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Dr. neeraj-presentation-23-des
1. Cardiology Top 5
Top 5 recent advances in 2011
(which will impact our practice in 2012)
Dr Neeraj Bhalla
Chairman and HOD
Deptt. of Cardiology
BLK Super Specialty Hospital
4. Clinical Trials in Perspective
Meta-analysis of ischaemic stroke
or systemic embolism
Warfarin vs: Favours Favours
warfarin other treatment
Placebo1
Low-dose warfarin1
Aspirin1
Aspirin + clopidogrel2
0.0 0.5 1.0 1.5 2.0
Error bars = 95% CI; BID = twice daily
Hazard ratio
1. Adapted from Camm J. ESC 2009; oral presentation #182; 2.Lip GYH. Edwards SJ. Thromb Res. 2006;118:321-333.
5. Targets for Novel Antithrombotic Agents in the
Coagulation Cascade1
Tissue factor/VIIa Vitamin K antagonist:
Tecarfarin (Ph II completed)2
X IX
VIIIa Indirect factor Xa inhibitors:
IXa Idraparinux (Ph III terminated)3
SSR 126517 (withdrawn 2009)4
Va
Direct factor Xa inhibitors:
Apixaban (Ph III ongoing)5,6 Xa AT
Rivaroxaban (Ph III completed)7
Edoxaban (Ph III ongoing)8
Betrixaban (Ph II ongoing)9 Direct thrombin inhibitors:
II Thrombin Dabigatran etexilate
(Approved)10
AZD0837 (Ph II completed)11
Fibrinogen Fibrin
AT, antithrombin; Ph, phase
6. New Oral Antiocoagulants
Initiation Contact TF VIIa
Phase
XII IX
XI Platelet X
Surface
Amplification
VIII
Propagation
Phase
Warfarin
Rivaroxaban1
Xa
Thrombin Apixaban
Common
Activity Pathway
Thrombin
Dabigatran2
etexilate
Fibrinogen Fibrin
1. Mahaffey KW et al. Presented at AHA 2010; Session LBCT02 21839; Available at:
http://sciencenews.myamericanheart.org/sessions/late_breaking.shtml#rocket . 2. Eikelboom J, et al. J Am Coll Cardiol. 2003;41:70S–78S.
7. Advantage of Direct Thrombin Inhibitors (DTIs)
DTIs block both circulating and clot-bound thrombin
Thrombin generation
Anti-
thrombin
DTIs: dabigatran etexilate
Heparin
Conversion of
fibrinogen to fibrin Amplification
DTIs: dabigatran etexilate
Clot-bound thrombin
Adapted from Eikelboom J, et al. J Am Coll Cardiol. 2003;41:70S–78S.
9. Dabigatran Etexilate
Potent and reversible oral DTI1
Inhibiting both c lo t b o u n d and fre e t h ro m b in 1
Predictable and consistent PK profile2,3 -Rapid onset/offset of action2 (Peak
plasma levels within 2 hours)
A n t ic o a g u la t io n m o n it o rin g — N o t re q u ire d 4
Half-life 12–17 hours (twice-daily dosing)1
L o w d ru g – d ru g in t e ra c t io n s (not metabolised by CYP450 enzymes)1,5
No food–drug interactions
Dosing independent of meals or dietary restrictions6
6 .5% bioavailability, ~80% renal excretion
1. Pradaxa: SmPC, 2009; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151 2. Stangier J, et al. Clin Pharmacokinet 2008;28:47–59. 3.
Stangier J. Clin Pharmacokinet. 2008;47:285-295. 4. Stangier J, et al. Br J Pharmacol. 2007;64:292–303. 5. Blech S, et al. Drug Metab Dispos.
2008;36:386-399. 6. Stangier J, et al. J Clin Pharmacol. 2005;45:555-563.
