturers
with FDA approval joining Dr Reddy’s and Watson
with more to come:
• Apotex, Mylan, Ranbaxy, Sandoz, Teva
Atorvastatin (Lipitor)
Brand
Generic
10mg
-39% LDL
$113.70
$4.35-5.66
20mg
-43%
$162.30
$6-7.66
40mg
-50%
$162.30
$6-7.66
80mg
-60%
$162.30
$6-7.66
• Cost is per 30 day supply WAC 10-16-2012
Dabigatran - Pradaxa
• A direct thrombin inhibitor indicated to
reduce the risk of stroke and systemic
embolism in patients with non-valvular atrial
fibrillation
• 75 mg and 150 mg capsules BID $253.00/60
• No need to monitor INR
• Not reversible with vitamin K or FFP
(consider factor concentrates or dialysis)
Dabigatran- Pradaxa
RE-LY (Randomized Evaluation of Long-term Anticoagulant
Therapy), a randomized trial comparing two blinded doses of
dabigatran (110 mg twice daily and 150 mg twice daily) with openlabel warfarin (dosed to target INR of 2 to 3) in 18,113 patients with
non-valvular, persistent, paroxysmal, or permanent atrial
fibrillation and one or more of the following additional risk factors:
(Mean CHADS2 Score 2.1)
• Previous stroke, transient ischemic attack (TIA), or systemic
embolism
• Left ventricular ejection fraction <40%
• Symptomatic heart failure, ≥ New York Heart Association Class 2
• Age ≥75 years
• Age ≥65 years and one of the following: diabetes mellitus,
coronary artery disease (CAD), or HBP
•The primary objective of this study was to determine if dabigatran
was non-inferior to warfarin in reducing the occurrence of the
composite endpoint, stroke (ischemic and hemorrhagic) and
systemic embolism.
Dabigatran- Pradaxa
Table 1: Event rates by INR time in range vs dabigatran 110 BID
and 150 mg BID
Event %/yr
Warf
n=6022
Warf Q 4
Warf Q 1-2
TTR < 53% TTR > 67%
Dabig 110
n=6015
Dabig 150
n=6076
Stroke* +
SEE
1.69
2.2
1.3
1.53
1.11**
NNT 173
Maj Bld
3.36
4.6
2.7
2.71**
3.11
MI
0.53
Na
Na
0.72
0.74**
NNH 476
Comp.
7.64
11.9
5.3
7.09
6.91
*"Stroke" includes hemorrhagic stroke, **stat. sig. vs warfarin in original report.
Comp = Stroke, systemic embolism, MI, PE, death, major bleeding. Warf 4th quartile = ITTR <
53.4%, 1st & 2nd quartile = ITTR > 67.1%.
N Engl J Med 2009; 361:1139-1151
Dabigatran- Pradaxa
Risk of extracranial and intracranial bleeding (% per year) by age
End point
Warfarin
(%)
Dabigatran 110
mg (%)
Dabigatran 150
mg (%)
P
Age <75
2.44
1.76
1.91
—
Age >75
3.44
4.10
4.68
0.001
NNH 81
Age <75
0.61
0.14
0.26
—
Age >75
1.00
0.37
0.41
0.28
Extracranial bleeding
(Mainly GI)
Intracranial bleeding
Circulation 2011;123:2363-2372
Dabigatran- Pradaxa
• The rates of adverse reactions leading to treatment
discontinuation in RE-LY were 21% for dabigatran
150 mg and 16% for warfarin. The most frequent
adverse reactions leading to discontinuation of
dabigatran were bleeding and gastrointestinal
events (i.e., dyspepsia, nausea, upper abdominal
pain, gastrointestinal hemorrhage, and diarrhea).
• NNH 20 patients
• Drug Interactions
• The concomitant use of dabigatran with P-gp
inducers (e.g., rifampin) reduces exposure to
dabigatran and should generally be avoided
• P-gp inhibitors ketoconazole, verapamil,
amiodarone, quinidine, and clarithromycin do
not require dose adjustments
Dabigatran- Pradaxa
ACCF/AHA/HRS 2011 Focused Update
Recommendation Class I
“Dabigatran is useful as an alternative to
warfarin for the prevention of stroke and
systemic thromboembolism in patients with
paroxysmal to permanent AF and risk factors
for stroke or systemic embolization who do not
have a prosthetic heart valve or
hemodynamically significant valve disease,
severe renal failure (creatinine clearance <15
mL/min), or advanced liver disease.” (Level of
Evidence: B)
• (Circulation. 2011;123:00-00 – on-line but in print
3-15-2011)
AT-9 Chest Guidelines
• For patients with AF, including those with
paroxysmal AF, who are at high risk of
stroke (e.g., CHADS 2 score >/= 2), we
recommend:
• oral anticoagulation rather than no
therapy (Grade 1A) , aspirin (75 mg to
325 mg once daily) (Grade 1B) , or
combination therapy with aspirin and
clopidogrel (Grade 1B).
• we suggest dabigatran 150 mg twice
daily rather than adjusted-dose VKA
therapy (target INR range, 2.0-3.0)
(Grade 2B)
Chest AT-9 (2/2012)
Dabigatran- Pradaxa
• AHA/ASA advisory on stroke prevention in atrial
fibrillation (Stroke 2012;
DOI:10.1161/STR.0b013e318266722a. Available at:
http://stroke.ahajournals.org)
• Warfarin, dabigatran, apixaban, and
rivaroxaban are all indicated for the prevention
of first and recurrent stroke in patients with
non valvular AF. "The selection of an agent
should be individualized on the basis of risk
factors, cost, tolerability, patient preference,
potential for drug interactions, and other
clinical characteristics, including time in INR
therapeutic range if the patient has been
taking warfarin."
Dabigatran- Pradaxa
• AHA/ASA advisory on stroke prevention
in atrial fibrillation (Stroke 2012)
• Dabigatran 150 mg twice daily is an
"efficacious alternative" to warfarin for the
prevention of first and recurrent stroke in
patients with non valvular AF and at least one
additional risk factor who have creatinine
clearance (CrCl) >30 mL/min.
• Use of dabigatran 75 mg twice daily may be
considered in patients with AF and at least
one additional risk factor who have a low
CrCl, in the range of 15 to 30 mL/min.
Dabigatran is not recommended in patients
with more severe renal failure (CrCl <15
mL/min).
Dabigatran- Pradaxa
• Converting from warfarin
• When converting patients from warfarin therap
to dabigatran, discontinue warfarin and start
dabigatran when the international normalized
ratio (INR) is below 2.0.
• Converting from dabigatran to warfarin,
adjust the starting time of warfarin based
on creatinine clearance as follows:
• For CrCl >50 mL/min, start warfarin 3 days
before discontinuing dabigatran.
• For CrCl 31-50 mL/min, start warfarin 2 days
before discontinuing dabigatran.
• For CrCl 15-30 mL/min, start warfarin 1 day
before discontinuing dabigatran.
Dabigatran- Pradaxa
• Management prior to surgery:
• CrCl ≥ 50 mL/min: Discontinue
dabigatran 1 to 2 days before
procedure
• CrCl < 50 mL/min: Discontinue
dabigatran 3 to 5 days before
procedure.
