YOUR MOST TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA INDONESIA AUGUST 2017

Highlights from APSC 2017

& EULAR Congress 2017 Southeast
Managing
prostate cancer
Asian patients
in primary care have highest
risk factor
burden for

HF
CONTENTS
MIMS DOCTOR - YOUR MOST TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA Managing Editor
Elvira Manzano

Contributing Editors
Roshini Claire Anthony, Pearl Toh,
Stephen Padilla, Jairia dela Cruz,
Elaine Soliven, Audrey Abella,
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AUGUST ISSUE Dr Joseph Delano Fule Robles

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Cover Story
6 Southeast Asian patients have highest risk factor burden for HF Production
Tetsuya Hamaki, Ho Wai Hung,
Agnes Chieng
Conference Coverage
21st Asia Pacific Society of Cardiology (APSC) Congress, July 13-15, Singapore Circulation Executive
Christine Chok
7 LVADs for HF: Is it time to abandon heart transplantation?
Accounting Manager
8 Expanding TAVR indications to AS patients Minty Kwan

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10 East Asian Paradox: Balancing bleeding and clotting in ACS Yasunobu Sakai

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 COVER STORY

Southeast
Asian patients
have highest
risk factor
Prof Carolyn Lam

burden for

HF

5
DOCTOR | AUGUST ISSUE

ROSHINI CLAIRE ANTHONY
T
here is significant heterogeneity
among Asian patients with heart
failure, with patients from South-
east Asia appearing to have the highest
risk factor burden, according to find-
ings of the ASIAN-HF* registry study
presented at the 21st Asian Pacific So-
ciety of Cardiology Congress (APSC
2017) held in Singapore.
“These first prospective multina-
tional data from Asia highlight the sig-
nificant heterogeneity among Asian
patients with [heart failure], the influence
of regional income level and ethnicity
on patient characteristics, and the large
burden of comorbidities despite their rel-
atively young age,” said Professor Caro-
lyn Lam from the National Heart Centre
Singapore who presented the results.
[APSC 2017, LBT 2]
“[T]hese data show that ‘Asian
[heart failure]’ is not a single phenotype.
Regional/ethnic differences may have
important implications for the design of
global [heart failure] clinical trials or al-
location of resources for management
of the [heart failure] ‘epidemic’ in Asia,”
said ASIAN-HF researchers in a publi-
cation of their initial findings. [Eur Heart
J 2016;37:3141-3153]
The ASIAN-HF registry was a pro-
spective, multinational (46 sites), ob-
servational study of Asian patients with
stage C heart failure and enrolled 5,276
patients with heart failure with reduced
ejection fraction (HFrEF; EF <40 per-
cent) and 1,204 patients with heart
failure with preserved ejection fraction
(HFpEF; EF ≥50 percent).
Countries were grouped according
to region: Northeast (ie, South Korea,
Japan, Taiwan, Hong Kong, and China;
n=2,201); South (ie, India; n=1,688),
and Southeast Asia (ie, Thailand, Ma-
laysia, Philippines, Indonesia, and Sin-
gapore; n=2,591), as well as by na-
tional income level (lower: Indonesia,
Philippines, and India; middle: China,
Thailand, and Malaysia; and higher:
COVER STORY
Singapore, Hong Kong, Taiwan, South
Korea, and Japan).
Asian patients with heart failure
were younger than their US or Euro-
pean counterparts be it patients with
HFrEF (60, 70, and 64 years, respec-
tively) or HFpEF (68, 73, and 69 years,
respectively). [APSC 2017, LBT2]
Participants from Southeast Asia
appeared to have the highest risk fac-
tor burden among Asian patients with
HFrEF with 64.2, 58.8, and 49.3 per-
cent having hypertension, coronary
artery disease (CAD), and diabetes,
respectively, compared with patients
from Northeast Asia (48.1, 38.2, and
31.8 percent, respectively) and South
Asia (37.9, 51.1, and 37.1 percent, re-
spectively).
Compared with Chinese partici-
pants with HFrEF, Malays and Indians
had higher risks of CAD (adjusted odds
ratio [adjOR], 1.97 and 1.44, respec-
tively), while Koreans and Japanese
had lower risks (adjOR, 0.38 and 0.44,
respectively).
Among patients with HFpEF, par-
ticipants from Southeast Asia also had
the highest prevalence of hyperten-
sion, diabetes, CAD, chronic kidney
disease (CKD), and anaemia, com-
pared with participants from South
and Northeast Asia.
Patients with CAD and CKD were
more likely to have HFrEF, while pa-
tients of older age or those with hy-
pertension, diabetes, anaemia, or atri-
al fibrillation were more likely to have
HFpEF, said Lam. Women were three
times more likely to have HFpEF, and
individuals with two or more comor-
bidities had an almost 50 percent in-
creased risk of HFpEF.
Patients from Southeast Asia also
had the highest proportion of six-month
all-cause mortality or hospitalization for
heart failure (18.7 percent vs 12.5 per-
cent [Northeast Asia] and 5.5 percent
[South Asia]).
6
DOCTOR | AUGUST ISSUE
“[T]he ethnic groups who appeared
most predisposed to premature [heart
failure] were Malays, Filipinos, and in-
digenous Southeast Asians. The nota-
ble interactions between ethnicity and
regional income level, a surrogate of ep-
idemiologic transition, further support
this concept and carry important public
health implications for the management
and prevention of cardiovascular risk
factors in these communities,” said the
researchers, who acknowledged that
the findings may still underestimate the
burden of heart failure in this region.
Only 12 percent of the 3,453 pa-
tients who were eligible for implantable
cardiac defibrillators (ICDs; EF ≤35 per-
cent and NYHA** status 2 or 3) actually
had the device implanted, with the re-
searchers noting a higher likelihood of
ICD implantation in patients from higher
income countries.
Results also demonstrated that ICD
implantation reduced the risk of all-
cause mortality (hazard ratio [HR], 0.71)
and sudden cardiac deaths (HR, 0.33)
over a median follow-up period of 417
days.
“Potentially life-saving ICDs are un-
derutilized with disparity across geo-
graphic regions and socioeconomic
status,” said Lam. “Modifiable risk
factors, better patient education, and
targeted healthcare reforms to address
the underutilization of ICDs represent
important opportunities for public
health intervention to improve patient
outcomes,” she said.
In his commentary, Professor Je-
roen Bax from Leiden University Med-
ical Center, Leiden, the Netherlands,
and current President of the Europe-
an Society of Cardiology stressed the
importance of primary prevention and
modification of lifestyle and risk factors
in tackling the high rate of heart failure
in this region.
*ASIAN-HF: Asian Sudden Cardiac Death in Heart
Failure
**NYHA: New York Heart Association

21st Asia Pacific Society of Cardiology (APSC) Congress
LVADs for HF: Is it time to abandon heart
transplantation?
ELVIRA MANZANO
H
eart transplant is the gold stan-
dard option for heart failure (HF)
patients when all other options
fail, says a cardiologist and heart fail-
ure specialist at the recent APSC 2017
Congress, with excellent long-term out-
comes.
“We’ve heard a lot of inspirational
CONFERENCE COVERAGE
• July 13-15 • Singapore
stories, from a Hollywood actress, to an
athlete who climbed the highest peaks
of the world including Mount Kiliman-
jaro and Mount Fuji, and many others
who are living spectacular lives after a
life-saving heart surgery,” said Dr Steve
Shaw, a cardiologist from the Wythen-
shawe Hospital in Manchester, UK.
Nearly 90 percent of those patients
will live an average of 10 years with a
7
DOCTOR | AUGUST ISSUE
new heart. “If we look at the ISHLT [In-
ternational Society for Heart and Lung
Transplantation] survival data for heart
transplant patients across the world,
the outcomes are spectacular as it
shows the average survival is about 12
years,” said Shaw.
Aside from the excellent long-term
survival and minimal activity limitation
post-heart transplantation, another ad-
vantage of the procedure is that it can
be utilized in a vast range of conditions
including biventricular failure and re-
strictive cardiomyopathy.
Nevertheless, the paucity of heart
donors translate to more patients in the
waiting list and even more patients dy-
ing without finding a suitable heart.
Closing the transplant
shortfall
“When we look at the distribution
of heart transplants around the world,
there is real disparity. The vast majori-
ty of heart transplants were performed
in Europe (32.30 percent) and the US
(55.80 percent), and yet in terms of
population, Europe and US together
account for only about 18 percent of
the world population,” said Shaw.
In Asia, heart transplantation for
advanced HF remains very low and the
number of heart transplants that would
be required of the Asian population is
13,200 per year, a figure that is impos-
sible to achieve. [J Heart Lung Trans-
plant 2017;36:13-18]
The supply of heart transplantation
could not meet the demand. Timing
of transplantation can also be unpre-
dictable in some patients who are very
 CONFERENCE COVERAGE
21st Asia Pacific Society of Cardiology (APSC) Congress
• July 13-15 • Singapore
sick and need therapy quickly, said
Shaw. In some countries, the quality
of organ donors can be variable. There
also lies the burden of post-transplant
care because of polypharmacy, im-
munosuppression, and frequent en-
domyocardial biopsy within the first
year of surgery. “Putting everything to-
gether, we do have limitations to heart
transplantation.”
With big strides in technology, ven-
tricular assist devices (VADs) are taking
an important place not only as a bridge
to transplant but as a destination (life-
time) therapy for patients with refrac-
tory HF who are not eligible for trans-
plantation.
Dr Steve Shaw
LVADs: A viable
alternative?
In patients not listed for transplant,
left ventricular assist device (LVAD) ther-
apy may help extend life and substan-
tially improve quality of life. “Timing of
surgery is under control, there is quick
turnaround time, and immunosuppres-
sion is not needed. The device is suit-
able both for transplant-eligible and -in-
eligible patients,” said Shaw.
In Asia, LVADs are predominantly
used as a bridge to transplant. In India
8
DOCTOR | AUGUST ISSUE
where heart transplantation is still in its
infancy, LVADs are used mostly as a
destination therapy. In Singapore, des-
tination therapy is being carried out as
a pilot programme with special funding;
the youngest patient to receive an im-
plant was only 14 years of age. [J Heart
Lung Transplant 2017;36:13-18]
In Asia, the axial flow device Heart-
Mate II is the most widely used and a
recent report demonstrated a remark-
able 4-year survival at 88 percent in
this region, said Shaw. However, in the
MOMENTUM trial, implantation of the
new fully magnetically levitated centrifu-
gal-flow pump HeartMate III in patients
with advanced HF was associated with
better outcomes at 6 months vs the
HeartMate II. There was no incidence
of pump thrombosis, haemolysis, or
pump malfunction with the newer de-
vice. Rates of death or disabling stroke
and gastrointestinal bleeding were sim-
ilar between the two devices. [N Eng J
Med 2017;376:440-450]
Implantable LVADs will continue to
evolve into smaller and more durable
devices. With further improvements,
major complications such as throm-
bosis, infection, and bleeding may be
better managed.
Is it time to abandon heart trans-
plantation? “No, I see both LVADs and
heart transplantation as complimentary
to each other rather in competition with
each other. We don’t have long-term
survival data yet with the newest LVADs
but both are wonderful treatments that
improve survival and quality of life of HF
patients.”
Now the challenge for cardiologist
surgeons is in identifying patients who
could benefit from LVADs and from
heart transplants. “The best option re-
ally depends on the specifics of the pa-
tient,” Shaw concluded.
 CONFERENCE COVERAGE
21st Asia Pacific Society of Cardiology (APSC) Congress • July 13-15 • Singapore

Expanding indications of TAVR to patients

with aortic stenosis
PEARL TOH

T
ranscatheter aortic valve replace-
ment (TAVR) is the standard of
care for high-risk patients with
severe aortic stenosis (AS), and may
be superior to open surgery in patients
with lower risk as newer generation de-
vices emerge, according to a presen-
tation at the APSC Congress 2017 in
Singapore.

With more data surfacing in time to

come, TAVR will probably be shown to
be superior to open surgery in interme-
diate-risk patients, according to Dr Paul
Chiam, senior consultant cardiologist
at The Heart & Vascular Centre, Mount
Elizabeth Hospital, Singapore.

In the initial PARTNER trial, TAVR sig-

nificantly reduced the rates of all-cause
mortality compared with open surgery
among high-risk patients with severe
AS, and the survival benefit has been
demonstrated up to at least 5 years. [N
Engl J Med 2010;363:1597-1607]
Dr Paul Chiam
associated with greater residual aortic
regurgitation, major vascular complica-
tions, and pacemaker requirement in
SURTAVI, Chiam pointed out.
jor vascular complication, or death re-
ported (except one noncardiac death)
at 1 year after the procedure. [Singa-
pore Med J 2016;57:401-405]

Moving down the risk scale to pa-
tients with intermediate risk, TAVR was
shown to be noninferior to surgical aor-
tic valve replacement (SAVR) in terms
of the composite endpoint of all-cause
mortality or disabling stroke at 2 years
in the PARTNER 2A trial using the SA-
PIEN XT valves and in the SURTAVI tri-
al using a self-expanding CoreValve or
Evolut R bioprosthesis. [N Engl J Med
2016;374:1609-1620; N Engl J Med
2017;376:1321-1331]
While TAVR was associated with
significantly improved AV haemody-
namics and lower rates of stroke at 30
days, atrial fibrillation, acute kidney in-
jury, and transfusion needs, it was also
Similarly, durable clinical and hae-
modynamic results have been ob-
served in Asian patients, with the first
Asian patient (77-year-old male) who
underwent TAVR via the transfemoral
route still surviving up to 8.5 years to
date after the procedure, said Chiam.
[Singapore Med J 2009; 50:534-537]
For AS patients with degenerated
aortic surgical bioprostheses, TAVR is
an attractive option to avoid the need
for open surgery, according to Chiam.
In a small case-series study involving
Asians who underwent valve-in-valve
TAVR, satisfactory haemodynamic re-
sults and clinical improvement were
sustained at 1 year, with no stroke, ma-
Off-label use of TAVR in bicuspid
valves, noncalcific AS, and selected
pure severe aortic regurgitation (AR) is
also feasible, said Chiam. Performing
TAVR in patients with pure AR might
entail a greater need for the use of two
valves, while a major concern to bear in
mind for both groups of patients (with
pure AR or bicuspid aortic valve steno-
sis) is the higher risk of valve emboliza-
tion, he cautioned.
“Newer and better devices [are
likely to] improve the results of the pro-
cedure,” said Chiam, who is optimistic
that indications for TAVR will contin-
ue to expand as newer and more im-
proved devices become available.

9
DOCTOR | AUGUST ISSUE
 CONFERENCE COVERAGE
21st Asia Pacific Society of Cardiology (APSC) Congress • July 13-15 • Singapore

Alirocumab effective, well tolerated

in Taiwanese patients in ODYSSEY KT-TW
ROSHINI CLAIRE ANTHONY

A
lirocumab has a positive effect
on low-density lipoprotein cho-
lesterol (LDL-C) levels and ap-
pears to be well tolerated in patients
with hypercholesterolaemia and high
cardiovascular risk, according to a
sub-analysis of Taiwanese patients en-
rolled in the ODYSSEY KT* trial.

“Alirocumab treatment provided a

favourable effect on LDL-C levels and
other lipid parameters, and was gener-
ally well tolerated in patients from Tai-
wan,” said Dr Chao Ting-Hsing from
the National Cheng Kung University in
Taiwan who presented the results at
APSC 2017.