10. RE-LY: Largest AF Outcomes Trial
RE-LY:
Randomized Evaluation of Long-term anticoagulant therapy
PROBE study design
18,113 patients randomised during 2 years, 951 centres in 44
countries1,2
50% of enrolled patients naïve to previous oral anticoagulant
Median treatment duration: 2 years
ESC = European Society of Cardiology
10
1. Ezekowitz MD et al. Am Heart J 2009;157:805–10 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51
11. RE-LY: Study Design
AF with ≥1 risk factor
Absence of contraindications*
R
Warfarin
Dabigatran Dabigatran
1 mg, 3 mg, 5 mg
110 mg BID 150 mg BID
(INR 2.0–3.0)
n = 6000 n = 6000
n = 6000
Primary objective: to establish the noninferiority of dabigatran to warfarin
Minimum 1 year follow-up, maximum of 3 years and median of 2 years of follow-up
*Severe heart-valve disorder, stroke ≤14 days or severe stroke ≤6 months before screening, increased haemorrhage risk, creatinine
clearance <30 mL/min, active liver disease, pregnancy; BID = twice daily; INR = international normalized ratio.
1. Ezekowitz MD et al. Am Heart J. 2009;157:805–810. 2. Connolly SJ, et al. N Engl J Med. 2009;361:1139–1151.
12. Patients with Valvular Heart Disease
(Haemodynamically Stable) were Included in RE-LY
Inclusion criteria
1. Documented AF
2. One additional risk factor for stroke:
• History of previous stroke, transient ischaemic attack or systemic embolism
• LVEF less than 40%
• Symptomatic heart failure, NYHA Class II or greater
• Age of 75 years or more
• Age of 65 years or more and one of the following additional risk factors: diabetes mellitus,
coronary artery disease or hypertension
Exclusion criteria
1. Severe heart-valve disorder
2. Stroke within 14 days or severe stroke within 6 months before screening
3. Any condition that increases the risk of haemorrhage
4. Creatinine clearance <30 mL/min
5. Active liver disease
6. Pregnancy
1. Ezekowitz MD, et al. Am Heart J. 2009;157:805–810. 2. Connolly SJ, et al. N Engl J Med. 2009;361:1139–1151.
13. Patients with Valvular Heart Disease were
Included in RE-LY
DE 110 mg BID DE 150 mg BID Warfarin Total
n (%) n (%) n (%) n (%)
Valvular heart disease 1288 (100.0) 1353 (100.0) 1303 (100.0) 3944 (100.0)
Aortic stenosis 152 (11.8) 163 (12.0) 156 (11.9) 471 (11.9)
Aortic regurgitation 264 (20.4) 281 (20.7) 272 (20.8) 817 (20.7)
Mitral stenosis 77 (5.9) 62 (4.5) 54 (4.1) 193 (4.8)
Mitral regurgitation 1035 (80.3) 1050 (77.6) 1016 (77.9) 3101 (78.6)
Other 470 (36.4) 496 (36.6) 492 (37.7) 1458 (36.9)
Data on file
15. Phase III RE-LY: Risk of Stroke or Systemic Embolism
Non-inferiority Superiority
P value P value
Dabigatran
110 mg BID <.001 .30
vs. warfarin
Margin = 1.46
Dabigatran
150 mg BID <.001 <.001
vs. warfarin
0.50 0.75 1.00 1.25 1.50
Hazard ratio
Error bars = 95% CI; BID, twice daily
Connolly SJ, et al. N Engl J Med. 2010;363:1875–1876.
16. Phase III RE-LY: Time to First Stroke or Systemic
Embolism
0.05 RR 0.90
Warfarin (95% CI: 0.74–1.10)
Dabigatran 110 mg BID P<.001 (NI)
P = .30 (Sup)
0.04 Dabigatran 150 mg BID
RRR
Cumulative hazard rates
35%
0.03
0.02 RR 0.65
(95% CI: 0.52–0.81)
P<.001 (NI)
P<.001 (Sup)
0.01
0.00
0.0 0.5 1.0 1.5 2.0 2.5
Years
BID, twice daily; NI, non-inferiority; RR, relative risk; RRR, relative risk reduction; Sup, superiority
Connolly SJ, et al. N Engl J Med. 2010;363:1875–1876.