• Major procedures, spinal
puncture, spinal or epidural
catheter placement may require
discontinuation for a longer period
of time.
Dabigatran- Pradaxa
• DOSING: Recommended Dose for patients with
creatinine clearance (CrCl) >30 mL/min, the
recommended dose of dabigatran is 150 mg taken orally,
twice daily, with or without food. For patients with CrCl 1530 mL/min, or patients 75 years of age or older the
recommended dose is 75 mg twice daily
• Instruct patients to swallow the capsules whole.
Breaking, chewing, or emptying the contents of the
capsule can result in increased exposure.
• Pradaxa capsules will hydrolyze over time when
exposed to humidity, causing a breakdown of active
ingredient, and rendering the medication less effective.
Pradaxa is packaged in a 30-day supply bottle with a
desiccant cap or in unit-of-use blister packaging to
minimize product breakdown from moisture.
• (Use within 4 months of opening and keep in original
container)
Don't use dabigatran off-label
with mechanical valves
•
Primary-care practitioners may be putting the lives of
patients with prosthetic heart valves at risk by switching their
anticoagulation from warfarin to newer agents such as
dabigatran (Pradaxa, Boehringer Ingelheim), say Canadian
researchers. Dr Joel Price (University of Ottawa Heart
Institute, ON) and colleagues report the cases of two women
who had undergone valve replacement some years before
and had been faring well on warfarin; they were switched to
dabigatran and subsequently suffered valve thromboses.
•
RE-ALIGN—a phase 2 dose-finding trial with dabigatran in
patients with mechanical valves—is now under way,
employing doses ranging from 150 to 330 mg twice daily,
adjusted based on renal function and the results of the
Hemoclot (Aniara, West Chester, OH) assay.
– http://content.onlinejacc.org/article.aspx?articleID=1361772
Rivaroxaban – Xarelto
by Bayer HealthCare AG and Janssen
Pharmaceuticals
• Rivaroxaban exhibits a linear pharmacokinetic
relationship with a rapid onset of action, resulting in
maximal factor Xa inhibition in approximately 3 hours.
Maintenance of the anti–factor Xa effect lasted 8 to 12
hours, depending on the dose of rivaroxaban.
• Terminal half-life of rivaroxaban is approximately 9 hours
in adults and 12 hours in elderly patients (older than 65
years of age). Elimination of rivaroxaban occurs by
multiple routes: renal (one-third is excreted unchanged),
biliary/fecal, and hepatic (through CYP-450 3A4). Renal
function impairment may influence elevated plasma
concentrations and increased anti-Xa activity; therefore,
dose adjustments may be required
Rivaroxaban - Xarelto
• July 5, 2011 The FDA approved rivaroxaban a factor
Xa inhibitor indicated for the prophylaxis of deep vein
thrombosis (DVT) which may lead to pulmonary
embolism (PE) in patients undergoing knee or hip
replacement.
• The recommended dose of is 10 mg taken orally
once daily with or without food. The initial dose
should be taken at least 6 to 10 hours after surgery
once hemostasis has been established.
• For patients undergoing hip replacement
surgery, treatment duration of 35 days is
recommended.
• For patients undergoing knee replacement
surgery, treatment duration of 12 days is
recommended.
Rivaroxaban - Xarelto
• RECORD 1 (Hip) R=1.1% vs. E=3.9%,
RRR 71%, ARR 2.8%, NNT=36
• RECORD 2 (Hip) R=2.0% vs. E=8.4%,
RRR 76%, ARR 6.4%, NNT=16
• RECORD 3 (Knee) R=9.7% vs.
E=18.8%,
RRR 48%, ARR 9.1%, NNT=11
• RECORD 4 (Knee) US approved
dosing R=6.9% vs. E=10.1%, RRR
31%, ARR 3.19%, NNT=32
AT-9 Chest Guidelines
• In patients undergoing THA or TKA,
irrespective of the concomitant use of
an IPCD or length of treatment, we
suggest the use of LMWH in preference
to the other agents we have
recommended as alternatives:
fondaparinux, apixaban, dabigatran,
rivaroxaban, LDUH (all Grade 2B),
adjusted-dose VKA, or aspirin (all Grade
2C).
• AT-9 Chest Guidelines 2-2012
AT-9 Chest Guidelines
• “The best estimates suggest that five fewer
symptomatic DVT per 1,000 achieved with
rivaroxaban over LMWH will be offset by
nine more major bleeding events.
• In summary, based on moderate-quality
evidence, both the possibility of increased
major bleeding events and the availability of
long-term safety data for LMWH makes
LMWH more appealing than rivaroxaban in
spite of the inconvenience of subcutaneous
administration.”
• AT-9 Chest Guidelines 2-2012
Rivaroxaban - Xarelto
• Avoid concomitant administration of
rivaroxaban with combined P-gp and strong
CYP3A4 inhibitors (e.g., ketoconazole,
itraconazole, lopinavir/ritonavir, ritonavir,
indinavir/ritonavir, and conivaptan) which
cause significant increases in rivaroxaban
exposure that may increase bleeding risk.
• When clinical data suggest a change in
exposure is unlikely to affect bleeding risk (e.g.,
clarithromycin, erythromycin), no precautions
are necessary during co administration with
drugs that are combined P-gp and CYP3A4
inhibitors.
ROCKET-AF Trial
• The ROCKET AF study was a multicenter,
double-blind, randomized trial of once-daily
oral rivaroxaban 20 mg or 15 mg daily in
patients with a creatinine clearance of 30 to
49 ml per minute) compared with doseadjusted warfarin (INR 2-3) in moderate-tohigh-risk patients with non valvular AF. The
authors hypothesized that rivaroxaban is non
inferior to warfarin at preventing the
composite of stroke (ischemic and
hemorrhagic) and systemic embolism. The
14,264 enrolled patients (median age, 73;
40% women) had a mean CHADS2 score of
3.5; about half had a CHADS2 score of 4.
• N Engl J Med 2011;365:883-91.
ROCKET-AF Trial
• Median follow-up was 707 days.
• In the warfarin group, the overall mean
proportion of time in therapeutic international
normalized ratio range was 55%.
-N Engl J Med 2011;365:883-91.
• On Sept 9, 2011 the FDA Cardiovascular and
Renal Drugs Advisory Committee
recommended approval of rivaroxaban for the
prevention of stroke and systemic embolism
in patients with non-valvular atrial fibrillation
(AF) by a 9-2 vote.
• The FDA had expressed concern over the
low rate of desired INR’s)
ROCKET-AF Trial
N Egl J Med 2011;365:883-91.
Rivaroxaban
Warfarin
Hazard ratio
Outcome
(n=7081)
(n=7090)
(95% CI)
p
Primary end point,
1.71
2.16
0.79 (0.66-0.96)
<0.001
non inferiority
Primary end point, on
NNT 222
1.70
2.15
0.79 (0.65-0.95)
0.015
2.12
2.42
0.88 (0.74-1.03)
0.117
3.11
3.63
0.86 (0.74-0.99)
0.034
treatment superiority
Primary end point,
intention-to-treat
superiority
Vascular death,
stroke,
NNT 193
embolism
Hemorrhagic stroke
0.26
0.44
0.59 (0.37-0.93)
0.024
NNT 556
Ischemic stroke
1.34
1.42
0.94 (0.75-1.17)
0.581
Unknown stroke
0.06
0.10
0.65 (0.25-1.67)
0.366
ROCKET-AF Trial
N Engl J Med 2011;365:883-91.