In the ODYSSEY KT trial, 199 in-

dividuals from South Korea and Tai-
wan with hypercholesterolaemia and
coronary heart disease (or risk equiv-
alent) inadequately controlled with a
maximum tolerated daily dose of statin
(atorvastatin, rosuvastatin, or simvas-
tatin) were randomized to receive sub-
cutaneous alirocumab (75 mg Q2W
with the option of increasing to 150
mg Q2W at week 12 if LDL-C at week
8 was >70 mg/dL) or placebo for 24
weeks.
These results detail the findings
from the 116 patients randomized at
10 sites in Taiwan (KT-TW analysis), of
whom 57 received alirocumab (mean
age 61.5 years, 89.5 percent male,
baseline LDL-C 101.5 mg/dL) and 59
placebo (mean age 60 years, 78 per-
cent male, baseline LDL-C 102.4 mg/
dL). More than 80 percent of patients in
both groups were on high-intensity sta-
tin therapy and 10.9 percent of patients
on alirocumab received an uptitration at
week 12.
Dr Chao Ting-Hsing
At week 24, mean LDL-C was low-
er in patients on alirocumab compared
with placebo (49.5 vs 102.2 mg/dL,
mean difference vs placebo, -53.5 per-
cent; p<0.0001). [APSC 2017, LBT 4]
Alirocumab also reduced the levels
of apolipoprotein B, non-high-density li-
poprotein cholesterol (non-HDL-C), lipo-
protein (a) cholesterol, and total choles-
terol (difference vs placebo, -38.7, -43.6,
-30.8, and -30.2 percent; all p<0.0001),
and increased HDL-C levels (difference
vs placebo, 6.2 percent; p=0.05).
More patients on alirocumab
achieved target LDL-C (<70 mg/dL) at
week 24 compared with placebo (81.3
percent vs 15.4 percent; p<0.0001).
The incidence of treatment emer-
gent adverse events (TEAEs) was sim-
ilar between patients on alirocumab
and placebo (68.4 percent vs 69.5 per-
cent) as was treatment discontinuation
due to TEAEs (two and one patient in
each group). The most common TEAEs
among patients on alirocumab were di-
arrhoea (n=5), dizziness (n=5), and na-
sopharyngitis (n=3).
“The results of the current analysis
were consistent with both the overall KT
study and the ODYSSEY programme,”
said Chao.
*ODYSSEY KT: Evaluation of alirocumab in addition
to lipid-modifying therapy in patients with high
cardiovascular risk and hypercholesterolaemia in
South Korea and Taiwan

10
DOCTOR | AUGUST ISSUE

21st Asia Pacific Society of Cardiology (APSC) Congress • July 13-15 • Singapore
East Asian Paradox: Balancing bleeding
and clotting in ACS
PEARL TOH
E
ast Asians with acute coronary
syndrome (ACS) or undergoing
percutaneous coronary interven-
tion (PCI) have a lower incidence of
thrombotic events but a higher risk of
bleeding compared with their Western
counterparts in response to antiplatelet
therapy, necessitating the need for guid-
ance on antiplatelet treatment strategies
specific for East Asian patients.
As the current clinical guidelines on
antithrombotic strategies were based
on randomized trials comprising mostly
Caucasians, they might not be appli-
cable across all races, said Dr Jeong
Young-Hoon, director of the Cardiovas-
cular Center at Gyeongsang National
University Hospital, Changwon, South
Korea, at the recent APSC Congress
2017 held in Singapore.
A paradigm shift from “one-guide-
line-fits-all races” to a more tailored
strategy should be considered for East
Asians, he urged.
“East Asians are different from West-
erners in terms of therapeutic window of
antiplatelet agents and their response to
P2Y12 inhibitors,” said Jeong.
Patients with a high on-treatment
platelet reactivity (HPR) to adenosine
diphosphate during dual antiplatelet
therapy (DAPT), or poor responders,
have been shown to have a higher risk
of ischaemic events following PCI, in
particular for those with ACS. Despite
demonstrating a greater HPR during
DAPT, East Asians showed a similar or
even a lower ischaemic event rate after
PCI compared with Caucasians – coined
by Jeong as the “East Asian Paradox”.
[Curr Cardiol Rep 2014;16:485-492]
CONFERENCE COVERAGE
Previous registry-based studies
have shown that Asian patients who
underwent coronary stent implanta-
tion had a lower risk for the composite
endpoint of myocardial infarction, re-
peat revascularization, and death than
Caucasian patients in the US NCDR*
(adjusted hazard ratio, 0.89, 95 percent
confidence interval, 0.82–0.96). [Circu-
lation 2013;127:1395-1403]
The difference in HPR could be at-
tributed to a higher prevalence of the
CYP2C19*2/*3 loss-of-function alleles
among East Asians than Westerners
(40.1–63.5 percent vs 20–35 percent),
explained Jeong. These mutant alleles
have been associated with a reduced
response to clopidogrel compared with
wild-type alleles in Asians with ACS. [J
Thromb Haemost 2009;7:897-899]
Hence, a lower target international
normalized ratio (INR) – a measure of
how long a blood clot takes to form –
has been suggested for East Asians
(target INR for Japanese: 1.6–2.6 [es-
pecially for those aged ≥70 years],
and for Chinese: 1.8–2.4) compared
with the target for European or Amer-
ican patients (2.0–3.0). [Intern Med
2014;40:1183-1188; Br J Clin Pharma-
col 2005;59:582-587]
While thrombosis risk was lower,
bleeding risk was higher in East Asians
compared with Caucasians, which
Jeong attributed to the difference in re-
sponse to P2Y12 inhibitors, among many
other factors such as an increased expo-
sure to active metabolites of antiplatelet
agents (due to interethnic differences in
the pharmacodynamics and pharmaco-
kinetics of potent P2Y12 inhibitors).
“In East Asians, excessive inhibition
of platelet function by potent P2Y12 re-
11
DOCTOR | AUGUST ISSUE
Dr Jeong Young-Hoon
ceptor inhibitors may markedly increase
the risk of serious bleeding without
protection against post-PCI ischaemic
event occurrence,” said Jeong.
“The findings also suggest that the
optimal ‘therapeutic window’ of platelet
reactivity might differ between [Cauca-
sian] and East Asian patients,” he added.
To balance the risk of bleeding and
ischaemia in the East Asian population,
Jeong suggested several approach-
es: (i) de-escalating the dose of P2Y12
inhibitors tailored to individual patient
based on clinical judgement and pa-
tient’s phenotype and genotype, or (ii)
switching the use of newer-generation
potent P2Y12 inhibitors (eg, ticagrelor,
prasugrel) to clopidogrel in low-to-inter-
mediate risk patients with ACS. None-
theless, he also cautioned that the ef-
ficacy and safety of such approaches
require further confirmation from larger
clinical trials on East Asians.
“These observations … should be
taken into consideration during the
development of regional and national
guidelines for East Asian patients with
ACS or undergoing PCI,” said Jeong.
*NCDR: National Cardiovascular Data Registry
 CONFERENCE COVERAGE
21st Asia Pacific Society of Cardiology (APSC) Congress
• July 13-15 • Singapore
SGLT2 inhibitors may
decrease heart failure risk
AUDREY ABELLA
T
he use of sodium-glucose
cotransporter 2 (SGLT2) inhib-
itors such as empagliflozin and
canagliflozin may lead to a decreased
risk of heart failure (HF), according to
an expert.
“Empagliflozin, canagliflozin, and
maybe metformin, are … beneficial
[in reducing HF risk],” said Dr Darren
McGuire from the University of Texas
Southwestern Medical Center in Dal-
las, Texas, US, who highlighted the de-
creased HF risk with antihyperglycae-
mic agents as shown in the EMPA-REG
OUTCOME* and CVD-REAL** trials.
In the EMPA-REG OUTCOME trial,
7,020 patients with prevalent athero-
sclerotic vascular disease and type 2
diabetes were randomized to receive
placebo (n=2,333), empagliflozin 10 mg
once daily (n=2,345), or empagliflozin
25 mg once daily (n=2,342). [N Engl J
Med 2015;373:2117-2128; Cardiovasc
Diabetol 2014;13:102]
The lower risk of HF among patients
on empagliflozin was observed within
the first 6–9 months of the trial (hazard
ratio [HR], 0.65, 95 percent confidence
interval [CI], 0.50–0.85; p=0.0017).
“[This] continued to divert slight-
ly throughout the follow-up period …
leading to the 35 percent relative risk re-
duction in incident [HF],” said McGuire,
who suggested an increase in haemato-
crit (4 percent) as a potential reason for
the reduction in HF. “This was a stun-
ning finding … [W]e were very interest-
ed [to determine if] this was unique to
empagliflozin or [if it was] a class effect.”
12
DOCTOR | AUGUST ISSUE
In the CVD-REAL trial, 154,528 par-
ticipants receiving an SGLT2 inhibitor
were matched with 154,528 individuals
receiving other glucose-lowering drugs.
[Circulation 2017;136:249-259]
Overall results revealed a decreased
risk of hospitalization for HF with SGLT2
inhibitors (HR, 0.61, 95 percent CI,
0.51–0.73; p<0.001), which is also sug-
gestive of a class effect, noted McGuire.
Given the favourable cardiovascular
outcomes resulting from SGLT2 an-
tagonist use, the European Society of
Cardiology (ESC) HF prevention guide-
lines encourage the use of this class of
glucose-control drugs, specifically em-
pagliflozin, for cardiovascular death and
HF risk reduction, noted McGuire.
McGuire pointed out that the bene-
fits of metformin in this aspect warrants
further investigation. “[There is] emerg-
ing data suggesting metformin may be
in fact beneficial … [however], to this
day, we have no idea what the cardio-
vascular safety or efficacy of metformin
is, specifically [in relation] to HF.”
*EMPA-REG OUTCOME: Empagliflozin,
cardiovascular outcomes event trial in type 2
diabetes mellitus patients
**CVD-REAL: Comparative effectiveness of
cardiovascular outcomes in new users of SGLT2
inhibitors

21st Asia Pacific Society of Cardiology (APSC) Congress • July 13-15 • Singapore
Updates on thrombectomy for PCI in STEMI
PEARL TOH
T
hrombectomy is known to im-
prove myocardial reperfusion in
ST-elevation myocardial infarc-
tion (STEMI), but no mortality benefit
has been clearly demonstrated with
this strategy, according to a presen-
tation at APSC 2017, which suggests
that thrombus aspiration in primary per-
cutaneous intervention (PCI) should not
be a routine procedure.
“Thrombectomy should be re-
served for cases with large thrombus
burden, or [as a] bailout for residual
thrombus or slow/no-reflow [phenom-
enon],” suggested Dr Choo Gim Hooi
from the Cardiac Vascular Sentral Kuala
Lumpur, Malaysia.
The latest ACC/AHA/SCAI update
(2015) on guideline for primary PCI in
patients with STEMI states that “rou-
tine aspiration thrombectomy before
primary PCI is not useful (level of ev-
idence: A)” and gives it a “class III
recommendation”, which indicates no
benefit. Recommendation for selec-
tive and bailout aspiration thrombec-
tomy before PCI has also been mod-
ified from class “IIa” in 2011/2013 to
“IIb” in the latest update, stating that
the usefulness of such procedure
“is not well established.” [Circulation
2016;133:1135-1147]
The initial enthusiasm for aspiration
thrombectomy was rekindled in 2008
with the publication of the TAPAS*
trial, which showed that thrombus
aspiration before stenting an infarct-
ed artery reduced cardiac death at 1
year (hazard ratio [HR], 1.93; p=0.02)
and the combined cardiac death or
nonfatal reinfarction at 1 year (HR,
1.81; p=0.009) compared with con-
ventional PCI for STEMI. [Lancet 2008;
371:1915-1920]
CONFERENCE COVERAGE
“Although aspiration thrombectomy
[is a] slightly more time-consuming pro-
cedure [than PCI alone, it] may facilitate
better lesion visualization, appropriate
stent selection, and direct stenting,”
said Choo.
However, the TASTE** trial which
involved 7,244 patients with STEMI un-
dergoing PCI revealed no reduction in
all-cause mortality at 30 days (HR, 0.94;
p=0.63) or 1 year (HR, 0.94; p=0.57)
with routine thrombectomy vs PCI alone.
[N Engl J Med 2014;371:1111-1120]
In the TOTAL*** study, not only was
there no reduction in the risk of the
composite primary endpoint of cardio-
vascular (CV) death, cardiogenic shock,
recurrent myocardial infarction, or
NYHA# class IV heart failure at 6 months
after thrombectomy compared with PCI
alone (HR, 0.99; p=0.86), there was an
increased stroke rate within 30 days af-
ter thrombectomy (HR, 2.06; p=0.02).
[N Engl J Med 2015;372:1389-1398]
Nonetheless, the stroke risk in the
TOTAL trial needs to be confirmed in
future studies, cautioned Choo.
“Although thrombectomy improves
myocardial reperfusion in STEMI, no
mortality benefit has been observed
with this strategy,” he said, underscoring
the updated recommendation in clinical
guideline that thrombectomy should not
be a routine procedure in primary PCI.
Still, he questioned, “do you need
mortality benefit before you decide
whether to remove aspiration cath-
eters from your cath lab?” and “are
there subsets that may still have im-
proved clinical outcomes with aspira-
tion thrombectomy?”
In a meta-analysis from the Throm-
bectomy Trialists Collaboration, which
13
DOCTOR | AUGUST ISSUE
Dr Choo Gim Hooi
pooled data from the TAPAS, TASTE,
and TOTAL studies, CV death (HR,
0.84; p=0.06) and stroke or transient
ischaemic attack (TIA) within 30 days
(HR, 1.43; p=0.06) were not significant-
ly different between the thrombectomy
group vs the PCI alone group. Howev-
er, subgroup analysis of patients with
high thrombus burden (TIMI## grade ≥3)
showed fewer CV deaths with thrombus
aspiration (HR, 0.80; p=0.03), albeit with
more strokes or TIA (odds ratio, 1.56;
p=0.04). [Circulation 2017;135:143-152]
As such, aspiration thrombectomy
should be reserved for patients with
high thrombus burden or as a bailout,
Choo said, adding that “if thrombus
aspiration is deemed necessary but
not possible/ineffective, other options
of thrombus management … [available
include using] other mechanical throm-
bectomy devices, embolic protection
stents, or pharmacological drugs.”
“I still have space in my cath lab shelf
for thrombectomy catheters,” he said.
*TAPAS: Thrombus Aspiration during Percutaneous
coronary intervention in Acute myocardial infarction
Study
**TASTE: Thrombus Aspiration in ST-Elevation
myocardial infarction in Scandinavia
***TOTAL: ThrOmbecTomy versus PCI Alone
#
NYHA: New York Heart Association
TIMI: Thrombolysis In Myocardial Infarction
##
 CONFERENCE COVERAGE

21st Asia Pacific Society of Cardiology (APSC) Congress

• July 13-15 • Singapore

Epicardial fat volume tied

to coronary microvascular
dysfunction
STEPHEN PADILLA

A
n association exists between
epicardial fat volume (EFV) and
coronary microvascular dys-
function (CMD), according to a study.

This finding highlights the impor-

tance of identifying surrogate markers
of CMD on computed tomography
coronary angiogram (CRCA), which is
commonly used to examine patients
presenting with chest pain, according
to the researchers.
referred to a cardiology OPD clinic for
In this study, patients (n=134, mean assessment of chest pain and had a
age 59.2 years, 49.2 percent male) had computed tomography coronary angi-
a mean body mass index of 27.5 kg/ ography (CTCA).
m2. Of these participants, 7 percent
were diabetic, 37 percent had hyper- There were 59 participants (44 per-
tension, and 43 percent were smokers. cent) who had completely normal coro-
[APSC 2017, abstract MP-06] nary arteries on CTCA.

