COURAGE

Clinical Outcomes Utilizing

Revascularization and
Aggressive Guideline-Driven
Drug Evaluation

Background
More than 1 million PCI procedures are performed in the
U.S. annually, the great majority of which are undertaken
electively in patients with stable CAD
Although successful PCI of flow-limiting stenoses might
be expected to reduce the rate of death, MI or
hospitalization for ACS, prior studies have shown only that
PCI decreases the frequency of angina and improves
short-term exercise performance

Conclusions

As an initial management strategy in patients with

stable coronary artery disease, PCI did not reduce
the risk of death, MI, or other major
cardiovascular events when added to optimal
medical therapy

As expected, PCI resulted in better angina relief

during most of the follow-up period, but medical
therapy was also remarkably effective, with no
betweengroup difference in angina-free status at 5
years

Implications

Our findings reinforce existing ACC/AHA clinical

practice guidelines, which state that PCI can be safely
deferred in patients with stable CAD, even in those
with extensive, multivessel involvement and inducible
ischemia, provided that intensive, multifaceted medical
therapy is instituted and maintained

Optimal medical therapy and aggressive management

of multiple treatment targets without initial PCI can be
implemented safely in the majority of patients with
stable CADtwo-thirds of whom may not require
even a first revascularization during long-term followup

Implications

Our findings reinforce existing ACC/AHA clinical

practice guidelines, which state that PCI can be safely
deferred in patients with stable CAD, even in those
with extensive, multivessel involvement and inducible
ischemia, provided that intensive, multifaceted medical
therapy is instituted and maintained

Optimal medical therapy and aggressive management

of multiple treatment targets without initial PCI can be
implemented safely in the majority of patients with
stable CADtwo-thirds of whom may not require
even a first revascularization during long-term followup


TriCardin

was successfully launched in

Pakistan by Trigen Pharma in March 2006

HIGHEST SELLING Cardiac Medicine
in China and is available worldwide in 34
countries

Single Largest Selling Drug in any
therapeutic category

Over 100,000 international clinical trials have

proved TriCardin as the most effective drug to
treat cardiovascular diseases and
microangiopathies
TriCardin is widely used in all Chinese Army
Hospitals and other hospitals as

FIRST LINE OF TREATMENT

TriCardin is a very high-profile, safe, multi-functional

research medicine, manufactured on 4th Generation HiTech Dripping Pills Technology Plant the only of its
kind in the world
Dripping Pills Technology ensures very quick onset of
action, rapid absorption and immediate improvement in
symptoms

Highest Quality Standards

Tasly Pharma Group is

highly certified
TriCardin is FDA
approved medicine, with
99.99% purity and
accurate composition of
ingredients, ensured by
patented multifingerprint technology
IND

International Registrations

USA

st
21

Century Concept
of

Treating Cardiovascular System &

Microangiopathies

COMPOSITION OF

TriCardin
Danshenform
Compound
Salvia Miltiorrhiza
207mg
Notogenseng
40.5mg
Borneol
2.5mg

The ingredients of
Tricardin are registered
in Chinese Pharmacopia

SALVIA MILTIORRHIZA (SM)

Water soluable
compounds of SM:

Protocatechuic aldehyde
Protocatechuic acid
Caffeic acid
3,4 dihydroxyphenol
lactic acid
Lithospermic acid
Salvianolic acid A & B
Rosmarinic acid

Lipophilic compounds of
SM:

Tanshinone I
Tanshinone IIA & IIB
Cryptotanshinone
Tanshinodiol C
15,16 dihydrotanshinone
I
Isotanshinone I
Isotanshinone II

ROLE OF TriCardin

Improves Microcirculation
Large Arteries & Veins only
act as a passage.
Microcirculation transports
blood cells and substances
(O2, CO2, Nutrients,
Hormones, Water) to and
from the tissues. It also
contribute to tissue colour
and stiffness

MICROCIRCULATION

Microcirculation comprises the greatest portion

of the peripheral vasculature in terms of length
and surface area of blood vessels, so it is the
bulk of peripheral circulation
Microcirculation is the key site of increased
vascular resistance in hypertension
(Microcirculation in Hypertension: Circulation. 2001;104:7352001;104:735-740)

REPERFUSION INJURY

Microcirculation is the prime site involved in the

pathophysiology of reperfusion injury. It is an important site of
nitric oxide production & superoxide (free radical) formation.
It is the primary location for leukocyte- endothelial cell
interaction which is the hall mark of reperfusion injury
Reperfusion injury is initiated within minutes of reperfusion by
the generation of superoxide radicals that inactivate NO. The
reduced bioavailability of NO triggers an endothelial dysfunction
that promotes neutrophil adherence and injury
(Dialogues in Cardiovascular Medicine Vol 3 No.3 1998)