Rivaroxaban
Warfarin
Hazard ratio
Outcome
(n=7081)
(n=7090)
(95% CI)
p
Major and non major
14.91
14.52
1.03 (0.96-1.11)
0.442
Major bleeding
3.60
3.45
1.04 (0.90-1.20)
0.576
>2 g/dL hemoglobin
2.77
2.26
1.22 (1.03-1.44)
NNH 197
0.019
Transfusion
1.65
1.32
1.25 (1.01-1.55)
NNH 304
0.044
Critical organ
0.82
1.18
0.69 (0.53-0.91)
NNT 278
0.007
0.24
0.48
0.50 (0.31-0.79)
NNT 455
0.003
0.49
0.74
0.67 (0.47-0.94)
NNT 400
0.019
bleeding
drop
bleeding
Bleeding causing
death
Intracranial
hemorrhage
Rivaroxaban - Xarelto
• Nonvalvular Atrial Fibrillation:
• For patients with CrCl >50 mL/min: 20 mg
orally, once daily with the evening meal
• For patients with CrCl 15 - 50 mL/min: 15 mg
orally, once daily with the evening meal
• Avoid use in patients with CrCl <15 mL/min
• The absolute bioavailability of rivaroxaban
at a dose of 20 mg in the fasted state is
approximately 66%. Co administration of
XARELTO with food increases the
bioavailability of the 20 mg dose (mean
AUC and Cmax increasing by 39% and
76% respectively with food). XARELTO 15
mg and 20 mg tablets should be taken with
the evening meal
Rivaroxaban - Xarelto
• Box Warning: “Discontinuing XARELTO
places patients at an increased risk of
thrombotic events. An increased rate of
stroke was observed following XARELTO
discontinuation in clinical trials in atrial
fibrillation patients. If anticoagulation with
XARELTO must be discontinued for a reason
other than pathological bleeding, consider
administering another anticoagulant”
• Rocket AF did not have a protocol for what
to do after the trial ended and the results
were not good
Switching Anticoagulants?
• Switching to XARELTO® from warfarin
• Discontinue warfarin and start XARELTO®
as soon as the INR is below 3.0 to avoid
periods of inadequate anticoagulation
• Switching from XARELTO® to warfarin
• No clinical trial data are available to guide
converting patients from XARELTO® to
warfarin. XARELTO® affects INR, so INR
measurements made during co
administration with warfarin may not be
useful for determining the appropriate dose
of warfarin. One approach is to discontinue
XARELTO® and begin both a parenteral
anticoagulant and warfarin at the time the
next dose of XARELTO® would have been
taken
Rivaroxaban - Xarelto
• Management prior to surgery
• Discontinue rivaroxaban at least
24 hours before surgery.
Canadian Cardiovascular
Society Atrial Fibrillation Guidelines
• We recommend that all patients with AF or AFL
(paroxysmal, persistent, or permanent), should be
stratified using a predictive index for stroke risk (e.g.,
CHADS2) and for the risk of bleeding (e.g., HAS-BLED),
and that most patients should receive either an OAC or
ASA (Strong Recommendation, High-Quality Evidence).
• We suggest, that when OAC therapy is indicated, most
patients should receive dabigatran, rivaroxaban, or
apixaban in preference to warfarin (Conditional
Recommendation, High-Quality Evidence).
• Practical tip. Among patients > 75 years and certainly
those > 80 years, dose reduction of the new OACs,
especially dabigatran, should be considered.
• Canadian Journal of Cardiology 28 (2012) 125–136
Canadian Cardiovascular
Society Atrial Fibrillation Guidelines
• For antithrombotic therapy of CKD patients,
therapy should relate to eGFR as follows:
• eGFR > 30 mL per minute: We recommend that suc
patients receive antithrombotic therapy according to
their CHADS2 score as detailed in recommendation
for patients for patients with normal renal function
(Strong Recommendation, High-Quality Evidence).
• eGFR 15-30 mL per minute and not on dialysis: We
suggest that such patients receive antithrombotic
therapy according to their CHADS2 score as for
patients with normal renal function. The preferred
agent for these patients is warfarin (Conditional
Recommendation, Low- Quality Evidence).
-Canadian Journal of Cardiology 28 (2012) 125–136
Rivaroxaban - Xarelto
• AHA/ASA advisory on stroke prevention in atrial
fibrillation (Stroke 2012;
DOI:10.1161/STR.0b013e318266722a. Available at:
http://stroke.ahajournals.org)
• In patients with non valvular AF who are at moderate
to high risk of stroke (prior history of transient ischemic
attack [TIA], stroke, or systemic embolization or more
than two additional risk factors), rivaroxaban 20
mg/day "is reasonable" as an alternative to warfarin.
• In patients with renal impairment and non valvular AF
who are at moderate to high risk of stroke (prior
history of TIA, stroke, or systemic embolization or
more than two additional risk factors), with a CrCl of
15 to 50 mL/min, 15 mg of rivaroxaban daily may be
considered, but its safety and efficacy have not been
established. Rivaroxaban should not be used if the
CrCl is <15 mL/min.
Rivaroxaban for Symptomatic Venous
Thromboembolism: Einstein DVT
• Open-label, randomized, event-driven, non inferiority study
that compared oral rivaroxaban alone (15 mg twice daily
for 3 weeks, followed by 20 mg once daily) with
subcutaneous enoxaparin followed by a vitamin K
antagonist (either warfarin or acenocoumarol) for 3 (12%),
6 (63%), or 12 (25%) months in patients with acute,
symptomatic DVT.
– Patients randomized to VKA had an unadjusted mean
percentage of time in the INR target range of 2.0 to 3.0
of 58% in EINSTEIN DVT study
• In parallel, we carried out a double-blind, randomized,
event-driven superiority study that compared rivaroxaban
alone (20 mg once daily) with placebo for an additional 6
or 12 months in patients who had completed 6 to 12
months of treatment for venous thromboembolism.
– N Engl J Med 2010;363:2499-510.
* Intent to treat population
N Engl J Med 2010;363:2499-510.
EINSTEIN DVT Trial
Endpoint
Xarelto
N=1731 (%)
Enox + Warf
N=1718 (%)
HR (95% CI)
Primary composite (DVT or
nonfatal or fatal pulmonary
embolism
36 (2.1%)
51 (3.0%)
0.68
(0.44-1.04)
Death (PE)
1 (<0.1%)
0 (0%)
Death (PE can not be excluded)
3 (0.2%)
6 (0.3%)
Symptomatic recurrent PE + DVT
1 (<0.1%)
0 (0%)
Symptomatic recurrent PE only
20 (1.2%)
18 (1.0%)
Symptomatic recurrent DVT only
14 (0.8%)
28 (1.6%)
Intent to treat population
N Engl J Med 2010;363:2499-510.