Overall, patients had a mean EFV
of 137.0 cm3 and a mean myocardial
blood flow reserve (MBFR) of 2.18. A
total of 54 patients (40 percent) pre-
sented with CMD, which is defined as
MBFR <2.0. Moreover, 43 participants
(32 percent) had coronary artery cal-
cium score (CACS) of 0, with a mean
CACS of 115. Their mean Framingham
Risk Score (FRS) was 17.6.
Univariate analysis revealed that
MBFR decreased with increasing age
(β=‒0.0143; p=0.002), EFV (β=‒0.0020;
p=0.012) and CACS (β=‒0.0004;
p=0.004). Based on multiple regression
analysis, EFV (β=‒2.22; p=0.016) and
CACS (β=‒0.37; p=0.008) remained
significant and were independent pre-
dictors of MBFR.
Patients included those who were
EFV was measured through seri-
al slices of parietal pericardium from
bifurcation of the pulmonary artery to
diaphragm with a range of -45 to -190
household unit. MBFR was calculated
using dipyridamole vasodilator myocar-
dial contrast echocardiography.
“Epicardial fat is a biologically active
fat depot around the heart, constrained
by visceral pericardium and directly
surrounds major epicardial arteries,”
according to researchers.
“EFV has been previously correlat-
ed with the presence of coronary artery
disease, CACS and FRV. More recently,
a single study has shown that epicardial
fat thickness but not volume, is associ-
ated with CMD. However, the relation-
ships between CACS, FRV and EFV
with CMD is unknown,” they added.

14
DOCTOR | AUGUST ISSUE
 CONFERENCE COVERAGE
21st Asia Pacific Society of Cardiology (APSC) Congress • July 13-15 • Singapore

CASE-J 10: Candesartan reduces risk of

new-onset diabetes among high-risk patients
ROSHINI CLAIRE ANTHONY

C
andesartan reduced the risk
of new-onset diabetes among
Japanese patients with hyper-
tension and high cardiovascular risk
after a 10-year follow-up period, con-
firming the findings of the CASE-J* tri-
al, according to a study presented at
APSC 2017.

“Candesartan treatment for hyper-

tension may have some potential ben-
efits on new-onset diabetes compared
with amlodipine. These findings corrob-
orate the results of the CASE-J and the
CASE-J extension by longer follow-up,”
said Dr Liu Jinliang from Kyoto Univer-
sity Hospital, Kyoto, Japan, who called Dr Liu Jinliang

for further research to confirm the find-

ings in other populations.
In the 10-year follow-up study
(CASE-J 10), researchers compared
data of 645 patients on candesartan
with 668 patients on amlodipine from
the CASE-J cohort (mean age 63 years,
48.2 and 56.1 percent female, respec-
tively), analysing study endpoints using
the CASE-J and CASE-J extension co-
horts (n=4,703). Blood pressure was
well-controlled in patients on either
treatment.
The incidence of first cardiovascular
event (a composite of cardiac, cerebro-
vascular, renal, and vascular events,
and sudden death) was comparable
between patients on candesartan and
amlodipine (14.7 percent vs 14.8 per-
cent; hazard ratio [HR], 0.94, 95 per-
cent confidence interval [CI], 0.70–1.27;
p=0.703). The risk of new-onset diabe-
tes was significantly lower among pa-
tients on candesartan compared with
amlodipine (4.7 percent vs 6.4 percent;
HR, 0.71, 95 percent CI, 0.52–0.97;
p=0.029). [APSC 2017, LBT 5]
The results reflected those of
CASE-J (n=4,728) which demonstrat-
ed no significant difference in the in-
cidence of cardiovascular events be-
tween patients on candesartan and
amlodipine after 3.2 years of follow up
(HR, 1.01, 95 percent CI, 0.79–1.28;
p=0.969), though there was a 36 per-
cent relative risk reduction (p=0.03) of
new-onset diabetes among patients on
candesartan. [Expert Rev Cardiovasc
Ther 2008;6:1195-1201]
The results of 2,232 patients who
were followed up for another 3 years
in the CASE-J extension trial were
similar, where cardiovascular event in-
cidence was comparable between pa-
tients on candesartan and amlodipine
(HR, 0.95, 95 percent CI, 0.77–1.18;
p=0.650), while new-onset diabe-
tes risk was lower among patients on
candesartan (HR, 0.71, 95 percent CI,
0.51–1.00; p=0.0495). [Hypertens Res
2011;34:1295-1301]
The most notable benefit of can-
desartan on new-onset diabetes and
mortality in CASE-J was among pa-
tients with the highest BMI, which sug-
gests that candesartan may be more
applicable to patients with hyperten-
sion and a more metabolic phenotype,
said Professor Carolyn Lam from the
National Heart Centre Singapore in her
commentary.
She also did not discount a poten-
tial negative impact of some antidiabet-
ic agents on cardiovascular outcomes,
as well as the low rate of new-onset
diabetes and cardiovascular events as
a confounding factor.
*CASE-J: Candesartan Antihypertensive Survival
Evaluation in Japan

15
DOCTOR | AUGUST ISSUE
 CONFERENCE COVERAGE
21st Asia Pacific Society of Cardiology (APSC) Congress
• July 13-15 • Singapore
Raising diuretic dose at
discharge does not lower
re-admission risk
PEARL TOH
I
ncreasing the dose of loop diuretic in
patients with heart failure (HF) at hos-
pital discharge was not associated
with a reduced risk of hospital re-ad-
mission for HF or any cause contrary to
previous reports suggesting that such a
dosing strategy could reduce re-admis-
sion, according to a study presented at
APSC 2017.
“Although a common practice is to
increase the loop diuretic dose at dis-
charge with reference to the admission
dose, evidence behind this practice is
lacking,” according to lead author Dr
Grace Chang Shu-Wen from the De-
partment of Pharmacy in Khoo Teck
Puat Hospital, Singapore, who noted
that there is little guidance available on
dosing at discharge.
“We did not find an association
between increased discharge diuretic
dose and re-admissions.”
The study included 134 patients ad-
mitted to Khoo Teck Puat Hospital who
had HF, ejection fraction ≤40 percent,
and were treated with loop diuretic at
both hospital admission and discharge.
The patients were classified into two
groups depending on whether the di-
uretic dose at admission was main-
tained/reduced (n=66) or increased
(n=68) at discharge, and were followed
up for at least 5 months. [APSC 2017,
abstract P101]
At 30 days, re-admission rates for
any cause and for HF-related cause ap-
peared to be lower with increased loop
diuretic dose vs same/reduced dose at
16
DOCTOR | AUGUST ISSUE
discharge (25.0 percent vs 33.3 percent;
p=0.19 and 11.8 percent vs 16.7 per-
cent; p=0.29 for all-cause and HF-relat-
ed cause, respectively), although the as-
sociation was not statistically significant.
Also, time to first all-cause re-ad-
mission was delayed in the group us-
ing increased dose compared with
the same/reduced dose at discharge
(hazard ratio [HR], 0.61; p=0.04), but
the significance was nullified after ad-
justment for variations in baseline char-
acteristics (adjusted HR, 0.70; p=0.15).
According to Chang, patients
whose diuretic dose were maintained
or reduced at discharge had significant-
ly more cardiovascular-related comor-
bidities (p=0.03), more atrial fibrillation
(p=0.048), and less use of beta-blocker
at discharge (p=0.04) compared with
those who had increased dose at dis-
charge.
“An increased discharge diuretic
dose trended towards a longer time to
first all-cause re-admission, though this
was not significant after adjusting for
baseline factors,” said Chang. “Based
on these data, routinely increasing dis-
charge dose may not apply to all pa-
tients and it is crucial to tailor doses to
clinical status instead.”
“This study provides important sta-
tistics for our hospital and aids us in
identifying at-risk patients who require
closer monitoring to prevent re-admis-
sions,” she added.
 CONFERENCE COVERAGE
21st Asia Pacific Society of Cardiology (APSC) Congress • July 13-15 • Singapore

Cardiac rehab after PCI improves

endothelial function
JAIRIA DELA CRUZ

C
ardiac rehabilitation appears to
improve endothelial function in
patients who have undergone
percutaneous coronary intervention,
being equally beneficial in acute coro-
nary syndrome (ACS) and stable angina
patients, according to a new study.

In a cohort of 119 patients (mean

age 54.9 years; 87.4 percent male) who
received successful PCI for their coro-
nary disease and attended a cardiac re-
habilitation programme after discharge,
flow-mediated dilation (FMD), a mea-
sure of endothelial function, significantly
improved after 6 months (9.0 percent
from 7.9 percent at baseline). [APSC
2017, abstract MP-20]
When patients were grouped ac-
cording to PCI indication, baseline
FMD was lower in patients with acute
coronary syndrome (ACS; n=69) than
in those with stable angina (n=50), al-
though the difference was not signif-
icant (7.7 vs 8.1 percent; p=0.180).
The beneficial effect of cardiac rehabil-
itation on FMD was noted in both pa-
tient subgroups, yielding an increase
of around 1.1 percent at 6-month fol-
low-up.
FMD at 6 months was 8.9 percent
in the ACS subgroup and 9.2 percent
in the stable angina subgroup, with no
significant between-group difference
(p=0.61).
Other notable improvements ob-
served after 6 months of cardiac reha-
bilitation included low-density lipopro-
tein cholesterol (116.9 to 82.7 mg/dL),
high sensitivity C-reactive protein (0.87
to 0.23 mg/L) and maximal aerobic ca-
pacity (29.2 to 31.9 ml/kg/min).
“Improvement of endothelial func-
tion is one of the important effect of car-
diac rehabilitation, reducing cardiovas-
cular risk for ACS and stable angina,”
the investigators said, noting that car-
diac rehabilitation is equally beneficial
to ACS and angina patients in terms of
improving FMD.
The endothelium which is one of
the largest organs of the human body,
interacts with nearly every system and
has been implicated in end-organ dis-
eases of systems including neurologic,
renal, hepatic, vascular, dermatolog-
ic, immunologic and cardiac. It plays
a crucial role in providing haemostatic
balance, formation of blood vessels,
and regulation of coagulation and
vascular tone. [Glob Cardiol Sci Pract
2014;3:291–308]
Given the key functions of the endo-
thelium, endothelial function has been
considered a barometer for cardiovas-
cular risk. A shift in the actions of the
organ toward reduced vasodilation, a
proinflammatory state and prothrombic
properties — also known as endotheli-
al dysfunction — is reported to be the
initial step in the pathogenesis of pe-
ripheral arterial disease, cardiovascular
diseases and stroke, among others. [Int
J Biol Sci 2013;9:1057-1069]
Exercise has been widely report-
ed as one of the potential interven-
tions to improve or ameliorate endo-
thelial dysfunction. Regular moderate
physical activity has been shown to
promote an antioxidant state and
preserve endothelial function. [Sports
Med 2009;39:797-812; Nitric Oxide
2015;45:7-14]
That exercise may have a beneficial
effect on the development of cardio-
vascular disease through preserving
endothelial function is supported by
the fact that every recent major evi-
dence-based guideline regarding the
management and prevention of coro-
nary heart disease provides a class 1
level recommendation for referral to a
cardiac rehabilitation programme, the
investigators said.

17
DOCTOR | AUGUST ISSUE
 CONFERENCE COVERAGE

21st Asia Pacific Society of Cardiology (APSC) Congress

• July 13-15 • Singapore

Type 2 Brugada pattern

in healthy individuals linked
to high SUD risk
ELAINE SOLIVEN

T
ype 2 Brugada pattern is highly
prevalent in healthy Filipinos and
is associated with sudden un-
explained death (SUD), according to a
study.

“The risk [of cardiac events] ap-

pears to be considerable even among
those with the type 2 [Brugada] pattern,
[which is] in contrast to other studies,
where the risk appears to be concen-
trated on the type 1 Brugada [pattern],”
said Dr Jaime Alfonso Aherrera from
the Department of Medicine, Universi-
ty of the Philippines-Philippine General
Hospital, Manila, Philippines.
Using data from the LIFECARE* co-
hort, researchers reviewed electrocar-
diogram (ECG) patterns of 3,072 as-
ymptomatic Filipinos aged 20–50 years,
163 (5.3 percent) of whom demonstrat-
ed Brugada patterns. The Brugada pat-
terns on ECG were classified into three
categories: type 1 (coved ST-elevation
≥2 mm, n=14), type 2 (saddleback
ST-elevation ≥1 mm, n=119), and type
3 (either coved or saddleback ST-eleva-
tion <1 mm, n=30). [APSC 2017, LBT1)
Brugada patterns were most com-
mon among participants aged 40–50
years (41 percent, n=67) and 20–29
years (35 percent, n=57), as well as
among current smokers (46 percent,
n=75) and alcohol drinkers (77 per-
cent, n=128).
Of the 144 participants followed
up at 5 years, 24 experienced cardiac
events (syncope, presyncope, and sud-
den death). Of the 24 individuals, three
had Brugada 1, 15 had Brugada 2, and
six had Brugada 3 patterns.
All six SUDS occurred in those with
Brugada 2 pattern. This high mortal-
ity rate is a ‘worrisome finding’, said
Aherrera.
He attributed the high prevalence of
type 2 Brugada pattern in the Philippines
to the warmer environment, as well as
the higher alcohol intake, and unknown
genetic factors among Filipinos.
“This study ... suggests that a type 2
Brugada pattern may not be as benign
as previously suspected,” commented
Dr Hugh Calkins from The Johns Hop-
kins Hospital, Baltimore, Maryland, US.
“Further research is needed to de-
termine if widespread screening should
be advised ... But at the very least, phy-
sicians need to be aware that an ECG
should be obtained in all syncope pa-
tients with a specific focus on whether
they have a Brugada pattern,” Calkins
added.
*LIFECARE: LIFE course study in CARdiovas-
cular disease Epidemiology

18
DOCTOR | AUGUST ISSUE
 CONFERENCE COVERAGE

European Heart Rhythm Association (EHRA) EUROPACE-CARDIOSTIM 2017

• June 18-21 • Vienna, Austria

Breast implants may skew ECG result,

leading to misdiagnosis of heart disease
PEARL TOH

B
reast implants may interfere with
electrocardiography (ECG) test,
resulting in misdiagnosis of a
heart attack or coronary artery disease,
suggests a study presented at the
EHRA EUROPACE-CARDIOSTIM 2017
Congress.

“Our experience shows that breast

implants make it difficult to see the
heart with echocardiography because
ultrasound cannot penetrate through
the implant,” said lead author Dr
Sok-Sithikun Bun from Princess Grace
Hospital in Monaco-Ville, Monaco, who
questioned whether the same scenario
also occurred with ECG.