17. Time to First Haemorrhagic Stroke
0.015
0.014
0.013 Warfarin
0.012
Dabigatran 110 mg BI D
0.011
0.010
Dabigatran 150 mg BI D
Cumulative hazard rates
0.009
0.008
0.007
0.006
0.005
0.004
0.003
0.002
0.001
0.000
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Time from randomisation (months)
FDA Briefing Document, Dabigatran etexilate, 2010.
19. 150 mg BID no Difference vs Warfarin for Major Bleeds
RR 0.80 P = .003 (Sup) RR 0.93 (95% CI: 0.81–1.07)
4.0 (95% CI:
0.70–0.93)
3.5 RRR P = .32 (Sup)
20% 3.57
3.0 3.32
Major bleeding (%/yr)
2.5 2.87
2.0
1.5
1.0
0.5
0.0
Dabigatran Dabigatran Warfarin
110 mg BID 150 mg BID
Events/n: 342/6015 399/6076 421/6022
BID, twice daily; RR, relative risk; RRR, relative risk reduction; Sup, superiority
Connolly SJ, et al. N Engl J Med. 2010;363:1875–1876.
20. Phase III RE-LY: Risk of Stroke or Systemic Embolism
Non-inferiority Superiority
P value P value
Dabigatran
110 mg BID <.001 .30
vs. warfarin
Margin = 1.46
Dabigatran
150 mg BID <.001 <.001
vs. warfarin
0.50 0.75 1.00 1.25 1.50
Hazard ratio
Error bars = 95% CI; BID, twice daily
Connolly SJ, et al. N Engl J Med. 2010;363:1875–1876.
22. Net Benefit Analysis Comparing Dabigatran 150 mg
with 110 mg Annual rate
Time to first event of HR (95% CI) D110 D150
ICH, stoke, SEE 1.6 1.3
Life threatening bleed, stroke, SEE 2.5
2.4
Major bleed, stroke, SEE 4.1 4.1
0.6 0.8 1.0 1.2
D150 Better D110 Better
CRDAC meeting, 9.20.10
FDA, Beasley
23. 110 mg BID Dose—Which Patients?
>75 years
Patients with higher risk of bleeding including:
– Moderate renal impairment (30–50 mL/min CrCl)
– P-glycoprotein-inhibitor co-medication
– ASA, NSAID, clopidogrel
– Congenital coagulation disorders
– Active ulcerative GI disease/recent GI bleed
– Recent intracranial haemorrhage
24. RE-LY in Perspective
Warfarin vs.: Meta-analysis of ischaemic stroke or systemic embolism
Favours Favours
warfarin other treatment
Placebo
Low-dose warfarin
Aspirin
Aspirin + clopidogrel
Ximelagatran
Dabigatran 110 mg BID
Dabigatran 150 mg BID
0.0 0.5 1.0 1.5 2.0
Hazard ratio
Error bars = 95% CI; BID = twice daily
Adapted from Camm J. ESC 2009; oral presentation #182; Lip GYH & Edwards SJ. Thromb Res 2006;118:321–33
25. The Newer Anticoagulants on the Horizon
Drug Dose Comparator N CHADS2
Trial score
RE-LY Dabigatran 150 mg and Warfarin 18,000 >0
110 mg* (INR 2.0–3.0)
BID
ROCKET-AF5,6 Rivaroxaban 20 mg* Warfarin 14,000 ≥2
OD (INR 2.0–3.0)
AVERROES3,4 Apixaban 5 mg Aspirin 6000 ≥1
BID (81–324 mg OD)
ARISTOTLE1,2 Apixaban 5 mg Warfarin 18,000 ≥1
BID (INR 2.0–3.0)
ENGAGE-AF TIMI Edoxaban 30 mg OD Warfarin 16,500 ≥2
487 60 mg OD (INR 2.0–3.0)
25
*Adjusted based on renal function. BID, twice daily; INR, international normalised ratio; OD, once daily
26. Direct Thrombin and Factor Xa Inhibitors (DTIs):
Approval for Stroke Prevention in AF
Dabigatran Rivaroxaban Apixaban
US Approved Submitted Submitted*
Canada Approved Submitted Submitted*
Europe Approved on August 4, Submitted Submitted*
2011
Asia Pacific
(Philippines, Japan,
Indonesia, Singapore, Approved
Korea, Malaysia)
Current as of June 10, 2011
*AVERROES Trial
27. Dabigatran vs Warfarin: Risk/Benefit by Dose
110 mg BID 150 mg BID
↓stroke/
↓
systemic
Haemorrhagic embolism
stroke
↓ Major bleeds ↓ Total & life-
threatening
↓ Ischaemic
bleeds, ICH stroke
↓ Vascular mortality
Adapted from Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6
28. Conclusions
Dabigatran etexilate has been shown to concurrently reduce both
thrombotic and haemorrhagic events
Both doses of dabigatran provide different and complementary
advantages over warfarin
– 150 mg BID has superior efficacy with similar bleeding
– 110 mg BID has significantly less bleedings with similar efficacy
– Similar net clinical benefit was seen between the two dabigatran doses
Dabigatran demonstrates high efficacy and safety in a variety of
clinically relevant populations
BID = twice daily; INR = international normalized ratio
Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6; Wallentin L et al. Lancet 2010;376:975–83