Rivaroxaban for Symptomatic Venous
Thromboembolism: Einstein DVT
• In parallel, we carried out a double-blind,
randomized, event-driven superiority study
that compared rivaroxaban alone (20 mg once
daily) with placebo for an additional 6 or 12
months in patients who had completed 6 to 12
months of treatment for venous
thromboembolism.
• In the continued-treatment study, which
included 602 patients in the rivaroxaban group
and 594 in the placebo group, rivaroxaban had
superior efficacy (8 events [1.3%], vs. 42 with
placebo [7.1%]; hazard ratio, 0.18; 95% CI,
0.09 to 0.39; P<0.001).
N Engl J Med 2010;363:2499-510
Rivaroxaban for Symptomatic Venous
Thromboembolism: Einstein DVT
• The principal safety outcome was
major bleeding or clinically relevant
non major bleeding in the initialtreatment study
• The principal safety outcome
occurred in 8.1% of the patients in
each group.
• In the long term follow=up period,
Four patients in the rivaroxaban
group had nonfatal major bleeding
(0.7%), versus none in the
placebo group (P = 0.11).
N Engl J Med 2010;363:2499-510
Rivaroxaban for the Treatment of
Symptomatic Pulmonary Embolism
• A randomized, open-label, event-driven, non
inferiority trial involving 4832 patients who had
acute symptomatic pulmonary embolism with or
without deep-vein thrombosis, we compared
rivaroxaban (15 mg twice daily for 3 weeks,
followed by 20 mg once daily) with standard
therapy with enoxaparin followed by an adjusteddose vitamin K antagonist for 3 (5%), 6 (57%), or
12 (37%) months.
– Patients randomized to VKA had an unadjusted
mean percentage of time in the INR target
range of 2.0 to 3.0 of 60% in EINSTEIN PE
study.
N Engl J Med 2012; 366:1287-1297
EINSTEIN PE Trial
Endpoint
Xarelto
N=2419 (%)
Enox + Warf
N=2413 (%)
HR (95% CI)
Primary composite endpoint
50 (2.1%)
44 (1.8%)
1.12
(0.75-1.68)
Death (PE)
3 (0.1%)
1 (<0.1%)
Death (PE cannot be excluded)
8 (0.3%)
6 (0.2%)
Symptomatic recurrent PE +
DVT
0 (0%)
2 (<0.1%)
Symptomatic recurrent PE only
23 (1.0%)
20 (0.8%)
Symptomatic recurrent DVT
only
18 (0.7%)
17 (0.7%)
Intent to treat population
N Engl J Med 2012; 366:1287-1297
N Engl J Med 2012; 366:1287-129
Rivaroxaban for the Treatment of
Symptomatic Pulmonary Embolism
• The principal safety outcome occurred in 10.3% of
patients in the rivaroxaban group and 11.4% of
those in the standard therapy group (hazard ratio,
0.90; 95% CI, 0.76 to 1.07; P = 0.23).
• Major bleeding was observed in 26 patients (1.1%)
in the rivaroxaban group and 52 patients (2.2%) in
the standard-therapy group (hazard ratio, 0.49;
95% CI, 0.31 to 0.79; P = 0.003).
• Rates of other adverse events were similar in the
two groups.
N Engl J Med 2012; 366:1287-1297
Rivaroxaban - Xarelto
• Nov 2, 2012 FDA approval for treatment of
DVT and PE based upon EINSTIEN Trials
non-inferior to warfarin (INR 2-3) and no
difference in bleeding rates
• Treatment of DVT, PE, and Reduction in the
Risk of Recurrence of DVT and of PE: 15
mg orally twice daily with food for the first 21
days for the initial treatment of acute DVT or
PE. After the initial treatment period, 20 mg
orally once daily with food for the remaining
treatment and the long-term reduction in the
risk of recurrence of DVT and of PE
Apixaban – Eliquis by
BMS/Pfizer
• Apixaban is a factor Xa inhibitor
anticoagulant indicated to reduce the risk
of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation.
• 1-P priority FDA approval 12-28-2012
• Available as a 2.5 and 5 mg tablet
• The recommended dose is 5 mg orally
twice daily. In patients with at least 2 of
the following characteristics: age > 80
years, body weight <60 kg, or serum
creatinine >1.5 mg/dL, the
recommended dose is 2.5 mg orally
twice daily
Apixaban-Eliquis
Apixaban is a direct-acting, reversible oral inhibitor of factor Xa, which
is responsible for the conversion of prothrombin (factor II) to thrombin
(factor IIa), ultimately leading to thrombus formation and clotting
• High affinity and high degree of selectivity for factor Xa
• Produces concentration-dependent anticoagulation
• No formation of reactive intermediates
• No organ toxicity or LFT abnormalities in chronic toxicology
studies
• Low likelihood of drug interactions or QTc prolongation
• Good oral bioavailability
• No food effect
• Balanced elimination (~25% renal)
• Apixaban produces several metabolites via CYP3A4-dependent
mechanisms. O-demethyl apixaban sulfate, a nonreactive
metabolite, is the primary metabolite produced; therefore, the
potential for apixaban to form reactive metabolites is expected to
be minimal
• Half-life ~12 hrs
Apixaban – Eliquis
• Apixaban should be discontinued at least 48
hours prior to elective surgery or invasive
procedures with a moderate or high risk of
unacceptable or clinically significant bleeding.
Apixaban should be discontinued at least 24
hours prior to elective surgery or invasive
procedures with a low risk of bleeding or where
the bleeding would be non-critical in location and
easily controlled.
Apixaban - Eliquis
• Switching from warfarin to Apixaban: Warfarin
should be discontinued and apixaban started
when the international normalized ratio (INR) is
below 2.0.
• Switching from Apixaban to warfarin: Apixaban
affects INR, so that INR measurements during
coadministration with warfarin may not be useful
for determining the appropriate dose of warfarin.
If continuous anticoagulation is necessary,
discontinue apixaban and begin both a
parenteral anticoagulant and warfarin at the time
the next dose of apixaban would have been
taken, discontinuing the parenteral anticoagulant
when INR reaches an acceptable range.
Apixaban-Eliquis
• Box Warning:”DISCONTINUING ELIQUIS IN
PATIENTS WITHOUT ADEQUATE
CONTINUOUS ANTICOAGULATION
INCREASES RISK OF STROKE”
• Drug Interactions
• Strong dual inhibitors of CYP3A4 and Pgp increase blood levels of apixaban:
Reduce apixaban dose to 2.5 mg or avoid
concomitant use
• Simultaneous use of strong inducers of
CYP3A4 and P-gp reduces blood levels of
apixaban: Avoid concomitant use
Apixaban - Eliquis
• In healthy subjects, administration of activated
charcoal 2 and 6 hours after ingestion of a 20mg dose of apixaban reduced mean apixaban
AUC by 50% and 27%, respectively. Mean
apparent half-life of apixaban decreased from
13.4 hours when apixaban was administered
alone to 5.3 hours and 4.9 hours, respectively,
when activated charcoal was administered 2 and
6 hours after apixaban, indicating that charcoal
blocked the continued absorption of apixaban
from the gut
AVERROES Trial
• 5599 patients with atrial fibrillation who were at
increased risk for stroke and for whom vitamin K
antagonist therapy was unsuitable to receive apixaban
(at a dose of 5 mg twice daily) or aspirin (81 to 324 mg
per day), to determine whether apixaban was
superior.