To answer this, Bun’s team col-

lected ECG readings from 48 healthy
women without any known structural
heart disease (28 with breast implants
and 20 matched controls) and sent
them for analysis by two experienced
electrophysiologists who were blinded
to the patient characteristics, including
baseline demography and presence of
breast implants. [EHRA 2017, abstract
40586]
Among the women with breast im-
plants, 38 percent were considered to
have abnormal ECG by one of the elec-
trophysiologists while 57 percent were
considered by the second electrophysi-
ologist to have abnormal ECG.
None of the ECG from the con-
trol women was considered abnormal
by the second electrophysiologist,
except one (5 percent) which was
deemed abnormal by the first electro-
physiologist.
The most common abnormalities
found among the women with breast
implants included negative T waves,
ST depression in inferolateral leads, ab-
sence of R wave progression from V1
to V4, long or short QT syndrome, and
hypertrophic cardiomyopathy.
“T wave inversion is an unspecific
sign but can indicate the presence of
coronary artery disease, while ST de-
pression indicates that a patient may
have a heart attack,” explained Bun.
“Doctors could mistakenly conclude
that a patient with breast implants has
a manifestation of coronary artery dis-
ease if they believe in the false ECG
findings.”
Women with breast implants should
inform their doctors before undergoing
an ECG, advised Bun. He believed that
implants may pose a barrier that dis-
rupt the electrical transmission from the
heart to the ECG leads.
“When a patient comes to the
emergency department with chest
pain, an ECG is performed to see if
they are having a heart attack … Doc-
tors should be aware that ECG inter-
pretation can be misleading in patients
with breast implants,” cautioned Bun,
who suggested that blood tests be
performed in case of any doubts on the
diagnosis, depending on the symptoms
presented.
“We do not want to frighten pa-
tients. But it may be wise to have an
ECG before a breast implant operation.
The ECG can be kept on file and used
for comparison if the patient ever needs
another ECG,” he said.

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 CONFERENCE COVERAGE

European Heart Rhythm Association (EHRA) EUROPACE-CARDIOSTIM 2017

• June 18-21 • Vienna, Austria

Withholding NOACs prior to ablation

for AF may yield brain lesions
ELVIRA MANZANO

W
ithholding new oral anti-
coagulants (NOACs) prior
to performing left atrial ra-
diofrequency ablation in patients with
atrial fibrillation (AF) is associated with
an increased risk of asymptomatic
cerebral lesions, a prospective study
has shown. This raises the question
of whether brain lesions on MRI could
lead to cognitive decline over time.

The rate of brain lesions in patients

who had previously been prescribed
a NOAC but went off the drug a day
before ablation (standard practice at
that time) was higher at 17.3 percent
(p=0.049). By comparison, those who
stayed on a prescribed vitamin K an-
tagonist (VKA) therapy throughout the
procedure had a 9.6 percent rate of
asymptomatic, mostly small, cerebral
lesions on MRI post ablation. [EHRA
EUROSPACE-CARDIOSTIM 2017, ab-
stract P247]
“The study does not imply that
VKAs should be preferred over NOACs
prior to AF ablation,” said lead author
Dr Michael Derndorfer from the Elisa-
bethinen University Teaching Hospital
in Linz, Austria said. Rather, it under-
scores the importance of uninterrupt-
ed anticoagulation throughout abla-
tion. “It was the discontinuation why
we had an astonishingly high rate of
asymptomatic cerebral lesions in the
NOAC group.”
The study included 410 patients
who had a routine cerebral MRI pre
and post standard pulmonary vein
isolation (PVI) for AF. Patients were
on a background NOAC (rivaroxaban,
dabigatran, or apixaban) or coumarin
derivatives (phenprocoumon or aceno-
coumarol). About two-thirds had parox-
ysmal AF and one-third had persistent
AF. Less than a third were women. The
duration of AF and history of hyperten-
sion, stroke, transient ischaemic attack,
and diabetes was comparable between
groups.
It was standard practice previous-
ly to stop NOACs prior to ablation due
to an increased risk of bleeding. How-
ever, greater experience with NOACs
shifts the practice to keeping patients
on anticoagulants or VKAs during the
procedure even if heparin is introduced
to prevent a stroke.
In the current study, larger left atri-
al diameter, higher stroke risk scores,
and a lower achieved activated clotting
time (ACT) at the time of the procedure
were among the predictors of cerebral
lesions. Derndorfer cannot say what
the long-term effects of cerebral lesions
are, but some studies suggest that they
could lead to cognitive decline in the
future.
Although procedural heparin was
titrated to an ACT of 300 to 400 sec-
onds according to current recommen-
dations, the mean achieved ACT was
significantly lower in those whom the
NOACs were withdrawn. Left atrial pro-
cedure time in minutes was compara-
ble between groups (179.5 vs 171.9
for NOACs and VKA, respectively) so
was distribution of PVI­ procedures. All-
cause mortality, stroke, and need for
cardiac surgery intervention did not oc-
cur in both groups.
Experts said the study is unrepro-
ducible as performing pre and post-
procedural MRI to check for cerebral
lesions in every patient is both complex
and costly. This puts a premium on
weighing the available evidence con-
cerning the risks and benefits of with-
holding NOACs prior to ablation.

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 CONFERENCE COVERAGE
European League Against Rheumatism (EULAR) Annual Congress • June 14-17 • Madrid, Spain

No increase in cancer risk with

biological DMARDs
NAOMI RODRIG

T
wo Swedish national registry
studies presented at EULAR An-
nual Congress 2017 suggest no
increased cancer risk for rheumatoid
arthritis (RA) patients treated with bio-
logical disease-modifying antirheumatic
drugs (bDMARDs), including tumour
necrosis factor (TNF) inhibitors.

“Drugs targeting the immune sys-

tem might affect cancer onset or re-
lapse. Because TNF is one of the
cytokines involved in the immunosur-
veillance of tumours, its inhibition may
theoretically increase the risk of tu-
mour recurrence or formation. Hence,
clinical guidelines caution against use
of anti-TNF drugs in patients with a
history of cancer in the past 5 to 10
years,” said lead author Professor
Johan Askling from the Karolinska
Institute, Stockholm, Sweden. “With
limited scientific evidence, rheuma-
tologists and patients are faced with
difficult decisions.”
To investigate the risk of recur-
rence of solid non-skin cancer in RA
patients receiving anti-TNF treatment
(adalimumab, etanercept, golimumab,
infliximab), the investigators compared
446 patients with a diagnosis of sol-
id cancer prior to the start of anti-TNF
drugs with 1,278 matched controls
who had a history of the same type of
cancer and were not receiving biologic
therapy for their RA. Only participants
with cancer remission for >6 months
prior to start of follow-up were includ-
ed. The primary outcome was first re-
currence or a second primary cancer
of the same type. [EULAR 2017, ab-
stract OP0308]
“During a 5-year follow-up period, 7
percent of patients in each group – 30
patients in the anti-TNF therapy group
and 89 among the matched biolog-
ics-naïve controls – had cancer recur-
rence,” reported Askling. “Statistical
analysis accounting for matching vari-
ables such as sex, age, year of index
cancer diagnosis, and index cancer
type and stage, and adjusting for edu-
cation level and comorbidities, indicat-
ed no increased risk associated with
any specific cancer type.”
“Rheumatologists should find our
data reassuring. However, it is not pos-
sible to extrapolate these new findings
to individuals with a very recent cancer
or a poor prognosis,” he concluded.
In the second study, researchers
used Swedish national registries to
evaluate different cohorts of RA pa-
tients who had initiated treatment with
a bDMARD (tocilizumab, abatacept,
rituximab or an anti-TNF agent). There
was also an additional cohort of pa-
tients initiating a second anti-TNF drug,
and a cohort of biologic-naïve patients
who were treated with conventional
synthetic DMARDs such as metho-
trexate or sulfasalazine. Outcomes
were defined as a first ever malignancy
during follow-up, excluding non-mel-
anoma skin cancer. Patients were
followed up from treatment start until
death, emigration, outcome or the end
of follow-up. [EULAR 2017, abstract
OP0100]
“Adjusting for age, gender, disease
and treatment characteristics, and ed-
ucational level, we found no statistically
significant differences in the risk of de-
veloping a first solid or haematological
malignancy between patients treated
with bDMARDs and those receiving
conventional synthetic DMARDs,” said
Dr Hjalmar Wadström from the Karo-
linska Institute, Stockholm, Sweden.
“This is very encouraging. Because im-
mune suppression may lower host sur-
veillance against developing tumours,
monitoring cancer incidence is an im-
portant aspect of the safety of biologics
used in rheumatology.”

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 CONFERENCE COVERAGE
European League Against Rheumatism (EULAR) Annual Congress • June 14-17 • Madrid, Spain

Romosuzumab cuts osteoporosis fracture risk

NAOMI RODRIG

R
omosuzumab, a novel agent
with a unique mechanism of ac-
tion, has demonstrated impres-
sive reductions in vertebral fracture risk
in postmenopausal women with osteo-
porosis, according to data from a large
international study [EULAR 2017, ab-
stract OP0048]

Romosuzumab is a monoclonal an-

tibody that increases bone formation by
binding and inhibiting sclerotin, an os-
teocyte-derived inhibitor of osteoblast
activity. This action has the dual effect
of increasing bone formation and de-
creasing bone resorption. Sclerotin in-
hibition is an attractive drug mechanism
because the gene that encodes sclero-
tin is expressed only in skeletal tissue,
potentially minimizing off-target effects.

“Previous research has shown that
romosozumab, administered subcuta-
neously [SC] at monthly intervals over
a period of 12 months, resulted in bone
mineral density [BMD] gains in both the
trabecular and cortical compartments
of the spine and hip regions,” said Pro-
fessor Piet Geusens from the University
of Maastricht, the Netherlands. [N Engl
J Med 2014;370:412-420; Calcified
Tissue International 2016;98:370-380]
New data from the international,
randomized FRAME study (Fracture
Study in Postmenopausal women with
Osteoporosis) showed an 83 percent
reduction in the risk of vertebral fracture
with romosuzumab vs placebo in post-
menopausal women with osteoporosis.
The study included 7,180 post-
menopausal women aged 55–58 years
with osteoporosis confirmed by BMD
T-score ≤ -2.5 at the total hip or fem-
oral neck. Patients were randomized
1:1 in a double-blind manner to receive
monthly romosozumab 210 mg SC or
placebo for 12 months, followed by
open-label monthly denosumab 60
mg SC in both arms for another 12
months. The primary endpoint was
the incidence of new vertebral fracture
through 12 and 24 months. Secondary
endpoints were the incidence of clinical
fracture, nonvertebral fracture or other
fractures through 12 and 24 months.
Initial results from FRAME showed
that romosozumab was associated with
a 73 percent reduction in the risk of ver-
tebral fracture vs placebo. “The effect
of romosozumab was rapid, with a 46
percent risk reduction at 6 months. Only
two out of the 16 vertebral fractures in
the romosozumab group occurred after
6 months of therapy,” said Geusens. [N
Engl J Med 2016;375:1532-1543]
The new data reported at EULAR
focused on the incidence of clinical
vertebral fractures in study subjects
who developed back pain consistent
with such fracture. Diagnosis was then
confirmed by X-ray. “Although a verte-
bral fracture carries a 5-fold increased
risk of another vertebral fracture within
12 months, nearly 70 percent of frac-
tures are not diagnosed due to the lack
of symptoms,” Geusens explained.
“Clinical vertebral fractures provide an
opportunity to identify patients at in-
creased risk and to initiate appropriate
treatment.”
Of the 119 women who reported
back pain over 12 months, 20 were di-
agnosed with a new or worsening clin-
ical vertebral fracture. “Only three of
them were in the romosozumab group,
translating into an 83 percent reduc-
tion in the risk of vertebral fracture vs
placebo,” pointed out Geusens. “All
clinical vertebral fractures in the romo-
sozumab group occurred in the first 2
months. The rapid and large reduction
in clinical vertebral fracture risk is an
important and highly relevant clinical
outcome.”

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 CONFERENCE COVERAGE
European League Against Rheumatism (EULAR) Annual Congress • June 14-17 • Madrid, Spain

Denosumab tops risedronate

in glucocorticoid-induced osteoporosis
CHRISTINA LAU

D
enosumab brings greater gains
in spine and hip bone mineral
density (BMD) than risedronate
in glucocorticoid-treated patients at
risk of osteoporotic fracture, according
to results of a phase III study.

In the randomized, double-blind,

double-dummy study in patients continu-
ing (n=505) or initiating (n=290) gluco-
corticoid therapy, treatment with denos-
umab (60 mg every 6 months) resulted in
significantly greater increases in lumbar
spine and total hip BMD at 12 months
compared with risedronate (5 mg daily).
[EULAR 2017, abstract OP0010]

Patients receiving prednisone

≥7.5 mg daily or its equivalent for ≥3
months (glucocorticoid-continuing
[GC-C] group) or <3 months (glucocor-
ticoid-initiating [GC-I] group) were ran-
domized 1:1 to receive denosumab or
risedronate for 24 months, along with
daily calcium (≥1,000 mg) and vitamin
D (≥800 IU) supplementation. All pa-
tients <50 years of age were required to
have a history of osteoporotic fracture,
while GC-C patients ≥50 years of age
were required to have a lumber spine,
total hip or femoral neck BMD T-score
of ≤-20, or a T-score of ≤-1.0 with a his-
tory of osteoporosis fracture.
“At 12 months, denosumab was
superior to risedronate in change in
lumbar spine BMD from baseline,” re-
ported study author Dr Willem Lems
of the VU University Medical Centre,
Amsterdam, the Netherlands. “Lumbar
spine BMD was increased by 4.4 per-
cent with denosumab vs 2.3 percent
with risedronate in the GC-C group,
and by 3.8 vs 0.8 percent in the GC-I
group [both p≤0.002].”
“The same pattern was observed in
total hip BMD, which favoured denos-
umab at 12 months,” noted Lems.
In the GC-C group, total hip BMD at
12 months was increased by 2.1 per-
cent with denosumab vs 0.6 percent
with risedronate (p≤0.001). In the GC-I
group, the corresponding increases
were 1.7 percent and 0.2 percent, re-
spectively (p≤0.001).
“In the bone turnover marker anal-
ysis, significantly larger decreases in
collagen type 1 cross-linked C-telo-
peptide [CTX] and procollagen type 1 N
propeptide [P1NP] were observed with
denosumab vs risedronate at all time
points evaluated, except for P1NP on
day 10 and P1NP and CTX at month
12,” said Lems.
In the study, rates of adverse events
(72.3 vs 69 percent), serious adverse
events (16 vs 16.9 percent), and ad-
verse events leading to discontinuation
of study drug (6.3 vs 7.6 percent) were
similar between the denosumab and
risedronate groups in the combined
GC-C and GC-I subpopulations.
Rates of serious infections, includ-
ing pneumonia (1.3 vs 1.6 percent),
diverticulitis (0.3 vs 0.3 percent), acute
pyelonephritis (0.3 vs 0.3 percent) and
bronchitis (0 vs 0.5 percent), were also
similar between denosumab and rise-
dronate.
“Our results suggest that denosum-
ab has the potential to become anoth-
er treatment option for patients newly
initiating or continuing glucocorticoid
therapy who are at risk of fractures,”
said Lems.
“Glucocorticoid-induced osteopo-
rosis is the most common second-
ary cause of osteoporosis. However,
despite the availability of approved
therapies, many patients still do not
receive prevention or treatment of glu-
cocorticoid-induced osteoporosis,” he
added.

23
DOCTOR | AUGUST ISSUE
 CONFERENCE COVERAGE
European League Against Rheumatism (EULAR) Annual Congress • June 14-17 • Madrid, Spain

Body fat and waist size associated with

higher risk of RA in women
ELAINE TAN

W
omen who are overweight or
obese, as defined by a high
body mass index (BMI), ab-
dominal obesity and a higher body fat
percentage, have a higher risk of devel-
oping rheumatoid arthritis (RA), results
of a Danish population cohort study
has shown.

“Overweight or obese women had

an approximately 50 percent increased
risk of developing RA. However, the
association was not so clear in men,”
reported lead author Dr Asta Linauskas
of the Aarhus University Hospital, Aar-
hus, Denmark, at the EULAR Annual
Congress 2017 held recently in Madrid,
Spain.