31. What is it?
• Ticagrelor is an oral adenosine
diphosphate antagonist which blocks ADP-
induced platelet aggregation
• Ticagrelor exhibits rapid onset and offset
of action with reversible binding
• Ticagrelor treatment is recommended for
up to 12 months
32.
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45. When should it be used?
• Ticagrelor is indicated for the prevention of
atherothrombotic events (Cardiovascular death,
MI and stroke) in all patients with Acute
Coronary Syndrome (ACS) regardless of mode
of therapy: Medical or Interventional vis a vis
Prasugrel ( only approved for ACS undergoing
PCI)
• Based on PLATO trial, latest ESC guideline give
Class I A recommendation in ACS
48. Igaki- Tamai Bioabsorbable Stent
• Igaki- Tamai Bioabsorbable Stent (Igaki Medical Planning Company, Kyoto,
Japan), the first absorbable stent implanted in humans, is constructed from
Poly-L-Lactic acid (PLLA)
• In the absorption process, hydrolysis of bonds between repeating lactide
units produce Lactic acid that enters Krebs cycle and is metabolized to
Carbon di-oxide and water
• Stent Design- Zig Zag helical coil with straight bridges
49. Bioabsorbable Magnesuim Stent
• The first bioabsorbable stent implanted in humans is the Magnesium alloy
stent
• This stent, laser cut from tubular magnesium WE-43
(Biotronik,Berlin,Germany) has sinusoidal in-phase hoops linked by straight
bridges
• It is a Balloon expandable stent and absorption is by surface erosion, such
that the strut thickness is decreased as the stent is absorbed
50. REVA Bioabsorbable Stent
• The REVA (Reva Medical Inc, San Diego, Calif) stent is constructed
from an absorable tyrosine-derived polycarbonate polymer that
metabolizes to amino acids, ethanol and carbon di-oxide
• It is a balloon expandable with a slide and lock (ratchet) design
51. Bioabsorbable Therapeutics Stent
• The Bioabsorbable therapeutics stent (Bioabsorbable Therapeutics Inc,
Menlo Park, Calif), a fully bioabsorbable sirolimus-eluting stent that also
releases salicylic acid.
• It has a polymer backbone that gives the stent the physical structure and a
polymer coating that contains and controls the release of the anti-
proliferative agent
• During absorption, the bonds between salicylic acid and linked molecules
are hydrolyzed releasing the anti-inflammatory drug, salicylic acid
52. BVS Everolimus-Eluting Bioabsorbable
PLLA Stent
• The BVS everolimus eluting stent (Abbott Vascular, Santa Clara, Calif.)