ENDOTHELIAL CELLS

These cells are the major

functional element of blood vessel
wall that allow arterioles,
capillaries and venules to carry
out their functions.
Endothelial cells produce variety
of substances that can affect
underlying smooth muscle cells
and circulating blood cells.
Endothelial dysfunction
contributes to the pathogenesis of
number of cardiovascular
diseases, including
atherosclerosis, hypertension,
insulin resistance (diabetes
mellitus) & hypercholesterolemia

LEUKOCYTE-ENDOTHELIAL CELL
ADHESION

Circulating leukocytes are

recruited to sites of
inflammation and tissue
injury by a highly coordinated process
Adhesion molecules are
expressed on the surface
of the endothelial cells and
their respective circulating
leukocytes
Selectins (P and E)
mediate leukocyte rolling

LEUKOCYTE-ENDOTHELIAL CELL
ADHESION

Endothelial cell adhesion molecules that ensure firm adhesion of

leukocytes includes intercellular adhesion molecule-1 (ICAM-1) &
vascular cell adhesion molecule-1 (VCAM-1)
Nitric oxide & Prostacyclin produced by endothelial cells tend
to prevent adhesion, while the oxygen radicals (superoxide,
hydrogen peroxide) generated by activated leukocytes and
endothelial cells promote leukocyte adhesion
Vascular endothelial cells serves as a barrier to the movement of
fluid and proteins from blood to interstitium. The barrier is lost
due to damage of endothelial cells which results in increase
vascular permeability.
Leukocyte-endothelial cell adhesion and increased vascular
permeability is present in cardiovascular system and regional
circulatory disorder (Hypertension, Stroke, Diabetes Mellitus)

MICROCIRCULATORY
DYSFUNCTION
Endothelial
Injury

Platelet
activation

Hypercoagulability

Microcirculatory
dysfunction
Cell
adhesion

Vascular
Permeability
peroxide

EFFECTS OF IMPAIRED
MICROCIRCULATION
ON BRAIN:
CERBRAL
ISCHEMIA

ON EYES:
DAMAGE TO
RETINAL
VESSELS

INFARCTION

RETINOPATHY

PARALYSIS

BLINDNESS

ON KIDNEY:
PARENCHYMAL
DAMAGE

ON HEART:

ON LUNGS:

ANGINA

PLUMONARY
INFARCTION

M.I

DEATH

ON LEGS:
GANGRENE

RENAL FAILURE

DEATH

DEATH

ACUTE RT. HEART

FAILURE

DEATH

Action of Tricardin on Heart



Tricardin stimulates nitric oxide production of endothelial cells by

increasing endothelial nitric oxide synthase (eNOS) expression level.
(Pharmacology & therapeutics doi:10.1016/j.pharmthera.2007.09.008)
doi:10.1016/j.pharmthera.2007.09.008)

TriCardin scavenge oxygen free radicals and inhibits myocardial cell

apoptosis.
(Journal of Clinical Pharmacology 2005;45:13452005;45:1345-1359)

TriCardin inhibits Ca++ aggregation in cardiac cells and prevents

Ca++ overload
(Journal of Clinical Pharmacology, 2005;45:13452005;45:1345-1359)

Tricardin inhibits homocysteine and protects the myocardial cells

against homocystenemia
(Journal of Clinical Pharmacology, 2005;45:13452005;45:1345-1359)

Tricardin inhibits DNA synthesis of noncardiomyocytes and inhibits

Stress-activated protein (SAP) kinase activity.
(Journal of Clinical Pharmacology, 2005;45:13452005;45:1345-1359)
(Journal of Cardiovascular Pharmacology, Volume 45, Number 5, May
May 2005)

Action of TriCardin on Blood Vessels



TriCardin increases endothelium derives prostacyclin or PGI2

(potent vasodilator & platelet aggregation inhibitor) and inhibits
Thromboxane A2 (potent vasoconstrictor) and B2
(Journal of Clinical Pharmacology, 2005;45:13452005;45:1345-1359) (Journal of Thoracic and Cardiovascular Surgery, 2003;126:1404
2003;126:1404-1410)

TriCardin inhibits endothelium-derived vasoconstrictor

endothelin-1 (ET-1)
(Journal of Thoracic and Cardiovascular Surgery, 2003;126:14042003;126:1404-1410)