“Previous studies investigating the

association between being overweight
and the development of RA have pro-
duced conflicting results. That is possi-
bly because in these studies, BMI was
the preferred surrogate measure for be-
ing overweight, and BMI correlates only
modestly with total body fat volume but
does not accurately reflect the distri-
bution of adipose tissue in the body,”
she said. “Adipose tissue in obesity has
been linked to low-grade inflammation.”
“The aim of our study, therefore,
was to investigate the potential asso-
ciations between BMI, waist circum-
ference, bio-impedence–derived total
body fat percentage and incidence of
RA,” said Linauskas.
The prospective cohort study in-
cluded a population of 54,284 subjects
(52 percent female) aged between 50
and 64 years at the time of recruitment
from 1993 to 1997. At enrollment, apart
from anthropometrical measurements
(weight, height, waist and hip circum-
ference, bio-impedence), researchers
also collected data on the participants’
smoking habits, food frequency (in-
cluding alcohol intake), detailed phys-
ical activity and other lifestyle-related
factors, as well as biobank data such
as blood, urine and fat tissue samples
and toenail clippings. The participants
were followed until development of RA,
loss to follow-up or death in October
2016, whichever came first. Those who
developed RA were identified through
linkage to The Danish National Patient
Registry.
During a median follow-up period of
21 years, 283 women and 110 men de-
veloped RA. The median time to onset
of RA was 7 years.
Multivariable (such as smoking and
socioeconomic status, alcohol con-
sumption, physical activity and total in-
take of n-3 fatty acids) adjusted hazard
ratios (HRs) for RA development in fe-
male participants who were overweight
(BMI of 25–29.99 kg/m2) or obese
(BMI >30 kg/m2) were 1.48 and 1.54,
respectively, as compared with nor-
mal-weight participants. In overweight
or obese men, the adjusted HRs were
0.83 and 0.69, respectively.
For abdominal obesity, defined as
a waist circumference >88 cm in wom-
en and >102 cm in men, the HRs were
1.24 and 1.16, respectively. “The HR
per 5 percent increment of body fat
were 0.97 and 1.16 in men and wom-
en, respectively, showing an unclear as-
sociation between body fat percentage
and RA development in men,” remarked
Linauskas. “This is further supported by
cox regression analyses using restrict-
ed cubic spline, which showed a posi-
tive, linear association in women but no
clear association in men.”

24
DOCTOR | AUGUST ISSUE
 CONFERENCE COVERAGE
European League Against Rheumatism (EULAR) Annual Congress • June 14-17 • Madrid, Spain

IL-6 receptor antibody efficacious for

rheumatoid arthritis nonresponsive
to methotrexate
DR JOSEPH DELANO FULE ROBLES

V
obarilizumab, a nanobody con-
sisting of an anti-interleukin 6
(IL-6) receptor domain devel-
oped for the treatment of rheumatoid
arthritis (RA), is shown to be safe and
efficacious in RA patients with inade-
quate response to methotrexate in a
study.

At the 24th week of this dou-

ble-blind, placebo-controlled trial of
345 patients, higher remission rates
were found in patients who received
vobarilizumab vs placebo (19–20 per-
cent vs 9–10 percent). [EULAR 2017,
abstract OP0098]

“Vobarilizumab is a bispecific nano-

body bound to human serum albumin
for half-life extension. It has no Fc por-
tion, which eliminates the possibility of
antibody-dependent cell cytotoxicity,”
said study author Professor Thomas
Dörner of the Rheumatology and Clin-
ical immunology, Charité University
Hospitals, Berlin, Germany.
Patients included in the study had
already been receiving methotrexate
(average dose, 17 mg/week) and were
assigned to receive either placebo or
one of four different doses of vobir-
ilizumab (75 mg or 150 mg every 4
weeks, or 150 mg or 225 mg every 2
weeks).
At week 24, more patients treated
with vobarilizumab achieved ACR50
(American College of Rheumatology 50
percent improvement) and ACR 70 re-
sponses vs placebo. Rates of ACR50
were up to 61 percent with vobarilizum-
ab vs 39 percent with placebo, while
rates of ACR70 were up to 45 percent
vs 17 percent.
The proportion of patients who sus-
tained ACR50 and ACR70 responses
was noted to be higher in the vobari-
lizumab vs the placebo group (ACR50,
29–39 percent vs 16 percent; ACR70,
11–13 percent vs 4 percent).
Moreover, a higher proportion of vo-
barilizumab-treated patients achieved
low disease activity as measured by
DAS28-CRP (Disease Activity Score
28-C reactive protein) (39–51 percent
vs 16 percent with placebo).
Vobarilizumab also exhibited a fa-
vourable safety profile through week
24 and subsequent follow-up periods.
The frequency of any treatment-emer-
gent adverse event (TEAE) was similar
among all treatment groups (52–65
percent).
“Our study showed that in patients
with RA not responsive to methotrex-
ate, treatment with vobarilizumab, a
newly developed IL-6R antibody, has a
positive impact on efficacy endpoints.
ACR responses and low disease activi-
ty were maintained in a substantial pro-
portion of patients,” Dörner concluded.
In a similar investigation also pre-
sented at EULAR Annual Congress
2017, the study group found that in
251 RA patients, vobarilizumab mono-
therapy had similar efficacy in terms of
ACR20 at week 12 vs tocilizumab (up
to 81 percent vs 78 percent). The rate
of TEAEs was also similar across the
vobarilizumab and tocilizumab groups.
[EULAR 2017, abstract FRI0239]

25
DOCTOR | AUGUST ISSUE
 CONFERENCE COVERAGE
European League Against Rheumatism (EULAR) Annual Congress • June 14-17 • Madrid, Spain

Dekavil shows initial signs of safety and

efficacy in rheumatoid arthritis
JACKEY SUEN

T
he fully-human immunocytokine
dekavil (also known as F8-IL10)
has demonstrated signs of safe-
ty and efficacy in patients with active
rheumatoid arthritis (RA) in a phase I
study, EULAR.

“A total of 35 patients were enrolled

in the study. They had a median age of
63 years, median disease duration of
17.5 years, and median Disease Ac-
tivity Score in 28 joints [DAS 28 score]
of 5.75,” said co-investigator Professor
Mauro Galeazzi of the University Hospi-
tal Siena, Italy. “All patients had received
prior treatment with methotrexate and
at least one anti-tumour necrosis factor
[anti-TNF] therapy. Most of them had
also received steroids previously.” [EU-
LAR 2017, abstract OP0099]
In this phase Ib dose escalation
study, patients with active RA received
four weekly subcutaneous injections of
dekavil 6–600 µg/kg plus methotrexate.
They were given an option to receive
an additional 4 weeks of treatment.
[https://clinicaltrials.gov/ct2/show/
NCT02076659]
“Overall, dekavil was well tolerated
up to the highest investigated dose of
600 µg/kg,” reported Galeazzi. “Mild in-
jection site reactions occurred in 60 per-
cent of the patients. Two patients had
treatment-related anaemia [grade 2 and
grade 3, respectively]. One patient expe-
rienced dose-limiting grade 2 purpura.”
“At the first efficacy assessment
after 4 weeks of treatment, 60 percent
of the patients demonstrated respons-
es according to the American College
of Rheumatology [ACR] criteria and/or
EULAR criteria. The response rate im-
proved to 62.5 percent after 8 weeks
of treatment,” he continued. “Notably,
two patients achieved 70 percent im-
provement according to the ACR cri-
teria [ACR70], and the responses were
maintained for more than 1 year after
the end of treatment. These patients re-
ceived dekavil 30 µg/kg and 60 µg/kg,
respectively, during the study period.”
In view of the good tolerability and
promising signs of efficacy of dekavil as
shown in the current study, the inves-
tigators have initiated a randomized,
double-blind, multicentre, placebo-con-
trolled phase II study to further evaluate
the safety and efficacy of dekavil 30 µg/
kg and 160 µg/kg in combination with
methotrexate in patients with active
RA. [https://clinicaltrials.gov/ct2/show/
NCT02270632]
“Chronic inflammatory and autoim-
mune conditions such as RA can cause
severe pain and affect patient’s qual-
ity of life. However, currently available
medical treatments for the disease help
only a subset of patients,” noted Ge-
leazzi. “Immunocytokines are antibody–
cytokine fusion proteins that allow for
selective induction of immunologic tol-
erance at the site of inflammation while
sparing healthy tissue. They represent
a novel class of drugs for the treatment
of chronic inflammation and autoim-
mune conditions.” [Drug Discov Today
2016;21:180-189]
Dekavil is a fully-human immunocy-
tokine comprising F8 antibody, which
brings the fusion protein to synovial tis-
sue by binding selectively to oncofaetal
fibronectin, and interleukin-10, which
exhibits immunosuppressive effects.
The drug was previously shown to sta-
bilize RA in a mouse model. [Arthritis
Res Ther 2009;11:R142]
Scan the
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full coverage
of EULAR
Congress 2017.

26
DOCTOR | AUGUST ISSUE

Lumacaftor-ivacaftor combo benefits children
with cystic fibrosis
PEARL TOH
A
combined therapy of lumacaftor
and ivacaftor improves lung
ventilation inhomogeneity, pre-
serves spirometric lung function, and
decreases sweat chloride concentra-
tions with a well-tolerated safety pro-
file in children with cystic fibrosis who
harbour the F508del mutation on both
CFTR* alleles (F508del-CFTR), accord-
ing to the VX14-809-109** study.
“Lung damage starts very early [al-
though infants and children may appear
asymptomatic] … our current treatment
strategies are insufficient to prevent irre-
versible structural damage,” according to
Dr Carla Colombo from the Cystic Fibro-
sis Centre at University of Milan, Italy, in
an accompanying commentary. “[C]hil-
dren with cystic fibrosis … could benefit
even more than adult patients from treat-
ment [with CFTR modulators] as it might
prevent the progression of lung disease.”
[Lancet Respir Med 2017;5:536-537]
“It is not uncommon for patients in
this age group to have normal spirome-
try, even when structural abnormalities
[associated with impaired ventilation
are present on CT scans and MRI],”
said the researchers.
Lung clearance index [LCI2.5#] –
which has been shown to be a more
sensitive measure of early structural
lung abnormalities related with cystic
fibrosis and ventilation inhomogeneity
– was chosen as the primary endpoint,
and shown to be responsive even in
children with normal spirometry. [Lan-
cet Respir Med 2017;5:557-567]
At 24 weeks, LCI2.5 significantly
improved from baseline in the luma-
caftor-ivacaftor vs the placebo arm
(least square [LS] mean, -1.01 vs 0.08
units; p<0.0001).
NEWSBITES
“[P]atients in this study were permit-
ted to continue receiving their existing
medications during the study period …
This suggests that the effect of luma-
caftor and ivacaftor on LCI2.5 would
have occurred over and above any
improvement caused by [the existing
medications],” said the researchers.
Sweat chloride concentration, a
biomarker of CFTR function, was also
significantly decreased (ie, improved)
at day 15 and week 4 (combined) from
baseline in the lumacaftor-ivacaftor vs
the placebo group (LS mean, -20.0 vs
0.8 mmol/L; p<0.0001).
Although the absolute change in
ppFEV1## from baseline through week 24
was not significant within either group,
the between-group difference in the
change from baseline was significant in
favour of lumacaftor-ivacaftor (LS mean,
1.1 vs -1.3; p=0.0182), with the mean
ppFEV1 in the placebo group falling be-
low the baseline at all study visits but
never below baseline among the luma-
caftor- and ivacaftor-treated patients.
The multinational double-blind
phase III study included 206 children
aged 6–11 years with cystic fibrosis
who weighed ≥15 kg, had predicted
FEV1 of ≥70, LCI2.5 ≥7.5, and were
tested positive for F508del-CFTR
mutation on both alleles. They were
randomized 1:1 to receive lumacaftor
200 mg and ivacaftor 250 mg Q12H
27
DOCTOR | AUGUST ISSUE
or placebo for 24 weeks.
Incidence of adverse events (AEs)
occurred at similar rates between the
two groups, of which a majority were mild
(43 percent) or moderate (48 percent) in
severity, with cough being the most fre-
quently reported AE in both groups (45
percent vs 47 percent). Compared with
placebo, lumacaftor-ivacaftor was as-
sociated with more frequent productive
cough, nasal congestion, rhinorrhoea,
oropharyngeal pain, upper abdominal
pain, and increased sputum.
Elevated liver enzymes (ALT and
AST###) were also detected in more pa-
tients in the lumacaftor-ivacaftor arm
than the placebo arm (13 percent vs 8
percent).
“In children, particularly those with
a history of liver enzyme elevation or
those exposed to other risk factors (an-
tibiotic therapy, malnutrition, antioxidant
deficiency), liver biochemistry should be
closely monitored,” advised Colombo.
*CFTR: Cystic fibrosis transmembrane conductance-
regulator
**VX14-809-109: A study to evaluate the efficacy and
safety of lumacaftor in combination with ivacaftor
in subjects with CF, homozygous for the F508del-
CFTR mutation
#
LCI2.5: Number of lung volume turnovers required
to reach 2.5 percent of starting tracer gas
concentrationx
##
ppFEV1: Percent predicted forced expiratory
volume in 1 s
###
ALT: Alanine aminotransferase; AST: Aspartate
aminotransferase
 NEWSBITES

Ticagrelor outdoes clopidogrel in ACS

AUDREY ABELLA

U
pstream use of the P2Y12 re-
ceptor antagonist ticagrelor pro-
vides benefit over clopidogrel in
patients with non-ST segment elevation
acute coronary syndrome (NSTE-ACS)
with a relatively rapid time to angiogra-
phy, according to a post hoc analysis of
the PLATO* trial.

“[Our findings suggest that] the clin-

ical benefit of ticagrelor over clopidogrel
was consistent in those undergoing
early and late angiography in patients
with NSTE-ACS,” said the researchers.
“[However], it is possible that the dura-
tion of therapy prior to angiography influ-
ences the efficacy of upstream therapy.”

Researchers evaluated 6,792 pa-

tients with unstable angina/NSTE
myocardial infarction (NSTEMI) who
have undergone angiography within
72 hours of randomization. Of these,
3,486 underwent early angiography (<3
hours) while 3,306 had late angiogra-
phy (≥3 hours). Participants were ran-
domized to receive a loading dose of
ticagrelor 180 mg followed by 90 mg
twice daily (n=3,446) or a loading dose
of clopidogrel 300–600 mg followed by
75 mg once daily (n=3,346). [Clin Car-
diol 2017;40:390-398]
Compared with clopidogrel, tica-
grelor reduced the overall risk of cardio-
vascular death, myocardial infarction,
and/or stroke postangiography (hazard
ratio [HR], 0.67; p=0.002 for day 7,
HR, 0.81; p=0.042 for day 30, and HR,
0.80; p=0.0045 for 1 year).
Major bleeding rates were lower in
patients with early angiography in the
ticagrelor vs the clopidogrel arm (HR,
0.79 at day 7, HR, 0.88 at day 30, and
HR, 0.88 at 1 year).
ticagrelor vs the clopidogrel arm (HR,
1.51; pinteraction=0.002 at day 7, HR,
1.22; pinteraction=0.037 at day 30, and HR,
1.33, pinteraction=0.003 at 1 year), consis-
tent with previous analyses which also
showed increased bleeding events with
ticagrelor during late angiography. [Am
J Emerg Med 2013;31:1005-1011; Eu-
roIntervention 2015;11:737-745]
“These findings are not surpris-
ing, as the level of platelet inhibition is
higher with the more potent agent, and
thus a higher risk of bleeding would be
expected over a long period of treat-
ment,” said the researchers.
The higher bleeding risk is a down-
side of upstream P2Y12 inhibition es-
pecially in cases requiring coronary
artery bypass grafting, they added,
citing a previous trial showing an in-
creased bleeding risk with upstream
therapy with the irreversible thieno-
pyridine prasugrel. [J Am Coll Cardiol
2014;64:2563-2571]
P2Y12 antagonists is that these agents
require time to be absorbed after dos-
ing and then exert their effects on
plaque instability and thrombus forma-
tion,” said the researchers.
Overall, the results support the up-
stream approach using the more po-
tent and rapid-onset ticagrelor in early
invasive management, noted the re-
searchers. “[O]ur results with ticagrelor
help to build the case that this revers-
ible agent can play an important role in
the upstream management of patients
with ACS.”
Furthermore, the results are con-
sistent with the most recent American
College of Cardiology and American
Heart Association NSTEMI guidelines
favouring ticagrelor over clopidogrel in
patients who “undergo an early invasive
or ischaemia-guided strategy,” noted
the researchers.