• The stent has a bioabsorbable polymer backbone of PLLA with a polymer
coating of Poly-D,L-lactide that contains and controls the release of the anti-
proliferative drug, everolimus
• Stent Design- Revision1.0 has circumferential out of phase zig zag hoops
linked either directly or by straight links; Revision1.1 has circumferential in
phase zig zag hoops linked by straight links
53. Potential Long Term Advantages of
“Removing” a Rigid Coronary Stent
• Restoration of epicardial coronary capacitance to
coronary flow regulation
• Restoration of shear stress modulation and flow
mediated dilation vital for the direct coupling of coronary
flow to metabolic demand
• Minimize chronic flow separations (turbulence) and low
endothelial shear stress (ESS) due to protruding struts
and / or vessel distortion
• Abolition of stress “shielding” and negative influences of
endothelial and SM cell function
• Reduce risk of late events or atheroprogression (all other
factors controlled)
SE2935049 Rev. B Information contained herein intended for healthcare professionals from outside the US only.
65. TAVI
• Potentially life-saving therapy for patients unsuitable for
conventional aortic valve replacement.
• No longer regarded as experimental
• At the end of 2009 c 8000 valves were implanted world-
wide.
• 2 major competitors
– Medtronic Core-Valve
– Edwards Sapien
• 3 methods of implantation
– Trans-arterially
– Trans-apically
– Subclavian approach
66. Valvular Aortic Stenosis in Adults
(Average Course)
“Surgical
intervention
should be
performed
promptly once
even… minor
symptoms occur”1
Chart: Ross J Jr, Braunwald E. Aortic stenosis. Circulation 1968;38 (Suppl 1)
1 C.M. Otto. Valve Disease: Timing of Aortic Valve Surgery. Heart 2000
Chart:: Ross J Jr, Braunwald E. Aortic stenosis. Circulation. 1968;38 (Suppl 1):61-
7.
67. Mortality in Aortic Valve Replacement
n = 1.984
Burr et al, Annals Thor Surg, 1995;60:S264-269
68. What is the risk?
• Initial mortality approximately 10%
• Improving
– Core valve May 2008: 30 day mortality = 8%
in first 1000 European implants
– Edwards May 2009: 30 day mortality = 6.3%
for TAVI and 10.3% for trans-apical in 1038
patients.
73. Relative risk and
95% Confidence
Intervals are shown
for the primary
end point of death
from any cause at
1 year among patients
randomly assigned to
TAVI
104. Background
• Vitamin D has been traditionally known as
anti-ricketic factor or sunshine vitamin.
• Vitamin D is unique because it is synthesized
by the body and it functions as a hormone
• Besides its pivotal role in calcium homeostasis
and bone mineral metabolism, evidences link
Vitamin D with chronic diseases like Diabetes,
Hypertension, Myopathic disorder, infections,
autoimmune disorder and cancer.
105. Different forms of Vitamin D
Cholecalciferol –
• naturally occurring form
• made in large quantities in skin when
exposed to sunlight (UVB rays 290 - 310
nm).
• Cholecalciferol transported to liver,
metabolized into calcidiol.
Calcidiol (25-hydroxyvitamin D) –
• Prehormone, storage form of vit D,
• Serum 25(OH)D-reliable indicator of vit D
adequacy. Tested routinely for vit D
deficiency.
Calcitriol (1,25- dihydroxyvitamin D) –
• made from calcidiol in kidneys and other
tissues
106. Vitamin D status in India
• Vitamin D deficiency is epidemic in India.
• Studies have documented low 25(OH)D level
in the Indian population despite abundant
sunshine.
• Low dietary Vitamin D intake is also been
documented.
• Prevalence varying from 50-100%
JAPI 2009., 57: 40-48
107. Why does this happen?
• Dress code
• Changing lifestyles
• Urban- less sun exposure
• Avoiding the sun
• Sunscreens
• Dark skin
• Rural- less calcium/Vit D intake
* other risk factors obese, drug intake, malabsorption
108. Indian Studies: Vitamin D status
in Middle age group (20-45 years)
Location N Study population Age (Yrs) 25(OH)D Unit
Delhi1 40 Indian Paramiltary forces - Men 20 – 30 18.4 + 5.3 ng/ml
Delhi1 50 Indian Paramiltary forces - 20 – 30 25.3 + 7.4 ng/ml
Women
Delhi2 32 Rural Males 42.8 + 16.6 44.2 + 24.4 nmol/l
Delhi2 32 Rural females 43.4 + 12.6 26.9 + 15.9 nmol/l
1. Tandon N et al., Natl Med J India 2003;16:298-302.
2. Goswami R et al. J Assoc Physicians India 2008;56:755-57.
109. Diagnostic Criteria for Vit D deficiency
• 25 (OH) is major circulating/storage form of Vitamin D, longer T1/2 than 1,25 (OH)
Vit D
• Measurement of 25(OH)D limited by methodological differences; overcome by RIA
• Currently available assays – antibodies co-specific to both 25(OH)D2 and
25(OH)D3; terminology 25(OH)D assays used.