Tricardin inhibits the activation of nuclear transcription factor NFkB by blocking its translocation from cytoplasm to nuclei
(Journal of Cardiovascular Pharmacology, Volume 45, Number 5, May
May 2005)

TriCardin stimulates glutathione synthesis (an intracellular

antioxidant) which inhibits NF-kB activation and resultant
adhesion molecule expression.
(Journal of cardiovascular pharmacology Vol 45, number 5 May 2005)

Action of TriCardin on Blood



TriCardin dissolves preformed microthrombi, interferes with

extrinsic blood coagulation and exhibit antithrombin III like
activity.
(Annals of Pharmacotherapy 2001 April, Volume 35)

Tricardin significantly decreases P-selectin, G IIb/IIIa

expression and intracellular calcium in both unactivated and
ADP activated platelet.
(Bllod coagulation & fibrinolysis 17:25917:259-264,2006. Lippincott Williams & Wilkins)

Inhibits mast cell degranulation

(Pharmacology & therapeutics doi:10.1016/j.pharmthera.2007.09.008)
doi:10.1016/j.pharmthera.2007.09.008)

Inhibits cytokines release

(Pharmacology & therapeutics doi:10.1016/j.pharmthera.2007.09.008)
doi:10.1016/j.pharmthera.2007.09.008)

Effectively reduces the expression of VCAM-1 and ICAM-1 on

vascular endothelium.
(Journal of Cardiovascular Pharmacology, Volume 45, Number 5, May 2005)

Action of TriCardin on Lipid Profile



Total cholesterol, TG and LDL cholesterol levels were

significantly reduced by 28.3%, 34.3% and 29.9% respectively
and HDL cholesterol was significantly high by 33.2%
(Journal of American Heart Association ATV. 1998;18;4811998;18;481-486)

Tricardin inhibits LDL oxidation by inhibiting 1-diphenyl-2picrylhydrazyl radicals.

(Journal of American Heart Association ATV. 1998;18;4811998;18;481-486)

Tricardin prevents of uptake of LDL by cultured macrophages.

(Journal of American Heart Association ATV. 1998;18;4811998;18;481-486)

VASCULAR COMPLICATIONS OF
DIABETES MELLITUS

Microvascular Complications

Diabetic Retinopathy
Diabetic Neuropathy
(diabetic foot)
Diabetic Nephropathy
Diabetic foot is often due to a
combination of neuropathy
and arterial disease, may cause
skin ulcer and infection and, in
serious cases, necrosis and
gangrene.

Macrovascular Complications
It leads to cardiovascular
disease, to which accelerated
atherosclerosis is a
contributor

Coronary Artery Disease

leading to Angina and MI
Stroke
Peripheral Vascular Disease

ROLE OF TriCardin IN DM

The effect of oral hypoglycaemics is only aimed to lower level of

blood glucose where as TriCardin acts multi dimensionally in
diabetes mellitus:

TriCardin minimizes insulin resistance by promoting blood

microcirculation
TriCardin reduces whole blood viscosity and decreases urinary albumin
& retards the process of diabetic nephropathy
TriCardin significantly increases the superoxide dismutase (SOD) levels;
it resists lipid peroxidation injury and be helpful for diabetic
complications
No side effects as compared to those of oral hypoglycaemics
(hypoglycaemia, lactic acidosis, GI upset)

ROLE OF TriCardin IN
METABOLIC SYNDROME

People with metabolic syndrome are at increased

risk of CHD, Stroke, PVD & DM
AHA recommendation for managing metabolic
syndrome is to reduce the risk for CV diseases &
DM Type2 by reducing LDL, controlling BP
and glucose levels
TriCardin (2xBID or 1xTID) is the only option
available to achieve above targets by improving
microcirculation

ROLE OF TriCardin IN
HYPERTENSION

The reduction or improvement in end organ damage seen

during anti-hypertensive therapy do not always correlate well
with the reduction in arterial blood pressure achieved. There seems
to be a need for new therapeutic perspective in the treatment of hypertension
One important new perspective is provided by an enhanced
appreciation of the importance of the microcirculation in the
pathophysiology and treatment of hypertension. (Microcirculation in
Hypertension: Circulation. 2001;104:7352001;104:735-740)

By adding Tricardin (2xBID or 1xTID) hypertension

control can be achieved because it overcomes the vascular
resistance offered by the microcirculation