However, bleeding rates increased “The underlying concept behind

in those with late angiography in the upstream oral antiplatelet therapy with *PLATO: Platelet Inhibition and Patient Outcomes

28
DOCTOR | AUGUST ISSUE

Azithromycin effective adjunct therapy
for uncontrolled asthma
ROSHINI CLAIRE ANTHONY
T
he macrolide antibiotic azithro-
mycin may be an effective ad-
junctive therapy for individuals
whose asthma symptoms persist de-
spite treatment with corticosteroids and
bronchodilators, a recent study found.
“Given the major impact of asth-
ma exacerbations on patients and the
community, and the ongoing risk posed
by these events in patients who remain
symptomatic on maintenance therapy,
we consider that azithromycin is a valu-
able addition to existing regimens for
treating asthma,” said the researchers.
Trial participants were 420 adults
(median age 60 years, median asthma
duration 32 years) with uncontrolled
symptomatic asthma (mean asth-
ma control score [ACQ6], 1.55, mean
forced expiratory volume in 1 second
[FEV1], 73 percent) currently on main-
tenance therapy of inhaled corticoste-
roids and long-acting bronchodilators.
They were randomized to receive oral
azithromycin (500 mg, n=213, 63 per-
cent female) or placebo (n=207, 58
percent female) thrice weekly for 48
weeks.
Patients on azithromycin demon-
strated a reduced rate of asthma
exacerbations compared with those
on placebo (1.07 vs 1.86 per per-
son-year; incidence rate ratio [IRR],
0.59; p<0.0001), a reduction evi-
dent in eosinophilic (0.96 vs 1.98
per person-year; IRR 0.52; p=0.030)
and noneosinophilic asthma (1.15
vs 1.74 per person-year; IRR, 0.66;
p=0.019). [Lancet 2017;doi:10.1016/
S0140-6736(17)31281-3]
Compared with patients on place-
bo, a smaller proportion of patients on
azithromycin experienced at least one
NEWSBITES
asthma exacerbation (44 percent vs
61 percent; p<0.0001). Severe asthma
exacerbation incidence was also lower
among patients on azithromycin com-
pared with placebo (0.61 vs 1.07 per
person-year; IRR, 0.59; p=0.002), as
was time to asthma exacerbation (haz-
ard ratio, 0.65; p=0.001).
Patients on azithromycin also ex-
perienced improved asthma-related
quality of life compared with patients
on placebo (adjusted mean difference,
0.36; p=0.001).
Incidence of serious adverse events
(AEs) was comparable between pa-
tients on azithromycin and placebo (8
percent vs 13 percent; p=0.27), though
a higher incidence of diarrhoea was
noted among patients on azithromycin
(34 percent vs 19 percent; p=0.001).
Infection-related AEs were lower in
the azithromycin vs placebo group (20
percent vs 36 percent; p<0.001), driven
mostly by the lower incidence of respi-
ratory tract infections (17 percent vs 31
percent; p=0.001).
“Since we observed a benefit of
azithromycin on both asthma exac-
29
DOCTOR | AUGUST ISSUE
erbations and respiratory infections,
we speculate that azithromycin might
be acting to prevent viral-induced epi-
sodes in asthma,” said the researchers.
As a majority of the trial population
was of older age, the researchers cau-
tioned against applying the findings to
children or young adults with asthma.
The study was also not adequately
powered to evaluate the impact of azi-
thromycin on microbial resistance.
“[T]he effects of long-term therapy
with macrolides on community micro-
bial resistance remain a public health
concern,” said Professor Guy Brusselle
from Ghent University Hospital, Bel-
gium, and Professor Ian Pavord from the
Nuffield Department of Medicine, Uni-
versity of Oxford, Oxford, UK, in a com-
mentary. [Lancet 2017;doi:10.1016/
S0140-6736(17)31547-7]
“[A]dd-on therapy with azithromy-
cin in asthma needs to be restricted to
those patients with the highest unmet
medical need ... and to time periods
with the greatest risk of exacerbations,”
they said, and called for further re-
search into nonantibiotic macrolides for
severe, uncontrolled asthma.
 NEWSBITES

Predictors of recurrent stroke in Chinese

population identified
JACKEY SUEN

C
hinese patients with ischaemic
stroke involving posterior circu-
lation should be more carefully
monitored for recurrence if they have
dysphagia at admission, repeated tran-
sient ischaemic attack (TIA) before the
stroke, ≥70 percent stenosis of the
responsible artery, multisector infarcts,
and no antithrombotic treatment at dis-
charge.

This recommendation is based on

a recent prospective study conducted
by researchers from Beijing and Hong
Kong to identify clinical and radiological
parameters that can assist in predict-
ing ischaemic stroke recurrence. Data
of 723 Chinese patients with noncar-
diogenic ischaemic stroke involving
posterior circulation were retrieved for
analysis. [Stroke 2017;48:1835-1841]
Among these patients, 5.5 percent
(n=40) had recurrent ischaemic stroke
or TIA at 1 year.
Dysphagia at admission (hazard ra-
tio [HR], 4.16; p=0.002), repeated TIAs
within 3 months before the stroke (HR,
15.4; p<0.0001), ≥70 percent steno-
sis of the responsible artery (HR, 7.91;
p=0.05) and multisector infarcts (HR,
5.38; p=0.02) were found to correlate
with recurrent ischaemic stroke or TIA
within 1 year after adjusting for age,
sex, and vascular risk factors.
In addition, patients who were not
on antithrombotic treatment at dis-
charge had a higher risk of recurrence
(HR, 3.06; p=0.03), reflecting the im-
portance of effective secondary pre-
vention following ischaemic stroke in-
volving posterior circulation.
“Preventive treatment should be
offered to patients with these high-risk
features as soon as possible,” the study
authors suggested.
“Ischaemic stroke involving poste-
rior circulation is associated with poor
prognosis due to its high rates of recur-
rence, mortality, and severe disability,”
they noted. “Several predictive scores
have been developed to identify pa-
tients at high risk of recurrent ischaemic
stroke. However, most of the scores do
not include stenosis of the responsible
artery and imaging features of acute in-
farcts as predictive factors of ischaemic
stroke.”
“Severe stenosis of the artery re-
sponsible for the ischaemic stroke may
cause hypoperfusion and embolism of
the distal artery as well as occlusion of
small penetrating artery, which in turn
increases the risk of recurrent stroke or
TIA as demonstrated in our study,” the
authors wrote.
“Multiple acute infarcts are often
caused by small emboli from an unsta-
ble source, such as rupture of plaque
in a large artery with atherosclerosis.
Therefore, thromboembolism may be
the predominant cause of ischaemic
stroke in patients with multisector in-
farcts,” they explained. “These patients
were found to have a higher risk of
recurrence because they may have a
higher chance of second rupture of un-
stable atherosclerotic plaque or acute
occlusion of the responsible artery.”
In the study, patients with dyspha-
gia at admission more often had mul-
tisector and multilevel infarcts, which
might explain the higher risk of recur-
rent ischaemic stroke or TIA in this sub-
group.
“In contrast, facial palsy was asso-
ciated with a lower risk of ischaemic
stroke or TIA recurrence [HR, 0.41;
p=0.04],” the authors noted. “This is
perhaps because the majority of pa-
tients with facial palsy at admission had
single infarct rather than multisector in-
farcts [78.1 vs 8.5 percent].”

30
DOCTOR | AUGUST ISSUE

Fear of future uncertainties mapped on
a specific brain region
DR JOSEPH DELANO FULE ROBLES
F
indings of a recent study revealed
that people who are very sensitive
to the uncertainty of future events
have an enlarged striatum, a part of the
brain actively involved in psychological
processes.
Among 61 healthy participants who
took part in the study, intolerance of
uncertainty (IU) was positively correlat-
ed with striatal volume, particularly the
putamen, and to a lesser extent the pal-
lidum based on MRI and voxel-based
morphometry [left: MNI (Montreal
Neurologic Institute) space -21, 12, 6,
t(55)=4.54, k=1,073 voxels; MNI space
22, 21 -8, t(55)=4.75, k=874 voxels;
p<0.05]. [Emotion 2017;doi: 10.1037/
emo0000331]
MRI data obtained from the partic-
ipants were submitted for voxel-based
morphometry. Images were first seg-
mented into grey matter, white matter
and cerebrospinal fluid. These images
were then spatially aligned into stan-
dard MNI space. To acquire volume
information for each voxel, grey and
NEWSBITES
white matter images were modulated
with determinants derived from nonlin-
ear spatial alignment procedure.
Consistent with the initial results,
hierarchical regression confirmed that
adding IU scores in the second step
significantly improved the model from
the first step that included age, sex,
intracranial volume, and trait anxiety,
for the bilateral putamen [left putamen,
first step: R2=0.217, F(4, 56)=3.883,
p=0.007; second step: ∆R2=0.179,
∆F(1, 55)=16.267, p=0.00017] [right
putamen, first step: R2=0.2, F(4,
56)=3.504, p=0.013; second step:
∆R2=0.144, ∆F(1, 55)= 12.03, p=0.001].
“Uncertainty and ambiguity of po-
tential future threats are central to un-
derstanding the generation of anxiety
and anxiety disorders,” said author Dr
Justin Kim of Dartmouth College, Ha-
nover, New Hampshire, US.
“In this study, we found no evidence
for other grey matter structures or white
matter tissue to be associated with
IU… Our data also demonstrate that
structural alterations of the striatum
31
DOCTOR | AUGUST ISSUE
are linked to normal variations in a per-
sonality characteristic [elevated IU] that
has ties with certain anxiety disorders
such as obsessive compulsive disorder
[OCD] or generalized anxiety disorder
[GAD],” the authors wrote.
“Having a large striatal volume
may be associated with how intol-
erant individuals are when facing an
uncertain future. It can be observed
in healthy individuals, and it does not
mean that individuals with a large stri-
atal volume have OCD or GAD,” the
authors added.
Participants of the study were
screened for past or current psychiatric
illness using the Diagnostic and Statisti-
cal Manual of Mental Disorders IV (DSM
IV) criteria for OCD and GAD, and had
no current use or history of use of psy-
chotropic medications.
Previous structural brain imaging
studies examining grey matter volumes
in patients with OCD and GAD have
consistently found increased volume in
the striatum, particularly the putamen.
[Psychiatry Res 2015;234:314-320]
 NEWSBITES

Short antibiotic course appears effective for

small abscesses
ROSHINI CLAIRE ANTHONY -12.9 percentage points; p<0.001 for

A
10-day course of clindamycin or
trimethoprim-sulfamethoxazole
after incision and drainage of a
small abscess is associated with a bet-
ter clinical cure rate than incision and
drainage alone, according to a recent
study.
“The cumulative data from our in-
vestigation and that of Talan et al [N
Engl J Med 2016;374:823-832] call
into question the perception ... that
cure rates do not improve with the ad-
dition of systemic antibiotic treatment
after incision and drainage,” said the
researchers.
Participants were 786 outpatients
(281 children and 505 adults, mean age
25.5 years, 57 percent male), each with
a single skin abscess ≤5 cm in diameter
and accompanied by ≥2 of the follow-
ing symptoms for ≥24 hours: erythema,
swelling or induration, purulent drain-
age, tenderness, or local warmth. The
abscesses were incised and drained
and patients were subsequently ran-
domized to receive a 10-day course of
oral clindamycin (300 mg TID, n=266),
trimethoprim-sulfamethoxazole (80 mg
trimethoprim + 400 mg sulfamethoxaz-
ole BID, n=263), or placebo (n=257).
Sixty-seven percent of patients
(n=527) were positive for Staphylococ-
cus aureus (S. aureus) and 49.4 per-
cent (n=388) positive for methicillin-re-
sistant S. aureus (MRSA).
Clinical cure rate at 7–10 days
post-therapy was comparable be-
tween patients on clindamycin and
trimethoprim-sulfamethoxazole (83.1
percent vs 81.7 percent; rate differ-
ence -1.3 percentage points; p=0.73)
and superior to that of placebo (68.9
percent; rate difference -14.2 and
both comparisons). [N Engl J Med
2017;376:2545-2555]
Cure rates were comparable be-
tween patients on clindamycin and tri-
methoprim-sulfamethoxazole who test-
ed positive for S. aureus (83.5 percent
vs 83.2 percent; p=0.99), and higher
than that of patients on placebo (63.8
percent; p<0.001 for both compari-
sons). Similar results were demonstrat-
ed among patients who tested positive
for MRSA (81.7 percent [clindamycin]
vs 84.6 percent [trimethoprim-sulfa-
methoxazole]; p=0.63 compared with
62.9 percent of patients on placebo
(p<0.001 and p=0.001 when compared
with clindamycin and trimethoprim-sul-
famethoxazole, respectively).
In patients without S. aureus,
cure rate was similar among all treat-
ments (83.8, 81.9, and 83.1 percent
of patients treated with clindamycin,
trimethoprim-sulfamethoxazole, and
placebo, respectively; p=0.99 for all
comparisons).
At 1-month follow-up, 78.6, 73.0,
and 62.6 percent of patients initially
treated with clindamycin, trimetho-
prim-sulfamethoxazole, and placebo,
respectively, remained cured.
Patients whose abscesses were
initially cured with clindamycin had a
lower likelihood of new infections (at a
different site or recurrence at original
abscess site) at 1-month follow-up (6.8
percent) compared with those initially
given trimethoprim-sulfamethoxazole
(13.5 percent; p=0.03) or placebo (12.4
percent; p=0.06).
More patients on clindamycin re-
ported an adverse event (21.9 percent)
compared with those on trimetho-
prim-sulfamethoxazole (11.1 percent)
or placebo (12.5 percent), with the
most common adverse events being
diarrhoea (16.2, 5.4, and 6.7 percent,
respectively) and nausea (2.3, 4.2, and
2.4 percent, respectively). Of the nine
serious adverse events reported, only
one was deemed treatment-related
(trimethoprim-sulfamethoxazole-related
hypersensitivity).
“Our findings show a clinical benefit
of antibiotic therapy in addition to inci-
sion and drainage that seems limited to
patients with S. aureus infection,” said
the researchers, who acknowledged
that a longer follow-up period may
have resulted in the detection of more
recurrences.
“Our findings suggest that there is
a trade-off between more adverse ef-
fects and a lower likelihood of infection
recurrence when one uses clindamycin
rather than [trimethoprim-sulfamethox-
azole]. Such information and the local
prevalence of resistance should be
used by treating physicians and policy
makers when choosing an antibiotic
for adjunctive therapy of cutaneous ab-
scesses,” they said.