• The trial was stopped early with a mean follow up
period of 1.1 years. because of a clear benefit in favor
of apixaban.
• The primary outcome was the occurrence of stroke or
systemic embolism.
– N Engl J Med 2011;364:806-17.
AVERROES: Primary and secondary end
points
Outcomes
Apixaban Aspirin
(n=2809) (n=2791)
Relative risk
(95% CI)
Stroke or systemic
embolic event
1.6
0.46 (0.33–0.64)
Stroke, embolic event,
MI, or vascular death
4.1
•MI
0.7
0.8
0.85 (0.48–1.50)
•Vascular death
2.5
2.9
0.86 (0.64–1.16)
Cardiovascular
hospitalizations
11.8
14.9
0.79 (0.68–0.91)
Total death
3.4
3.6
ARR 2.0/NNT 50
6.2
0.66 (0.53–0.83)
ARR 2.1/NNT 48
ARR 3.1/NNT 33
4.4
Connolly S. European Society of Cardiology 2010 Congress;
August 31, 2010; Stockholm, Sweden.
0.79 (0.62–1.02)
AVERROES: Bleeding events
Outcomes
Apixaban Aspirin
(n=2809) (n=2791)
Relative risk
(95% CI)
Major bleeding
1.4
1.2
1.14 (0.74–1.75)
Clinical relevant
nonmajor bleeding
3.0
2.6
1.18 (0.88–1.58)
Minor bleeding
5.2
4.1
1.27 (1.01–1.61)
Fatal bleeding
0.1
0.1
0.84 (0.26–2.75)
Intracranial
0.4
0.3
1.09 (0.50–2.39)
Connolly S. European Society of Cardiology 2010 Congress;
August 31, 2010; Stockholm, Sweden.
Atrial Fibrillation with at Least One
Additional Risk Factor for Stroke
Inclusion risk factors
Age ≥ 75 years
Prior stroke, TIA or SE
HF or LVEF ≤ 40%
Diabetes mellitus
Hypertension
Mean CHADS 2 Score 2.1
Randomize
double blind,
double dummy
(n = 18,201)
Apixaban 5 mg oral twice daily
(2.5 mg BID in selected patients IE. ≥ 80
years, body weight ≤ 60 kg, serum
creatinine ≥ 1.5 mg/dL )
Exclusion
 Mechanical prosthetic valve
 Severe renal insufficiency
 Need for aspirin plus
thienopyridine
Warfarin
(target INR 2-3)
Warfarin/warfarin placebo adjusted by INR/sham INR
based on encrypted point-of-care testing device
Primary outcome: stroke or systemic embolism
Hierarchical testing: non-inferiority for primary outcome, superiority for
primary outcome, major bleeding, death
N Engl J Med 2011;365:981-92.
Apixaban and Warfarin Dosing
• Apixaban (or matching placebo) was dosed at 5 mg twice daily,
or 2.5 mg twice daily for a subset of patients with 2 or more of
the following criteria: age ≥ 80 years, body weight ≤ 60 kg,
serum creatinine ≥ 1.5 mg/dL (133 µmol/L).
• Warfarin (or matching placebo) was dosed guided by blinded
encrypted INR point-of-care device, with target INR of 2.0–3.0.
N Engl J Med 2011;365:981-92
ARISTOTLE Main Trial Results (Mean 1.8 yrs)
Stroke or systemic embolism
ISTH major bleeding
International Society of Thrombosis and Hemostasis
21% RRR
Apixaban 212 patients, 1.27% per year
Warfarin 265 patients, 1.60% per year
HR 0.79 (95% CI, 0.66–0.95); P=0.011
ARR 0.33% NNT 303
31% RRR
Apixaban 327 patients, 2.13% per year
Warfarin 462 patients, 3.09% per year
HR 0.69 (95% CI, 0.60–0.80); P<0.001
ARR 0.96% NNT 105
Median TTR 66%
N Engl J Med 2011;365:981-92.
Summary
Treatment with apixaban as compared to warfarin in patients
with AF and at least one additional risk factor for stroke:
• Reduces stroke and systemic embolism by 21% (p=0.01)
ARR 0.33%/NNT 303
• Reduces major bleeding by 31% (p<0.001)
ARR 0.96%/NNT 105
• Reduces mortality by 11% (p=0.047) ARR 0.42%/NNT 238
with consistent effects across all major subgroups and with
fewer study drug discontinuations on apixaban than on
warfarin, consistent with good tolerability.
N Engl J Med 2011;365:981-92
Apixaban-Eliquis
• . Available at: http://stroke.ahajournals.org) AHA/ASA
advisory on stroke prevention in atrial fibrillation
(Stroke 2012; DOI:10.1161/STR.0b013e318266722a
• Apixaban 5 mg twice daily is an "efficacious alternative" to
aspirin in patients with nonvalvular AF deemed unsuitable for
vitamin-K-antagonist therapy who have at least one additional
risk factor and no more than one of the following
characteristics: age >80 years, weight <60 kg, or serum
creatinine >1.5 mg/dL.
• Apixaban 2.5 mg twice daily may be considered as an
alternative to aspirin in patients with nonvalvular AF deemed
unsuitable for vitamin-K-antagonist therapy who have at least
one additional risk factor and more than two of the following
criteria: age >80 years, weight <60 kg, or serum creatinine
>1.5 mg/dL.
Is the patient a good candidate for a
new anticoagulant? (CRABI)
• C => Good prescription coverage?
• R => Normal renal function?
• A => Are you an early adopter willing to take
a new drug with one large trial in AF?
• B => No history of GI bleeding?
• I => For patients on warfarin, has there been
INR instability requiring frequent dose
changes?
– Seth D Bilazarian MD, Private practice
blog on theheart.org (9/2012)
Ticagrelor – Brilinta
by Astra Zeneca
• Indicated to reduce the rate of thrombotic
cardiovascular events in patients with acute
coronary syndrome (ACS) (unstable angina, nonST elevation myocardial infarction, or ST
elevation myocardial infarction).
• Shown to reduce the rate of a combined
endpoint of cardiovascular death, myocardial
infarction, or stroke compared to clopidogrel.
The difference between treatments was driven
by CV death and MI with no difference in
stroke.
• In patients treated with PCI, it also reduces the
rate of stent thrombosis.
Ticagrelor – Brilinta
by Astra Zeneca
• 90 mg tablets Loading dose 180
mg, then 90 mg BID
• $217.20 per month WAC
Ticagrelor - Brilinta
• Ticagrelor and its major metabolite
reversibly interact with the platelet P2Y12
ADP-receptor to prevent signal transduction
and platelet activation. Ticagrelor and its
active metabolite are approximately
equipotent.
• Transitioning from clopidogrel to ticagrelor
resulted in an absolute inhibition of platelet
inhibition (IPA) increase of 26.4% and from
ticagrelor to clopidogrel resulted in an
absolute IPA decrease of 24.5%. Patients
can be transitioned from clopidogrel to
ticagrelor without interruption of antiplatelet
effect.
Mean inhibition of platelet aggregation (±SE) following single
oral doses of placebo, 180 mg ticagrelor, or 600 mg clopidogrel
Ticagrelor - Brilinta
Effects of Other Drugs on Ticagrelor
• CYP3A4 is the major enzyme responsible for ticagrelor
metabolism and the formation of its major active
metabolite.