• Conversion: ng/mL to nmol/L – multiply by 2.496
• nmol/L to ng/mL – divide by 2.496
Condition nmol/l ng/ml
Normal 75 – 80 30 -32
Insufficiency 20 – 75 8 -30
Deficiency < 20 <8
110. Sources of Vitamin D in India
• Diet is a poor source – average Indian dietary
intake is low (<100 IU/d)
• Food supplementation with vitamin D is limited
• Exposure to sunlight – a balance between
adequate exposure to increase serum vitamin D
or increasing risk of skin cancer is required
• Vitamin D supplements – 1000 IU (D3) or cod
liver oil capsules 400 - 800 IU (D3 and vitamin A*)
112. Vitamin D conversion to 25(OH)D
• 1000 I.U. per day of Vitamin D(3) on daily basis
increases circulating 25(OH)D by 1ng/ml after
3 months
113. What is adequate supplementation in the Indian
context ?
• If typical serum 25 (OH)D level in Indians is 10
ng/ml…
• And if target serum 25 (OH)D level is 30
ng/ml…
• They would require about 2000 IU/day
114. Safety of Vitamin D*
• Doses of 5000-10000 IU/day for 4-
5 months have not resulted in
elevated serum or urinary calcium
levels*
• Found to be safe
• Upper tolerable limit of intake in
adults: 2000 IU/day
*Down to the bone, Medscape CME, June 2007
+ European Commission Opinion on tolerable upper intake levels of vit D, 2002
115. Low Vitamin D: A Potential Risk factor
for CVD and Type 2 DM
Low levels of vitamin D is found to be associated with
• Diabetes mellitus
• Metabolic syndrome
• Obesity
• Hypertension
• Stroke
• Congestive heart failure
Vitamin D deficiency may be a contributor to the
development of CVD potentially through
associations with diabetes or hypertension.
Curr Opin Clin Nutr Metab Care. 2008;11(1):7–12.
116. Potential Mechanisms for Diabetes & CVD
due to Vitamin D Deficiency
Vitamin D Deficiency
PTH
Insulin resistance
+ RAAS
Inflammation
Pancreatic Beta Cell Dysfunction
Hypertension &
Diabetes &
Hypertrophy
Metabolic Syndrome
Atherosclerosis
Adverse
Cardiovascular Events
J Am Coll Cardiol. 2008;52:1949–1956.
118. How much Vitamin D Do We
Need?
• “For five of the six authors, the minimum
desirable 25(OH)D concentration clusters
between 70 and 80 nmol/L.” (28-32 ng/ml)
“This requires~1000 IU/day”
Dawson-Hughes, Heaney,Holick, Lips,Meunier &Vieth, Osteoporosis Int, 16,713-716,2005
119. Hypertension
• Prospectively followed two cohorts:
– Nurses’ Health Study – 1198 women
– Health Professionals Follow-up Study – 613 men
• Relative risk of hypertension:
– < 15 ng/mL vs > 30 ng/mL 25(OH)D
– Men: RR = 6.13
– Women: RR = 2.67
120. Hypertension
• BP higher in winter
• BP higher with increasing latitude
• BP higher with darker skin pigmentation
• HTN pts given UV light treatments 3x/week for 6 weeks had Vit D level
increases of 162% and saw mild decreases in BP
Krause et al. Lancet. 1998;352(9129):709.
• Small doses of Vit D (800IU) for 8 weeks → decreased BP and pulse rate
Pfeifer et al. J Clin Endocrinol Metab. 2001;86(4):258.