32
DOCTOR | AUGUST ISSUE

Risk of DKA doubles with SGLT2 inhibitors
PEARL TOH
S
odium-glucose cotransporter
2 (SGLT2) inhibitors were as-
sociated with twice the risk of
diabetic ketoacidosis (DKA) as dipep-
tidyl peptidase-4 (DPP4) inhibitors in
patients with type 2 diabetes shortly
after initiation of medication, although
the overall risk was low, a recent study
suggested.
Due to previous reports of an in-
creased DKA risk with SGLT2 inhibi-
tors, the US FDA issued a warning in
2015.
Using a commercial claim data-
base in the US, the researchers iden-
tified patients (mean age 54 years,
52.8 percent males) who had been
newly prescribed with either an SGLT2
inhibitor (n=50,220) or a DPP4 in-
hibitor (n=90,132). [N Engl J Med
2017;376:2300-2302]
NEWSBITES
Within 180 days after medication
initiation, hospitalization rate for DKA
– the primary outcome – was twofold
higher after initiating an SGLT2 inhibitor
than a DPP4 inhibitor (4.9 vs 2.3 events
per 1,000 person-years, unadjusted
hazard ratio [HR], 2.1). The results re-
mained similar after propensity-score
matching for potential confounders (ad-
justed HR, 2.2, 95 percent confidence
interval [CI], 1.4–3.6).
In sensitivity analyses, the risk of
DKA with SGLT2 inhibitors remained
at least twice that of initiating DPP4
inhibitors, regardless of whether it was
within 30 days (HR, 2.3, 95 percent CI,
1.1–4.8) or 60 days of medication initi-
ation (HR, 2.5, 95 percent CI, 1.3–4.7).
“DPP4 inhibitors were chosen as
the comparator medication because
they are similarly used as a second-line
treatment for diabetes but have no
known association with DKA,” ac-
33
DOCTOR | AUGUST ISSUE
cording to study authors Drs Michael
Fralick, Sebastian Schneeweiss, and
Elisabetta Patorno from the Brigham
and Women’s Hospital in Boston, Mas-
sachusetts, US.
Patients who received SGLT2 inhib-
itors were younger with fewer comor-
bidities than those treated with DPP4
inhibitors, but were also more likely to
be on insulin.
After excluding patients receiving
insulin in the analysis, the risk of DKA
was still higher in patients receiving
SGLT2 inhibitors than in those receiving
DPP4 inhibitors (HR, 2.5, 95 percent
CI, 1.1–5.5).
“The increased risk of DKA with
SGLT2 inhibitors is among the factors to
be considered at the time of prescribing
and throughout therapy if patients pres-
ent with symptoms suggestive of DKA,”
advised Fralick and co-authors.

Targeting risk factors from childhood can cut
dementia cases by one-third
JACKEY SUEN
A
round one in three cases of de-
mentia can potentially be pre-
vented by modifying risk factors
from as early as childhood, a recent
study has shown.
The study modelled the impact of
nine health and lifestyle risk factors
for dementia at various stages in life.
These risk factors were less education
in early life; hearing loss, hypertension
and obesity in mid-life; and smoking,
depression, physical inactivity, so-
cial isolation and diabetes in later life.
[Lancet 2017; doi: 10.1016/S0140-
6736(17)31363-6]
“Although dementia is diagnosed
later in life, brain changes usually begin
to develop years before, with demen-
tia risk factors occurring throughout
the whole life,” said study lead author
Professor Gill Livingston of the Univer-
sity College London, London, UK. “A
broader approach to the prevention of
dementia that reflects these changing
risk factors will benefit our ageing so-
cieties and help prevent the rising num-
ber of dementia cases globally.”
Based on their results, the re-
searchers estimated that 35 percent of
dementia cases could be prevented by
completely eliminating the nine modifi-
able risk factors. In comparison, finding
a treatment that targets the apolipo-
protein E ε4 allele, a major genetic risk
NEWSBITES
factor of dementia, would prevent only
7 percent of the cases.
Among the nine risk factors, reduc-
ing hearing loss in midlife (9 percent),
increasing education in early life (8 per-
cent) and smoking cessation in later
life (5 percent) were the most effective
ways to prevent dementia. These were
followed by preventing depression (4
percent), increasing physical activity (3
percent), improving social life (2 per-
cent), and reducing hypertension (2
percent), diabetes (1 percent) and obe-
sity (1 percent).
“The recognition of hearing loss as a
risk factor for dementia is relatively new.
This has not been included in previous
estimations, nor has it been a priority
34
DOCTOR | AUGUST ISSUE
in the management of those at risk of
cognitive impairment,” wrote the study
authors. “Hearing loss might either add
to the cognitive load of a vulnerable in-
dividual leading to changes in the brain,
or lead to social disengagement or de-
pression and accelerated atrophy, all of
which could contribute to accelerated
cognitive decline.”
The study was conducted by 24
international experts from the Lancet
Commission on Dementia Prevention,
Intervention, and Care, who met to
consolidate currently available evidence
for the prevention and management of
dementia.
“We call on all governments to tackle
the impending dementia crisis by gener-
ating updated action plans, drawing on
the latest evidence, and incorporating
awareness strategies and public health
campaigns for dementia,” wrote Helen
Frankish and Richard Horton from The
Lancet, in an accompanying editorial.
[Lancet 2017, doi: 10.1016/S0140-
6736(17)31756-7] “This Lancet Com-
mission will help inform the development
and implementation of these strategies.”
“Although it is not feasible to ad-
dress all potentially modifiable cases of
dementia, delaying the age of dementia
onset would bring enormous benefits,
with estimates suggesting that a 1-year
delay in onset could prevent more than
9 million cases of dementia by 2050,”
they added.

Fish oil supplementation may help treat
GI cancer cachexia
TRISTAN MANALAC
D
espite progression, lean body
mass and skeletal muscle mass
have increased while the sys-
temic inflammatory response has re-
mained stable in gastrointestinal (GI)
cancer patients with cachexia receiving
fish oil (FO)-enriched nutrition, a new
retrospective cohort study reveals.
“[O]ur systematic and compre-
hensive assessment provided novel
evidence for the clinical feasibility of
providing FO-enriched nutrition during
systemic chemotherapy for patients
with GI cancer. Nutritional interventions
with FO supplementation could be one
component in a multimodal therapeu-
tic approach for GI cancer, especially in
patients with high serum CRP levels,”
said researchers.
Serum concentrations of C-reac-
tive protein (CRP) rose significantly over
time and with progression of GI cancer
(p=0.049) in patients without FO-en-
riched nutrition. In contrast, CRP levels
remained constant in those who were
given FO-enriched nutrition (p=0.26).
[Sci Rep 2017;7:4826]
Subsequent analyses showed that
high CRP concentrations were associ-
ated with poor overall survival (hazard
ratio [HR], 2.88, 95 percent CI, 1.26
– 6.54; p=0.01) and poor tolerance to
chemotherapy (odds ratio [OR], 3.68;
1.35 – 10.0; p=0.011), indicating the
involvement of the systemic inflamma-
tory response to poor prognosis and
tolerance.
Skeletal muscle mass (p=0.26) and
lean body mass (p=0.19) remained un-
changed in patients who did not receive
FO-enriched nutrition and increased
significantly in those who did (p=0.0002
and p<0.0001, respectively).
NEWSBITES
Even in high-risk patients (modified
Glasgow prognostic scores [mGPS] of
1 or 2), FO-enriched nutrition was an
independent predictor of better prog-
nosis (HR, 0.24, 0.06 – 0.98; p=0.045).
Moreover, those who received FO
had significantly improved survival
(p=0.0096) compared with those who
did not.
Cachexia, along with malnutrition
and skeletal muscle wasting, is com-
mon in cancer patients and has been
implicated in low chemotherapy tol-
erance. Nutrition, particularly FO, has
been previously established in numer-
ous studies as an effective intervention
measure for cancer cachexia.
“Previous reports combined with
our present data clearly suggest that organ cells to undergoing apoptosis, as
FO-enriched nutrition plays a pivotal well as other noninflammation-based
role in controlling the inflammatory re- mechanisms,” explained Nicholas Syn,
sponse and maintaining nutritional sta- a student of Soong.
tus during chemotherapy in GI cancer
patients,” according to the researchers. “It is possible, for example, that the
omega-3 fatty acids reversed insulin
However, Dr Richie Soong, senior resistance in some of these patients,
principal investigator at the Cancer which led to an improvement in skeletal
Science Institute of Singapore, recom- muscle and lean body mass,” he added.
mended caution.
The study included 128 advanced
While he conceded that “it is good or recurrent GI cancer patients who
to engage the public with promising experienced pre-illness body weight
scientific news, and give hope to those loss of at least 5 percent. Patients were
with cachexia and systemic inflamma- randomized to receive either FO oral
tion,” he warned that “such [an] article supplementation (n=37) or not (n=91).
could be used to lend credibility to the Laboratory measurements were per-
questionable selling of FO to patients formed using enzyme immunoassays
and the public before more definitive while body composition measurement
evidence is garnered.” were obtained using bioelectrical im-
pedance.
Among the remaining uncertain-
ties is the possibility that FO may have “Notwithstanding, the results of this
worked through other mechanisms. study are an encouraging development
After all, “the pathogenesis of cachex- in the field, and has the potential to im-
ia has also been attributed to the de- pact clinical practice in the future if the
velopment of insulin resistance, an results are replicated in larger random-
increased susceptibility of muscle and ized trials,” said Syn.
35
DOCTOR | AUGUST ISSUE