– Strong CYP3A inhibitors (e.g., atazanavir,
clarithromycin, indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin and voriconazole) substantially increase
ticagrelor exposure and are not recommended
– Moderate CYP3A inhibitors have lesser effects (e.g.,
diltiazem and verapamil) and do not require a dosage
adjustment
– CYP3A inducers (e.g., rifampin, dexamethasone,
phenytoin, carbamazepine, and phenobarbital)
substantially reduce ticagrelor blood levels and are not
recommended
Ticagrelor - Brilinta
Effects of Ticagrelor on Other Medications:
• Patients receiving more than 40 mg per day of
simvastatin or lovastatin may be at increased risk
of statin-related adverse effects.
• Monitor digoxin levels with initiation of or any
change in ticagrelor because of P-glycoprotein
transporter inhibition
• Concomitant Aspirin Maintenance Dose: In
PLATO, use of ticagrelor with maintenance doses
of aspirin above 100 mg decreased the
effectiveness of ticagrelor. Therefore, after the
initial loading dose of aspirin (usually 325 mg), use
ticagrelor with a maintenance dose of aspirin of
75-100 mg
Ticagrelor – Brilinta
N Engl J Med 2009;361:1045-57
• PLATO Trial, a randomized double-blind study
comparing ticagrelor (180 mg LD then 90 mg
BID)(N=9333) to clopidogrel (300mg LD then 75 mg
QD) (N=9291), both given in combination with
aspirin (75-100 mg QD but higher doses were
allowed per investigator) and other standard therapy,
in patients with acute coronary syndromes (ACS).
Patients were treated for at least 6 months and for
up to 12 months.
– Patients were predominantly male (72%) and
Caucasian (92%). About 43% of patients were
>65 years and 15% were >75 years.
– Primary endpoint was the composite of first
occurrence of cardiovascular death, non-fatal MI
(excluding silent MI), or non-fatal stroke. The
components were assessed as secondary
endpoints
– Median exposure to study drug was 277 days
Ticagrelor – Brilinta
N Engl J Med 2009;361:1045-57
Endpoint
Ticagrelor
N=9333
Clopidogrel
N=9291
Hazard Ratio
(95% CI)
P-value
ARR/NNT
Primary Composite
(CV death, MI, CVA)
9.8%
11.7%
0.84
(0.77-0.92)
0.0003
1.9%/53
CV death
4.0%
5.1%
0.79
(0.69-0.91)
0.0013
1.1%/91
MI
5.8%
6.9%
0.84
(0.75-0.95)
0.0045
1.1%/91
Stroke
1.5%
1.3%
1.17
(0.91-1.52)
0.22
All cause mortality
4.5%
5.9%
0.78
(0.69-0.89)
0.0003
1.4%/72
In-stent thrombosis
(11,289 pts with
PCI/stenting)
1.3%
1.9%
0.67
(0.50-0.91)
0.0091
0.6%/167
Secondary Endpoints
Ticagrelor – Brilinta
N Engl J Med 2009;361:1045-57.
• No significant difference in the rates of major
bleeding was found between the ticagrelor and
clopidogrel groups (11.6% and 11.2%, respectively;
P = 0.43)
• Ticagrelor was associated with a higher rate of
major bleeding not related to coronary-artery bypass
grafting (4.5% vs. 3.8%, P = 0.03, ARI = 0.7%, NNH
= 143) including more instances of fatal intracranial
bleeding and fewer of fatal bleeding of other types.
• In a genetic sub study of PLATO (n=10,285), the
effects of ticagrelor compared to clopidogrel on
thrombotic events and bleeding were not
significantly affected by CYP2C19 genotype.
PLATO: CV Death, MI, Stroke by maintenance
aspirin dose in the US and outside the US
PLATO Trial: ticagrelor compared with
clopidogrel and who underwent CABG
• In a sub-group of 1,261 patients with CABG performed within 7
days after stopping study drug, reviewers blinded to treatment
assignment classified causes of death.
• Numerically more vascular deaths occurred in the clopidogrel
versus the ticagrelor group related to myocardial infarction (14
vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death
(9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2).
• Clopidogrel was also associated with an excess of nonvascular
deaths related to infection (8 vs. 2). Among factors directly
causing or contributing to death, bleeding and infections were
more common in the clopidogrel group compared with the
ticagrelor group (infections: 16 vs. 6, p <0.05, and bleeding:
27 vs. 9, p <0.01, for clopidogrel and ticagrelor, respectively).
– http://dx.doi.org/10.1016/j.jacc.2012.07.021
Ticagrelor – Brilinta
N Engl J Med 2009;361:1045-57
Ticagrelor – Brilinta
• Dyspnea was usually mild to moderate in intensity and
often resolved during continued treatment. If a patient
develops new, prolonged, or worsened dyspnea during
treatment with ticagrelor, exclude underlying diseases that
may require treatment. If dyspnea is determined to be
related to ticagrelor, no specific treatment is required;
continue ticagrelor without interruption.
• Although the mechanism of dyspnea remains unknown, it
appears to be related to adenosine-mediated stimulation of
pulmonary C fibers. We do know that ticagrelor inhibits
adenosine uptake by erythrocytes.
• Given the frequency of dyspnea as a side effect, with
reports ranging from 6% to 38.6%, it may affect long-term
compliance if the agent is to be used routinely. For
clinicians, it could be problematic during the recovery
phase of ACS, because the presence of dyspnea could be
confused with an angina equivalent, leading to further
testing to exclude ischemia only to ascertain that it is
produced by the administration of ticagrelor.
Ticagrelor – Brilinta
DOSAGE AND ADMINISTRATION:
• Initiate ticagrelor treatment with a 180 mg (two
90 mg tablets) loading dose and continue
treatment with 90 mg twice daily with or without
food
• After the initial loading dose of aspirin (usually
325 mg), use ticagrelor with a daily
maintenance dose of aspirin of 75-100 mg
(typically 81mg)
COST: $7.24 per day or $217.20 per month WAC
AT-9 Chest Guidelines
For patients in the first year after an ACS who
have not undergone percutaneous coronary
intervention (PCI):
• We recommend dual antiplatelet therapy
(ticagrelor 90 mg twice daily plus low-dose
aspirin 75-100 mg daily or clopidogrel 75 mg
daily plus low-dose aspirin 75-100 mg daily)
over single antiplatelet therapy (Grade 1B).
• We suggest ticagrelor 90 mg daily plus low
dose aspirin over clopidogrel 75 mg daily plus
low-dose aspirin (Grade 2B) .
– Chest AT-9 Feb 2012
AT-9 Chest Guidelines
For patients in the first year after an ACS who have
undergone PCI with stent placement:
• We recommend dual antiplatelet therapy (ticagrelor
90 mg twice daily plus low-dose aspirin 75-100 mg
daily, clopidogrel 75 mg daily plus low-dose aspirin,
or prasugrel 10 mg daily plus low-dose aspirin over
single antiplatelet therapy) (Grade 1B).
• We suggest ticagrelor 90 mg twice daily plus lowdose aspirin over clopidogrel 75 mg daily plus lowdose aspirin (Grade 2B).