INDICATIONS OF TriCardin

Tricardin is indicated in the treatment &

prevention of the following:
Ischemic Heart Diseases (Angina Pectoris/MI)

Hyperlipidemia

Atherosclerosis/Arteriosclerosis

Diabetic & Hypertensive Nephropathy, Retinopathy
& Neuropathy

Stroke & PVD

Metabolic Syndrome

DOSAGE OF TriCardin

TriCardin AS AN ANTI-ANGINAL
A Meta Analysis
TriCardin (SM) for the treatment of chronic stable angina
pectoris compared with Nitrates
Med Sci Monit,
Monit, 2006;12(1):SR12006;12(1):SR1-7
PMID: 26369479
www.MedSciMonit.com

Compared with Nitrates,treatment with TriCardin had

significant effect on improvement of angina symptoms,
showed greater increased effect on the improvement of
ECG results and the percentage of patients with adverse
events was significantly decreased in comparison with
nitrates

TriCardin AS ANTI-ATHEROSCLEROSIS, ANTITHROMBOTIC & ANTI-HYPERLIPIDEMIC

Increase of Vitamin E content in LDL and Reduction
of Atherosclerosis in Cholesterol-Fed Rabbits by
TriCardin (Salvia Miltiorrhiza)
Arterioscler.Thrombi.Vasc.Biol.1998;18;481-486 published by the American Heart
Association http://atvb.ahajournals.org/cgi/content/full/18/3/481

TriCardin (SM) acts as a potent anti-oxidant thus

inhibiting LDL oxidation, TriCardin reduced
endothelial damage and severity of atherosclerosis

TriCardin AS AN ANTI-PLATELET
Inhibitory Effects of TriCardin on Platelet Function
in Dogs Fed a High-Fat Diet
Blood Coagulation & Fibrinolysis 2006, 17:259-264 Lippincott Williams & Wilkins

Compared with Aspirin, TriCardin showed a more

exaggerated inhibitory effect on platelet function.
The lipid lowering and anti-oxidant effects of
TriCardin are responsible for this result.
Research has suggested that TriCardin produce
multiple beneficial effects on cardiovascular
protection.

VERY HIGH SAFETY PROFILE &

TOLERABLITY OF TriCardin

Rarely reported mild effects are headache,

dizziness and flushing (1.93%) and GI upset
(1.14%). Will disappear with continuous usage
No animal died even after administration of 700
times oral dose or 350 times intraperitoneal dose
of that used clinically for adults
Proven wide safety margin

CONTRAINDICATIONS TriCardin




Pregnant and lactating women

When patient is on Warfarin
When patient is on Heparin

CONVENTIONAL MANAGEMENT
OF ISCHEMIC HEART DISEASE

Aspirin
Clopidogrel
Anti-anginal
Beta-Blockers

Calcium Antagonists

Nitrates

Statins

ADDITION OF TriCardin
Adding TriCardin 1-2 Capsules
two to three times a day

Aspirin
Clopidogrel
Anti-anginal

Beta-Blockers
Calcium Antagonists
Nitrates

Statins

Net Result:

Reduction in number of
medications. Patient will feel
good
Significant decrease in
anginal episodes
Marked improvement in
ECG and ETT
Improvement in Ejection
fraction
Remarkable improvement in
General Condition of patient
within weeks
Better quality of life

Recently Concluded
Local Clinical Trials

Clinical Trial Conducted at

The Department of
Cardiology, Lady Reading
Hospital, Peshawar

Efficacy of TriCardin for

improving Ischemic Symptoms &
reducing episodes of Angina in
patients with known cases of CAD
Professor Dr. Mohammad Hafizullah
Dr. Mahmood ul Hassan
Dr. Saqib Qureshi
Dr. Mohammad Fahim
Dr. Cheragh Hassan
Cardiology Department,Postgraduate Medical Institute, Lady Reading Hospital,
Peshawar.

LRH

Objective: To assess the efficacy of TriCardin in patient with angina

pectoris already on optimal dose for reducing the duration of episode of angina
attacks subjectively and to see it objectively on ETT in our population.

Material and methods: Twenty patients who are known cases of CHD
with CCS-II Angina included in the study who were already taking optimum
doses of anti anginal medications like aspirin,beta blocker, lipid lowering
nitrates,ACE inhibitors and clopidegrol.
Patients were exercised on treadmill according to Bruce protocol at baseline and
one week later. At second week TriCardin 500mg was given for four weeks. At
the end of four weeks again exercise tolerance test was performed. Duration and
number of anginal episodes before and at the end of fourth week recorded.
Total exercise time, onset of ST segment depression before and after treatment
with TriCardin recorded.