Alcohol more than doubles risk of MACE
in young hypertensive smokers
STEPHEN PADILLA
A
lcohol consumption increases
the risk of major adverse cardio-
vascular events (MACE) in stage
1 hypertensive smokers younger than
45 years, a recent study has found.
“Our data indicate that alcohol more
than doubles the risk of MACE in young
hypertensive smokers, and that the al-
cohol-related risk is even quadrupled
in heavy smokers,” researchers said.
“This calls for early surveillance and
prompt intervention to improve these
unhealthy behaviours.”
A total of 74 fatal and nonfatal MACE
occurred during a follow-up of 12.6
years. Multivariable Cox models revealed
that current smoking and alcohol drink-
ing correlated with the risk of MACE.
[Am J Med 2017;130:967–974.e1]
Based on multivariable model in-
cluding follow-up changes in blood
pressure and body weight, hazard ra-
tio (HR) was 1.48 (95 percent CI, 1.20
–1.83) for smoking and 1.82 (1.05 to
3.15) for alcohol use. Furthermore,
there was an interactive effect between
alcohol and smoking on risk of MACE
(p<0.001).
The risk of MACE more than dou-
bled among smokers who were alcohol
drinkers (n=142, HR, 4.02, 1.98–8.15)
compared with smokers who abstained
from drinking (n=112, HR, 1.64, 0.63–
4.27). Moreover, the risk of MACE qua-
drupled among heavy smokers who
also drank alcoholic beverages (n=51,
HR, 7.79; 4.22–14.37).
“In this prospective cohort study
of young-to-middle-aged subjects
screened for stage 1 hypertension, we
observed an interaction of smoking and
alcohol on risk of MACE, suggesting
NEWSBITES
that these two factors may have a syn-
ergistic effect on the association with
cardiovascular disease,” researchers
said.
“The association of smoking and al-
cohol appeared particularly deleterious
in heavy smokers, as over one-quarter
of these subjects developed one event
within the 12.6 years of follow-up, with
a sevenfold increase in risk compared
with nonsmokers who abstained from
drinking,” they added.
Multiple factors, such as genetic
and environmental factors, are believed
to cause early cardiovascular disease
onset. Parental history also significantly
predicted MACE in this study, but the
combination of smoking and alcohol
undermined its prognostic contribu-
tion, according to the researchers. [J
Am Coll Cardio. 2011;57:619–627; Eur
J Intern Med 2010;21:511–515; Am J
Hypertens 1994;7:7S–12S]
“At least part of the presumed effect gories of cigarette smoking and three
of smoking and alcohol use on cardio- classes of alcohol use.
vascular disease may be due to the risk
factors that were adjusted for. Howev- One of the strongest risk factors
er, adjustment for traditional risk factors for cardiovascular disease worldwide
did not markedly change the associa- is smoking, which also has the largest
tions of smoking and alcohol with risk potential health gains. In addition, alco-
of adverse outcomes, suggesting that hol use has been linked to elevated risk
they are direct causal factors in the of MACE. [J Hypertens 2002;20:1759-
pathogenesis of MACE,” the research- 1764; BMC Public Health 2016;16:734;
ers explained. Circulation 2016;133:979-987]
These findings stress the impor- More than 60 percent of hyper-
tance of these two lifestyle factors in tensive younger adults have stage
young hypertensive individuals and 1 hypertension, and most of these
support the prevention of cardiovas- people are treated with antihyperten-
cular events through lifestyle changes sive drugs despite lack of evidence
early in life. about the benefit from drug treat-
ment, according to researchers. [BMJ
A total of 1,204 untreated patients 2014;349:g5432; Cochrane Database
(mean age 33.1 years) were included in Syst Rev 2012;8:CD006742; JAMA
this prospective cohort study. The par- 2013;310:959–968; N Engl J Med
ticipants were classified into four cate- 2015;372:447–455]
36
DOCTOR | AUGUST ISSUE
 RESEARCH REVIEW
Heater-cooler devices
in open-heart surgery,
contaminated?
B
M
ore than one-third of 89 heater-cooler units used
during open-heart surgery in hospitals in the US and
Canada were found to be contaminated with dead-
ly Mycobacterium chimaera in an assessment conducted
between July 2015 and December 2016, according to new
research findings presented at the 44th Annual Conference
of the Association for Professionals in Infection Control and
Epidemiology (APIC).
The units contain water tanks that provide tempera-
ture-controlled water during surgery. Although used to control
the temperature of a patient’s blood and organs during heart
bypass surgery, the water does not come into direct contact
with the patient. However, the water can aerosolize and bac-
teria can be transmitted into the surgical environment by air.
The researchers assessed 653 water samples taken from
89 units used in 23 hospitals before and after decontamina-
tion. The aim of the study was to test for the presence of
non-tuberculous mycobacteria, including M. chimaera.
Thirty-three (37 percent) units were positive for M. chi-
maera and four for Legionella. Numerous other mycobacteria
were also detected, and 97 cultures could not be interpreted
because of the extent of bacterial and fungal contamination.
In some units, M. chimaera contamination was present for
months, indicating that decontamination may be difficult.
The researchers commented that their findings highlight
the importance of decontamination monitoring and routine
testing as well as strict adherence to the cleaning and disin-
fection instructions provided by the manufacturer.
Rihs J, et al. Presented at the APIC 2017 Annual Conference, Portland, Oregon, US.
37
DOCTOR | AUGUST ISSUE
Body mass, BMI drop
after high-altitude
climbing
ody mass, body mass index (BMI), irisin, 25-hydroxyvi-
tamin D (25(OH)D) levels and fat free mass decrease
significantly after hypobaric hypoxia from high-altitude
climbing, a new study shows.
On the other hand, hypobaric hypoxia increases myoglobin,
interleukin (IL)-6, osteoprotegerin (OPG), and high-sensitivity
C-reactive protein (hsCRP) levels.
Eight men (mean age 27 years) who underwent a 2-week
climbing expedition in the Alps were subjected to body compo-
sition measurements. Concentrations of hsCRP, myoglobin, iri-
sin, 25(OH)D, OPG and other biomarkers were measured from
collected blood samples.
Body mass (72.3 vs 70.7 kg), BMI (22.7 vs 22.2 kg/m2) and
fat-free mass (84.2 vs 84.1 percent) decreased significantly
from baseline following 2 weeks of hypobaric hypoxia (p<0.05
for all). Similarly, levels of 25(OH)D and irisin decreased signifi-
cantly from baseline (p<0.05 for both). OPG, IL-6, hsCRP and
myoglobin concentrations significantly increased vs baseline
values (p<0.05 for all).
Lean body mass was positively associated with irisin levels
at baseline (p=0.0009) and after climbing (p=0.0366). Similarly,
hsCRP was positively associated with OPG (p=0.0465) and the
ratio between OPG and high sensitivity soluble receptor activa-
tor of NF-κB ligand (sRANKL; p=0.0102).
Significant positive correlations were also found between
IL-6 and myostatin (p=0.028), irisin and 25(OH)D (p=0.0366),
hsCRP concentrations and OPG/sRANKL ratio (p=0.0009),
and myostatin levels and OPG/sRANKL ratio (p=0.0065).
The results suggest that certain myokines may play a role
in skeletal muscle regeneration and energy processes following
hypobaric hypoxia exposure.
Śliwicka et al, Serum irisin and myostatin levels after 2 weeks of high-altitude
climbing; PLoS One 2017;doi:10.1371/journal.pone.0181259
 CLINICAL INSIGHTS | DEVICE
Microneedle patch for flu
Photo credit: Georgia Tech
vaccination effective in first
human trial
PEARL TOH
I
ntradermal influenza vaccination with
a dissolvable microneedle patch was
well tolerated with robust antibody
responses, according to the first-in-hu-
man TIV-MNP 2015* study.
The patch contains microneedles –
micron-scale conical structures – which
dissolve after application to the skin,
thereby delivering vaccine into the skin
while leaving behind a patch that can
be disposed of as nonsharps waste.
“Having the option of a flu vac-
cine that can be easily and painlessly
self-administered could increase cov-
erage and protection by this important
vaccine [besides reducing immuniza-
tion cost],” said lead author and princi-
pal investigator Dr Nadine Rouphael of
Emory University School of Medicine in
Atlanta, Georgia, US.
The partly blinded phase I study ran-
domized 100 adults (aged 18–49 years),
who were naïve to the influenza vaccine
for the 2014-2015 season, to any one of
the four groups: single-dose inactivated
influenza vaccine delivered (i) by mi-
croneedle patch, or (ii) by intramuscular
injection, or (iii) placebo by microneedle
patch, or (iv) self-administered vaccina-
”
tion using microneedle patch [groups (i)
to (iii) were administered by healthcare
workers]. The inactivated vaccine com-
“Having the option of prised surface antigens from the H1N1
a flu vaccine that can (18 µg), H3N2 (17 µg), and B strains (15
µg). [Lancet 2017;doi:10.1016/S0140-
be easily and painlessly
6736(17)30575-5]
self-administered could
increase coverage No incidence was reported for the
and protection by this primary safety outcomes of treatment-re-
lated serious adverse events (AEs) within
important vaccine”
180 days and treatment-related unsolic-
ited grade ≥3 AEs within 28 days after
administration. There was also no report
38
DOCTOR | AUGUST ISSUE
of new-onset chronic illnesses by 180
days, the secondary safety outcome.
Within 8 days of vaccination, local
and systemic reactions to vaccination
were mostly mild and transient, with
tenderness (60 percent) and pain (44
percent) being commonly associated
with the intramuscular route, whereas
tenderness (66 percent), erythema (40
percent), and itch (82 percent) were
commonly reported after vaccination
by microneedle patch.
Compared with intramuscular injec-
tion, vaccination through microneedle
patch by healthcare workers showed
comparable levels of functional anti-
body induction, as reflected by similar
geometric mean titres at day 28 for all
strains of influenza vaccine.
Similarly, participants who self-vac-
cinated through the microneedle patch
achieved geometric mean titres com-
parable to that administered by health-
care workers (p>0.05 for all strains),
implying that the patch was easy to use
for the general public.
“Microneedle patches have the po-
tential to become ideal candidates for
vaccination programmes, not only in
poorly resourced settings, but also for
individuals who currently prefer not to
get vaccinated, potentially even being
an attractive vaccine for the paediatric
population, provided late-stage clinical
development confirms vaccine effica-
cy,” wrote Drs Katja Höschler and Ma-
ria Zambon from the National Infections
Service at Public Health England in
London, UK, in an accompanying com-
mentary. [Lancet 2017;doi:10.1016/
S0140-6736(17)31364-8]
*TIV-MNP 2015: Inactivated influenza vaccine
delivered by microneedle patch or by hypodermic
needle
 CLINICAL INSIGHTS | IN PRACTICE
Managing prostate cancer
in primary care
P
rostate cancer in its early stages
is curable with many treatment
options available. Hence, ear-
ly detection is essential for patients to
Dr Daniel Tan
have the best chance of cure and also
to have the option of the widest range
of therapeutic options based on their
acceptance of each side effect profile.
Diagnosis
Prostate cancer is often silent in
its early stages. Patients may present
with urinary symptoms of obstruction
such as hesitancy, dysuria, frequency,
nocturia, poor stream, and occasional-
ly, haematuria. In the GP clinic, digital
rectal exam (DRE) and prostate-specific
antigen (PSA) testing are useful in pick-
ing up prostate cancer. Patients with
suspicious results are then referred to
a urologist for a prostate biopsy to con-
According to the firm the diagnosis.
Singapore National
There is controversy over routine
Registry of Diseases population-based screening for pros-
Office (NRDO), prostate tate cancer, mainly because it has not
cancer is the third most been shown to save lives and may
common cancer and also lead to extra tests and treatments
the sixth most common which may be harmful to those who un-
dergo them.
cause of cancer-related
deaths affecting men Anecdotally, most oncologists
in Singapore. Dr Daniel have treated the screening-diagnosed
Tan, radiation oncologist prostate cancer patient which demon-
and medical director strates that screening does pick up
of Asian American asymptomatic prostate cancers. The
problem is what may work for an indi-
Radiation Oncology at
vidual may not benefit the population at
Gleneagles Hospital, large. Thus, patients who wish to pay
Singapore, speaks to for their own prostate cancer screen-
Roshini Claire Anthony ing may do so after being adequately
on the importance counselled about the pros and cons of
of early detection of doing so.
prostate cancer and the
Men who are at higher risk of
challenges associated prostate cancer (eg, those who have
with diagnosing and a familial history due to faulty genes)
treating this condition. may benefit from regular PSA screen-
39
DOCTOR | AUGUST ISSUE
ing. This is still an ongoing research
question.
The main challenge in diagnos-
ing prostate cancer is that presenting
symptoms are similar to other condi-
tions such as benign prostatic hyper-
plasia, prostate infection (prostatitis), or
physiological activities such as exercise
or sexual activity. This may result in
false alarms which may lead to unnec-
essary anxiety and additional tests for
the patient. GPs can overcome these
by adequately counselling patients (be-
fore they undergo screening) about the
possible outcomes and tests, and for
patients not to be unduly alarmed until
a final diagnosis is made.
Treatment
Prior to commencing treatment,
patients should be adequately worked
up and staged so that the appropriate
treatments can be determined. GPs
should refer patients to a urologist for
a transrectal ultrasound (TRUS)-guid-
ed biopsy to confirm the diagnosis and
thereafter refer their patients to the var-
ious treating specialists for an informed
discussion of the most appropriate
treatment option. Given that there are
different treatments which are equally
effective for prostate cancer, it is im-
portant for patients to understand the
available options and their possible side
effects before making a decision.
Treatment of prostate cancer varies
from active surveillance in early, low-risk
prostate cancers to radical prostatec-
tomy or radiation therapy alone or in
combination with hormonal therapy in
localized prostate cancer, to hormonal
therapy or chemotherapy in late, ad-
vanced prostate cancer.
There are different types of radiation
therapy such as internal radiotherapy

(brachytherapy), external beam radio-
therapy in the form of intensity-modu-
lated radiation therapy or stereotactic
body radiation therapy, and proton
beam therapy. Each of these treatment
options has their own efficacy, cost, du-
ration, and side effect profile.
Recently, a new scanning technique
called multi-parametric Magnetic Res-
onance Imaging (mpMRI) was shown
to be able to better identify men who
would benefit from a prostate biopsy
among those screened using PSA and
DRE. Furthermore, the ability to visual-
ize the suspicious nodules within the
prostate using this scan enables the
biopsy to be more focused. Finally, the
MRI scan would also demonstrate the
extent of tumour invasion, which will
help specialists decide whether surgery
or radiation is a better treatment option
for the patient.
GPs should keep in contact with
the treating specialist to be updated
CLINICAL INSIGHTS | IN PRACTICE
Practice Guidelines
Society for Men’s Health
Singapore
http://media.wix.com/ug-
d/0647cb_8089072f3f1b-
424d985e4b1c149f5929.pdf
National Comprehensive
Cancer Network (NCCN)
https://www.nccn.org/profes-
sionals/physician_gls/f_guide-
lines.asp
European Society for Medical
Oncology (ESMO)
http://www.esmo.org/Guide-
lines/Genitourinary-Cancers/
Cancer-of-the-Prostate
of their patient’s treatment details and
expected side effects. The treating spe-
cialist will be able to advise the GP what
side effects to look out for and how to
optimally manage them.
Conclusion
Prostate cancer is increasing in in-
cidence due to an ageing population
as well as the widespread practice of
PSA screening. Not all prostate can-
cers need to be treated and for those
which need treatment, many equally ef-
fective modern treatments exist. These
options vary in cost, duration, and side Scan the
effect profile, and patients should be QR code to
given their full options so that they will view more of
receive the most appropriate treatment MIMS clinical
and the option they are most com- news
fortable with. GPs can work together
with the patient’s urologist or radiation
oncologist to understand the patient’s
condition so as to provide seamless
continuum of care from the point of
diagnosis to treatment and post-treat-
ment surveillance.
40
DOCTOR | AUGUST ISSUE
Delivering a complete
MIMS experience
Doctors with a MIMS.com account get to enjoy full and exclusive
access to a suite of MIMS services and professional resources.

T
he story of MIMS goes way back,
with a rich history dating back to
1963. Its early years were rooted
in providing independent drug informa-
tion guidebooks to healthcare profes-
sionals. Widely known for its high level
of editorial integrity and independence,
MIMS has quickly grown into the single
most trusted source of comprehensive
drug information amongst healthcare
communities.
Over the years, MIMS has digitally
transformed the business and currently
owns the largest healthcare database
in Asia. In line with evolving needs of
healthcare professionals and a rising
demand for real-time news, the MIMS.
com platform was launched in 2007.
Apart from serving the needs of doc-
tors with up-to-date clinical news and
a comprehensive drugs and disease
catalogue, the portal also hosts special
reports, global medical congress cov-
erage, interviews and insights from key
opinion leaders, evidence-based clini-
cal calculators, CME modules and even
a job portal.
Exclusive to doctors
In a bid to meet the professional
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ing exclusive access to MIMS services
and resources for doctors once they ver-
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cently kicked off in Singapore and Hong
Kong in June this year, and will eventually
be rolled out to other countries.
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go to aid their workflow, access a com-
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to enhance their professional develop-
ment; and tap into a wide network of
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practices and latest specialty develop-
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Other perks include receiving com-
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event coverage as well as accumulating
MIMS Points, which can be exchanged
for vouchers, by participating in online
MIMS activities.

The one-stop drug search engine The verification process aims to

was designed with the understanding
that healthcare professionals needed
credible and authoritative prescrib-
ing information in their daily workflow
practice across multiple platforms.
Today, the leading online medical
resource in Asia reaches 15.3 million
page views per month and contin-
ues to grow in reputation and reach.
communicate the value of MIMS pro-
fessional resources designed to sup-
port doctors in their daily practice and
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them in an environment of greater trust
and security.
By completing their profiles online,
doctors are able to obtain essential

For a limited time, doctors will also receive complimentary

MIMS publications (worth $139 a year), including:

• MIMS Doctor, a multi-specialty magazine with the latest on medicinal research,

conference reports and key medical news.

•M
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tion designed for healthcare professionals.
 Unlock full access to
MIMS professional
resources in 3 easy steps!

1 Visit
Go to mims.asia/
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2
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E
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88%
of doctors use
independent drug and
disease informational
resources like MIMS,
when looking up clinical
information.
MIMS Survey, 2015

WHAT DOCTORS THINK OF MIMS.COM:

DR TAN TOH LICK DR KOH SHUNJIE, KELVIN

Specialist in Obstetrics & Gynaecology General Practitioner and General Manager

I frequently consult MIMS.com in my daily practice. The MIMS.com gives healthcare professionals quick and easy
comprehensive information on the various drugs allow me access to information on drugs and their dosages. It also
to prescribe with confidence. The information is laid out offers updates on medical news and current research top-
systematically and allows me to discuss the indications, ics. It is a useful tool that supports my daily practice.
side effects, safety profile in pregnancy with my clients.
The MIMS App on my smartphone affords me the conve-
nience of accessing this information on the go.
 CALENDAR

AUGUST SEPTEMBER SEPTEMBER

26-30
SATURDAY - WEDNESDAY
08-12
FRIDAY - TUESDAY
09-13
SATURDAY - WEDNESDAY

European Society of Cardiology European Society for European Respiratory Society

(ESC) Congress 2017
Location: Barcelona, Spain
Tel: +33 4 92 94 76 00
Fax: +33 4 92 94 76 01
Website: www.escardio.org/ESC2017
Medical Oncology (ESMO) 2017
Congress
Location: Madrid, Spain
Tel: +41 (0) 91 973 19 00
Fax: +41 (0) 91 973 19 02
Email: esmo@esmo.org
Website: www.esmo.org
(ERS) International Congress
Location: Milan, Italy
Tel: +41 212 13 01 64
Email: exhibition@ersnet.org / kristof.kemp@
ersnet.org
Website: www.erscongress.org

SEPTEMBER SEPTEMBER SEPTEMBER

11-15
MONDAY - FRIDAY
13-17
WEDNESDAY - SUNDAY
23-26
SATURDAY - TUESDAY

53rd European Association for
the Study of Diabetes (EASD)
Annual Meeting
Location: Lisbon, Portugal
Tel: +49 211 758 469 0
Fax: +49 211 758 469 29
Email: info@easdcongress2017.org
Website: www.easdcongress2017.org
26th European Academy of
Dermatology and Venereology
(EADV) Congress
Location: Geneva, Switzerland
Tel: +41 91 973 45 20
Fax: +41 91 973 45 30
Email: info@eadvcongress.org
Website: www.eadvgeneva2017.org
Asia Pacific Digestive Week
(APDW) 2017
Location: Hong Kong
Tel: +852 2155 8557
Email: meeting.hk@mims.com
Website: www.apdw2017.org

OCTOBER OCTOBER OCTOBER

15-18
SUNDAY - WEDNESDAY
15-18
SUNDAY - WEDNESDAY
20-21
FRIDAY - SATURDAY

18th World Conference
on Lung Cancer
Location: Yokohama, Japan
Tel: 720 325 2951
Fax: 720 325 2848
Email: Pia.Hirsch@iaslc.org
Website: www.iaslc.org
10th World Congress
on Developmental Origins of
Health and Disease (DOHaD)
Location: Rotterdam, The Netherlands
T: +31 10 704 38 79
Email: dohad.2017@erasmusmc.nl / secre-
tariat.dohad17@erasmusmc.nl
Website: www.dohadsoc.org
Singapore Prevention & Cardiac
Rehabilitation Symposium 2017
Location: Novotel Clarke Quay, Singapore
Tel: +65 6290 7532
Email: enquiry@spcrs.sg
Website: www.spcrs.sg

43
DOCTOR | AUGUST ISSUE