– Evidence suggests that prasugrel results in no
benefit or net harm in patients with a body
weight of , <60 kg, age . >75 years, or with a
previous stroke/transient ischemic attack.
– Chest AT-9 Feb 2012
ADA 2012 Clinical Practice
Recommendations (Diabetes
Care 2012;35: S11-S63)
• “Growing evidence suggests that there is
an association between increase in sleeptime blood pressure and incidence of CVD
events. A recent RCT of 448 participants
with type 2 diabetes and hypertension
demonstrated reduced cardiovascular
events and mortality with median follow-up
of 5.4 years if at least one antihypertensive
medication was given at bedtime.”
• “Administer one or more antihypertensive
medications at bedtime. (A)”
Influence of Time of Day of Blood Pressure–
Lowering Treatment on Cardiovascular Risk in
Hypertensive Patients with Type 2 Diabetes
Diabetes Care 2011; 34:1270-76
• A prospective, randomized, single study center in Spain,
open-label, blinded end point trial on 448 hypertensive
patients with type 2 diabetes, 255 men/193 women, mean
age 62.5 years, randomized to ingest all their prescribed
hypertension medications upon awakening or 1 or more of
them at bedtime.
• Ambulatory blood pressure was measured for 48 hrs at
baseline and again annually or even more frequently
(quarterly) after adjustments in treatment.
• The mean follow-up was 5.4 years.
• This was a subset of the original MAPEC Trial in 2156
hypertensive subjects from Spain (Chronobiology
International 2010; 27(8): 1629–1651)
Influence of Time of Day of Blood Pressure–Lowering
Treatment on Cardiovascular Risk in Hypertensive
Patients with Type 2 Diabetes
(Diabetes Care 2011; 34:1270-76)
• Results: patients ingesting one or more
hypertension medications at bedtime showed a
significantly lower cardiovascular risk (adjusted by
age and sex) than subjects ingesting all medications
upon awakening (hazard ratio 0.33 [95% CI 0.21–
0.54]; P , 0.001).
• The difference between groups in the adjusted risk
of major events (cardiovascular death, myocardial
infarction, and stroke) was also statistically
significant (0.25 [0.10–0.61]; P = 0.003).
• There was a significant 12% cardiovascular risk
reduction per each 5 mmHg decrease in asleep
systolic blood pressure during follow-up (P , 0.001).
Dronedarone – Multaq
by Sanofi Aventis
• Indicated to reduce the risk of
cardiovascular hospitalization in patients
with paroxysmal or persistent atrial
fibrillation (AF) or atrial flutter (AFL), with
a recent episode of AF/AFL and
associated cardiovascular risk factors.
• Dose 400 mg tablets BID with food
$297.00/60
Dronedarone - Multaq
ATHENA was a double blind, and
randomized placebo-controlled study of
dronedarone in 4628 patients with a recent
history of AF/AFL who were in sinus rhythm
or who were to be converted to sinus rhythm.
The objective of the study was to determine
whether dronedarone could delay death from any
cause or hospitalization for cardiovascular
reasons.
Subjects were randomized and treated for up to 30
months (median follow-up: 22 months) with either
MULTAQ 400 mg twice daily (2301 patients) or
placebo (2327 patients), in addition to conventional
therapy for cardiovascular diseases that included
beta-blockers (71%), ACE inhibitors or angiotensin
II receptor blockers (ARBs)(69%), digoxin (14%),
calcium antagonists (14%), statins (39%), oral
anticoagulants (60%), aspirin (44%), other chronic
antiplatelet therapy (6%) and diuretics (54%).
Dronedarone - Multaq
ATHENA Results:
• Primary endpoint (median follow up
22 months)
• Cardiovascular hospitalization or death
from any cause 913 (39.2%) placebo vs.
727 (31.6%) dronedarone HR 0.76 or
24% RRR, 7.6% ARR, NNT=14,
p<0.0001
• Components of the endpoint (as first
event)
• Cardiovascular hospitalization 856 (36.8%)
placebo vs. 669 (29.1%) dronedarone
• Death from any cause 57 (2.4%) placebo vs.
58 (2.5%) dronedarone
Dronedarone - Multaq
ANDROMEDA Study (Increased Mortality in Patients
with Severe Heart Failure)
• Patients recently hospitalized with symptomatic
heart failure and severe left ventricular systolic
dysfunction were randomized to either MULTAQ
400 mg twice daily or matching placebo, with a
primary composite end point of all-cause mortality
or hospitalization for heart failure.
•
After enrollment of 627 of 1000 planned patients
(310 and 317 in the dronedarone and placebo
groups, respectively), and a median follow-up of 63
days, the trial was terminated because of excess
mortality in the dronedarone group. Twenty-five
(25) patients in the dronedarone group (8.1%)
versus 12 patients in the placebo group (3.8%) had
died, hazard ratio 2.13; 95% CI: 1.07 to 4.25;
p=0.027. ARI 4.3%, NNH = 26.
Dronedarone - Multaq
BOX WARNING: HEART FAILURE
• MULTAQ is contraindicated in patients with NYHA
Class IV heart failure, or NYHA Class II - III heart failure
with a recent decompensation requiring hospitalization
or referral to a specialized heart failure clinic
• Contraindications:
• Second- or third-degree atrioventricular (AV) block
or sick sinus syndrome (except when used in
conjunction with a functioning pacemaker)
• Bradycardia less than 50 bpm
• Concomitant use of strong CYP 3A inhibitors, such
as ketoconazole, itraconazole, voriconazole,
cyclosporine, telithromycin, clarithromycin,
nefazodone, and ritonavir
• Concomitant use of drugs or herbal products that
prolong the QT interval and might increase the risk
of Torsade de Pointes, such as phenothiazine antipsychotics, tricyclic antidepressants, certain oral
macrolide antibiotics, and Class I and III
antiarrhythmics
Dronedarone - Multaq
• DIONYSOS Trial evaluating the efficacy and
safety of dronedarone versus amiodarone for the
maintenance of sinus rhythm in 504 patients with
persistent Atrial Fibrillation (AF) for a short
treatment duration (mean follow up of 7 months).
• AF recurrence or premature drug
discontinuation for intolerance or lack of
efficacy). There were 184 patients (73.9%) who
reached the primary endpoint in the
dronedarone arm as compared to 141 (55.3%)
in the amiodarone arm (p<0.001). In the
primary endpoint, atrial fibrillation after
electrical cardioversion occurred in 36.5% of
patients in the dronedarone arm vs. 24.3 % of
patients in the amiodarone arm.
• Less thyroid and neurological adverse effects
with dronedarone but more diarrhea, nausea,
and vomiting
Dronedarone - Multaq
• January 14, 2011 Multaq (dronedarone) – FDA
Drug Safety Communication: Risk of Severe Liver
Injury The FDA has received several case reports of
hepatocellular liver injury and hepatic failure in
patients treated with dronedarone, including two postmarketing reports of acute hepatic failure requiring
transplantation.