121. Vitamin D deficiency and risk of CVD
• 1739 Framingham study participants (M,F)
• Followed up for CV event-mean 5.4 yrs
• 25(OH)D <15 ng/ml vs >15 ng/ml- RR1.62
• Greater risk if 25(OH) D <10 ng/ml
Wang et al, Circulation 2008
122. 25(OH)D and risk of MI in Men
• Prospective, 18225 men in
Health Professionals follow up
study; 10 yr follow up
• 25 (OH)D level <15 ng/ml vs
>30 ng/ml- RR for MI 2.42
• Greater risk even in the 15-30
ng/ml group – RR 1.43-1.6
Giovannuci et al, Arch Int Med 2008
123. Heart disease
• MI risk doubles in pts with 25OHVitD levels <34ng/ml
Scragg et al. Int J Epidemiol. 1990;19(3):559.
• CHF pts have much lower 25OHVitD levels than
controls
Zitterman et al. J Am Coll Cardiol. 2003;41:105.
• Deaths from CAD more common in winter
Scragg. Int J Epidemiol. 1981;10(4):337.
124. Mechanisms of Vit D in CVD
prevention
• Inhibition of vascular smooth
muscle proliferation by an
acute influx of Ca into the cells
• Suppression of vascular
calcification by ↑sing matrix
Gla synthesis by chondrocytes
& vascular smooth muscle
cells
• Down-regulation of pro-
inflammatory cytokines TNF-α
and IL-6
• Up-regulation of anti-
inflammatory cytokines
• Action of vit D as a negative
endocrine regulator of the
renin-angiotensin system.
125. Polycystic Ovary Syndrome
A study, 120 untreated women with PCOS; median age: 28 yrs
– Low levels of vit D assoc with insulin resistance & obesity.
– In all subjects, conc of 25-OH-D inversely assoc with BMI, body fat,
HOMA-IR, hyperinsulinemia & levels of leptin, while being positively
assoc with HDL levels.
• Additional analysis found 25-OH-VD levels to be significantly correlated
with SHBG and free androgen index.
Hahn S, Haselhorst U, et al. 2006; 114(10): 577-583
126. Metabolic Syndrome
• Third National Health & Nutrition Examination Survey (NHANES III)
– 8,421 men and non-pregnant women > 20 yrs of age and had fasted > 8 hrs
• Unadjusted prevalence of metabolic syndrome - 21.9%
• After adjustments for known risk factors, odds of metabolic syndrome decreased
progressively across increasing conc of 25(OH)D
• Relative risk compared with bottom quintile of vitamin D level:
– 2nd quintile – 0.85
– 3rd quintile – 0.75
– 4th quintile – 0.62
– 5th quintile – 0.46
Ford et al., 2005
127. Vitamin D and Obesity
Obese subjects vs. normal weight controls have
• Lower serum 25OHD levels
• Higher PTH and inconsistent results for
1,25(OH)2 D
Liel et al, Calcif Tissue Int, 1988
Two possible explanations
• Less sunlight exposure
• Decreased bioavailability of Vit D due to sequestration in
adipose tissue
Wortsman et al, Am J Clin Nutr, 2000
• Vit deficiency also associated with higher BMI and
visceral adiposity
Cheng S et al., Diabetes 2010
128. Overall high levels of Vit. D are associated with a 43% reduction in
cardiometabolic disorders,
this finding applied to outcomes reported,
like CVD, DM or MetS.
129. Calcium supplements with or without vitamin D and risk of cardiovascular
events: reanalysis of the Women's Health Initiative and meta-analysis.
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR.
•Reanalysis of WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and
vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal
women.
RESULTS:
•In the 16,718 women (46%) who were not taking personal calcium supplements at
randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged
from 1.13 to 1.22 (P = 0.05 for clinical myocardial infarction or stroke, P = 0.04 for clinical
myocardial infarction or revascularisation),
•In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of
myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P = 0.04), stroke
(1.20 (1.00 to 1.43), P = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to
1.32), P = 0.02).