LRH

CLINICAL VARIABLES OF THE

RESPONDENTS
Total no.
Male
Female
Age (years)
Heart rate
Prior MI
HTN
DM

19
13 (68.4%)
6 (31.6%)
46.74 + 8.73
77.37 + 15.86
3 (15.8%)
6(31.6%)
1( 5.3%)

Total duration of Angina

8.5 + 7.7 months

Total duration of anti-anginal med 7.95 + 7.7 months

LRH

Comparison of variables
variables

Before Treatment After treatment

P value

Anginal episodes

4.26+ 2.42

1.47+ 1.64

0.001

Exercise duration

6.52 + 1.93

8.32 + 2.33

0.001

Onset of ST
depression

5.85 + 1.74

7.71+ 1.68

0.001

LRH

RESULTS

The number of anginal episodes after 4

weeks treatment with TriCardin was

reduced significantly from 4.2 to 1.6 /

week (p=0.001)

Anginal

class improved significantly

after 4 weeks treatment with

TriCardin(p=0.001)
LRH

CONCLUSION
TriCardin is effective in

reducing

anginal episodes

increasing exercise duration

improving functional anginal class

delaying the onset of ST depression on
ETT in patients with ischemic heart
disease
LRH

Clinical trial at NICVD 2006-07

Name of doctors participating in the trial

Dr. Azhar Masood A. Farooqui
Dr. Tariq Ashraf
Dr. Syed Ishtiaq Rasool
Dr. Hamid Tirmizi

NICVD

NICVD TRIAL

Objective: To observe ST segment changes in patients undergoing

ETT after giving TriCardin

Materials and Method: Thirty patients were taken from ETT

department. After having history and physical examination, patients taking
no cardiac medication and ETT positive for ischemia were taken. These
patients were given TriCardin caps 250mg, 2+2+2 for ten days and 2+0+2
for eleven days as a monotherapy. Patients called on first day of fourth week
for repeat ETT.
Another group of 30 patients with similar characteristics, diagnosis and
ECG changes or ETT were given isosorbide dinitrate(Elantan) 10 mg TDS
for three weeks and Aspirin 150mg OD.
The two groups with ECG changes were compared.

NICVD

Result: Before treatment(n=20)

ST-Segment
depression(m
m)

1mm
2mm
3mm

Treatment
TriCardin

P-value

ISDN

2(10%)
15(75%)

16(80%)

5(25%)

2(10%)

0.190

NICVD

After Treatment(n=20)
ST-Segment
depression (mm)

Treatment

P-value

TriCardin

ISDN

None

1(5%)

5(25%)

0.184

1mm

14(70%)

2(10%)

0.001*

2mm

3(15%)

11(55%)

0.008*

3mm

2(10%)

2(10%)

0.598

After TriCardin treatment ST-segment depression 1 mm were

Significantly high (70%) as compared to ELANTAN patients (10%) p<0.05

NICVD

Side Effects
Side effects

Treatment
TriCardin

ISDN

NO

18(90%)

3(15%)

YES

2(10%)

17(85%)

Headache

1(5%)

17(85%)

Dizziness

1(5%)

P-value
0.001*

Side effects were significantly less in TriCardin (10%)

as compared to Elantan (85%) (p<0.05)

NICVD

Ongoing trials

300 patients of unstable angina registered.

150 Post-PCI and post-CABG patients.
50 patients of ischemic cardiomyopathy.
Also being evaluated in ischemic stroke.

Evaluation for its role proposed in HAPE, HACE.

HIGHLIGHTS TriCardin

100% Imported
FDA IND approved
Improves Microcirculation at all levels
Inhibits platelet adhesion & aggregation (more effective than aspirin)
Potent antioxidant; eliminates free radicals
Promotes the production of nitric oxide & inhibits endothelin-1
Lowers total blood cholesterol; inhibits oxidation of LDL; improves HDL
More effective than nitroglycerin for improving heart function and circulation
Significantly improves ECG, ETT and general condition of patient
Improves survival rate after heart attack
Effectively treat & prevent diabetic vascular complications
Modern TCM with virtually no side effects

SUMMARY
When u add Tricardin 2 x BID or 1 x TID to
your patient, you will get:

Amazing improvement in the general
condition within days

Significant improvement in ECG and ETT

Significant reduction in anginal episodes

Significant improvement in ejection fraction
Your patient will definitely share smile with you