• February 8, 2011 FDA Drug Watch List Dronedarone hydrochloride (Multaq, Sanofi-Aventis)
Drug interaction with warfarin (increased
anticoagulant effect)
• Drug Interactions:
• Dronedarone is metabolized primarily by CYP 3A
and is a moderate inhibitor of CYP 3A and CYP
2D6. Dronedarone's blood levels can therefore be
affected by inhibitors and inducers of CYP 3A, and
dronedarone can interact with drugs that are
substrates of CYP 3A and CYP 2D6.
Dronedarone - Multaq
Recommendation for Rate Control During Atrial Fibrillation
• 2011 Focused Update Recommendation Comments Class
III–No Benefit
• Treatment to achieve strict rate control of heart rate (<80 bpm
at rest or <110 bpm during a 6-minute walk) is not beneficial
compared to achieving a resting heart rate <110 bpm in
patients with persistent AF who have stable ventricular
function (left ventricular ejection fraction <0.40) and no or
acceptable symptoms related to the arrhythmia, though
uncontrolled tachycardia may over time be associated with a
reversible decline in ventricular performance.3 (Level of
Evidence: B)- New recommendation
• (The RACE II study shows that lenient-rate control <110
bpm is not inferior to strict-rate control <80 bpm. As
lenient-rate control is generally more convenient, requiring
fewer outpatient visits and examinations, lenient-rate
control may be adopted as a reasonable strategy in
patients with permanent AF – (N Engl J Med.
2010;362:1363–73).
• 2011 ACCF/AHA/HRS Focused Update on the
Management of Patients With Atrial Fibrillation (Updating
the 2006 Guideline) Circulation. 2011;123:104-123
Dronedarone - Multaq
Recommendations for Use of Dronedarone in
Atrial Fibrillation
2011 Focused Update Recommendations
Comments Class IIA
• 1. Dronedarone is reasonable to decrease the
need for hospitalization for cardiovascular events in
patients with paroxysmal AF or after conversion of
persistent AF. Dronedarone can be initiated during
outpatient therapy. (Level of Evidence: B) –
New recommendation Class III–Harm
• 2. Dronedarone should not be administered to
patients with class IV heart failure or patients who
have had an episode of decompensated heart
failure in the past 4 weeks, especially if they have
depressed left ventricular function (left ventricular
ejection fraction <35%).30 (Level of Evidence: B)New recommendation
Dronedarone - Multaq
New Safety Concern July 7, 2011 Paris,
France
Sanofi, maker of dronedarone (Multaq), has
suspended its phase 3b trial of its
antiarrhythmic drug due to a significant
increase in cardiovascular events seen in
patients randomized to dronedarone. The
PALLAS trial (begun 7-2010) was testing
the drug in ~10,000 patients with
permanent atrial fibrillation and at least one
other cardiovascular disease risk factor; at
present, dronedarone is approved in
patients with nonpermanent AF.
Events during the PALLAS study as of
June 30, 2011.
(FDA MedWatch 7-21-2011)
Multaq
N=1572
n (%)
CV Death, Myocardial Infarction,
32 (2)
Stroke, Systemic Embolism*
Placebo
N=1577
n (%)
Hazard
Ratio/NNH
p-value
14 (0.9)
2.3/91
0.009
118 (7.5)
81 (5.1)
1.5/42
0.006
Death
16 (1)
7 (0.4)
2.3
0.065
Myocardial Infarction
3 (0.2)
3 (0.2)
1.0
1
Stroke
17 (1.1)
7 (0.4)
2.4/143
0.047
Heart Failure Hospitalization
34 (2.2)
15 (1)
2.3/84
0.008
Death, Unplanned CV
Hospitalization*
*co primary endpoints
FDA Drug Safety Communication: Multaq (dronedarone)
and increased risk of death and serious cardiovascular
adverse events 12-19-2011
• Healthcare professionals should not prescribe Multaq to
patients with AF who cannot or will not be converted into
normal sinus rhythm (permanent AF), because Multaq
doubles the rate of cardiovascular death, stroke, and
heart failure in such patients.
• Healthcare professionals should monitor heart (cardiac)
rhythm by electrocardiogram (ECG) at least once every
3 months. If the patient is in AF, Multaq should be
stopped or, if clinically indicated, the patient should be
cardioverted.
• Multaq is indicated to reduce hospitalization for AF in
patients in sinus rhythm with a history of non-permanent
AF (known as paroxysmal or persistent AF)
• Patients prescribed Multaq should receive appropriate
antithrombotic therapy.
Canadian Cardiovascular
Society Atrial Fibrillation Guidelines
• We recommend that dronedarone not be used in
patients with permanent AF nor for the sole purpose of
rate control(Strong Recommendation, High-Quality
Evidence).
• We recommend dronedarone not be used in patients
with a history of heart failure or a left ventricular
ejection fraction < 0.40 (Strong Recommendation,
Moderate- Quality Evidence).
• We suggest dronedarone be used with caution in
patients taking digoxin (Conditional Recommendation,
Moderate- Quality Evidence).
• Canadian Journal of Cardiology 28 (2012) 125–136
Azilsartan medoxomil - Edarbi
by Takeda
• Approved for the treatment of
hypertension, alone or in combination with
other antihypertensive agents.
• No outcome data
• A pro drug that is structurally related to
candesartan. Azilsartan medoxomil is
rapidly hydrolyzed to azilsartan in the GI
tract.
• T ½ ~ 11 hours
• Cost $86.00 per 30 tablets drugstore.com
• Usual dose 80 mg QD with or without food
Azilsartan medoxomil - Edarbi
Azilsartan medoxomil/chlorthalidone - Edarbyclor
First ARB in combination with chlorthalidone (40 mg
with either 12.5 or 25 mg of chlorthalidone)
Change in systolic blood pressure:
Azilsartan
Chlorthalidone
40/25 (n=355)
Azilsartan
Chlorthalidone
80/25 (n=352)
Olmesartan
HCTZ
40/25 (n=364)
P
Clinic SBP
(change from baseline, mm
Hg)
- 42.5
- 44.0
- 37.1
<0.001
*
Change in 24-h mean SBP
(change from baseline, mm
Hg)
- 33.9
- 36.3
- 27.5
<0.001
*
End point
*p<0.001 for azilsartan/chlorthalidone 40/25 mg vs olmesartan/HCTZ and
azilsartan/chlorthalidone 80/25 mg vs olmesartan/HCTZ
Presented during American Society of Hypertension (ASH) 2011 Scientific Meeting 5/24/2011
Hypertension
Implementing NICE guidance
August 2011
NICE clinical guideline 127
Aged under
55 years
Aged over 55 years or
black person of African
or Caribbean family
origin of any age
C1
A
Summary of
antihypertensive
drug treatment
Step 1
A + C1
Step 2
A+C+D
Step 3
Resistant hypertension
Step 4
A + C + D + consider further diuretic (low
dose spironolactone 25 mg or alpha- or
beta-blocker
Consider seeking expert advice
Key
A – ACE inhibitor or low-cost
angiotensin II receptor blocker
(ARB)
C – Calcium-channel blocker
(CCB)
D – Thiazide-like diuretic
(chlorthalidone 12.5-25 mg or
indapamide 2.5 mg)
(1) - A CCB is preferred but consider a thiazide-like
diuretic if a CCB is not tolerated or the person has
oedema, evidence of heart failure or a high risk of
heart failure.