CONCLUSIONS:
•Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular
events, especially myocardial infarction, A reassessment of the role of calcium supplements in
osteoporosis management is warranted
BMJ. 2011 Apr 19;342:d2040. doi: 10.1136/bmj.d2040.
130. Systematic review: Vitamin D and calcium supplementation in
prevention of cardiovascular events.
Wang L, Manson JE, Song Y, Sesso HD.
•Five prospective studies of patients receiving dialysis and 1 study involving a
general population showed consistent reductions in cardiovascular disease (CVD)
mortality among adults who received vitamin D supplements.
•Four prospective studies of initially healthy persons found no differences in
incidence of CVD between calcium supplement recipients and nonrecepients.
•Results of secondary analyses in 8 randomized trials showed a slight but
statistically nonsignificant reduction in CVD risk (pooled relative risk, 0.90 [95%
CI, 0.77 to 1.05]) with vitamin D supplementation at moderate to high doses
(approximately 1000 IU/d) but not with calcium supplementation (pooled
relative risk, 1.14 [CI, 0.92 to 1.41]), or a combination of vitamin D and
calcium supplementation (pooled relative risk, 1.04 [CI, 0.92 to 1.18]) compared
with placebo.
CONCLUSION:
•Evidence from limited data suggests that vitamin D supplements at moderate to
high doses may reduce CVD risk, whereas calcium supplements seem to have
minimal cardiovascular effects. Further research is needed to elucidate the role of
these supplements in CVD prevention.
Ann Intern Med. 2010 Mar 2;152(5):315-23.
131. • Very few foods in nature contain vitamin D. The flesh
of fatty fish (such as salmon, tuna, and mackerel) and
fish liver oils are among the best sources [1,11]. Small
amounts of vitamin D are found in beef liver, cheese,
and egg yolks. Vitamin D in these foods is primarily in
the form of vitamin D3 and its metabolite 25(OH)D3 [12
]. Some mushrooms provide vitamin D2 in variable
amounts [13,14]. Mushrooms with enhanced levels of
vitamin D2 from being exposed to ultraviolet light
under controlled conditions are also available.
132. But…
What is the recommendation from
• For most people daily Vitamin D supplementation is necessary, particularly
through the winter months.
• A daily amount of 800-1000IU per day will satisfy body’s basic requirement
and higher doses are needed to correct deficiency.
• Leading advocates recommends 5,000 IU per day for 2–3 months, then
obtain a 25-hydroxyvitamin D test and adjust dosage so that blood levels are
between 50–80 ng/mL (or 125–200 nM/L) year-round, usually a minimum of
2000 IU a day 132
133. Preventive Measures1
Direct exposure to
sunlight, at least 30 Preventive use of
minutes/day sun screens
Good dietary
calcium intake
Outdoor
activities of the
Artificial elderly and aged
fortification Making physical training
Supplementation of infant food
to lactating
to children in the schools
products compulsory daily
mothers 133
J Assoc Physicians India 2009 Jan;5740-48
134. Vitamin D & Spectrum of Vascular Protection
Vitamin D
Endothelial &
Glucose Metabolism Cardiovascular Protection Nephroprotection
• Increased insulin secretion • Suppression of RASS • Decreased inflammation
• Increased insulin sensitivity • Control of inflammation • Antiproteinuric effect
• Increased glucose uptake • Inhibition of smooth muscle cell • Suppression of renin, AT II,
• Proliferation AT 1R
• Expression of insulin receptor
• Decreased NF-αB activation
136. How much Vitamin D Do We
Need?
• “For five of the six authors, the minimum
desirable 25(OH)D concentration clusters
between 70 and 80 nmol/L.” (28-32 ng/ml)
“This requires~1000 IU/day”
Dawson-Hughes, Heaney,Holick, Lips,Meunier &Vieth, Osteoporosis Int, 16,713-716,2005
137. Conclusions
• Vitamin deficiency is common in India
• There is need to improve vitamin D status
through increased sun exposure, food
fortification, supplements.
• Vitamin D may have beneficial effects on in
prevention of Diabetes, other CVD risk factors
and CVD events
• Need for further research regarding extra
skeletal effects of Vitamin D