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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
Advancements in Anticoagulation
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.
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                                                                             SSR 126517 (withdrawn 2009)4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
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.
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.
DIRECT THROMBIN INHIBITORS
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.
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
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.
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.
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
Incidence of Stroke or Systemic Embolism
                                          RR 0.90 (95% CI: 0.74–1.10)
                                                P<.001 (NI)                    RR 0.65 (95% CI: 0.52–0.81)
                                   1.8
 Stroke/systemic embolism (%/yr)




                                                                                    P<.001 (Sup)
                                                                                                                1.71
                                   1.5                                                      RRR
                                            1.54                                            35%
                                   1.2
                                                                              1.11
                                   0.9

                                   0.6

                                   0.3

                                   0.0
                                         Dabigatran                         Dabigatran                      Warfarin
                                         110 mg BID                         150 mg BID
Events/n:
                                           183/6015                             134/6076                    202/6022
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.
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.
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.
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.
RE-LY: SAFETY RESULTS
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.
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.
Significantly Lower Intracranial Bleeding with Dabigatran
                                      RR 0.30
                                      (95% CI:      P<.001 (Sup)
                                0.9    0.19–0.45)                          RR 0.41 (95% CI: 0.28–0.60)

                                0.8                                                   P<.001 (Sup)

                                0.7
 Intracranial bleeding (%/yr)




                                                                                                          0.76
                                0.6
                                                                                         RRR
                                0.5
                                                                                         59%
                                                      RRR
                                0.4                   70%
                                0.3
                                                                                  0.32
                                0.2            0.23
                                0.1

                                 0
                                           Dabigatran                       Dabigatran                   Warfarin
                                           110 mg BID                       150 mg BID
                                              27/6015                            38/6076                  90/6022
Events/n:
BID, twice daily; RR, relative risk; RRR, relative risk reduction; Sup, superiority
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
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
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
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
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
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
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
Ticagrelor
New Antiplatelet Therapy
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
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
Bioabsorbable stent:

  The 4th Step…
Balloon                Bare metal Stent Drug Eluting Stent
                                      Angioplasty
                Decade                    1980s                       1990s                      2000s
    Acute Success rate                   70-85%                        >95%                      >95%
             Restenosis                  40-45%                      20-30%                      <10%
      Early Thrombosis                     3-5%                        1-2%                      1-2%
          <30 days

       Late Thrombosis                      NA                        <0.5%                       1%
           >30 days

  Very Late Thrombosis                      NA                          ≈0%                    0.6%per yr
          (>1y)
       © 2009 Abbott      Pipeline product. Currently in development at Abbott Vascular. Not
       Laboratories                               available for sale.
SE 2928803 Rev C
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
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
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
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
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
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.
Poly Lactide - Hydrolysis
                        PLA                                                                  PLA – Poly Lactic Acid
                                                             H2O

        ↓ Molecular Weight                                   Hydrolysis


                       Lactide

                                                         O                                            O
                   Mass Loss                    R                    +     H2O              R             +   HO      R′
                                                         O     R′                                 OH
                                                                                         carboxylic acid      alcohol
             Mass Transport

                                              CO2 + H2O
                       Krebs
                       Cycle
       © 2009 Abbott             Pipeline product. Currently in development at Abbott Vascular. Not
       Laboratories                                      available for sale.
SE 2928803 Rev C
Bioresorbable Polymer: ABSORB
                                                                                 •   Everolimus/PDLLA Matrix
                                                                                     Coating
                                                                                 •   Thin coating layer
                                                                                 •   Amorphous (non-crystalline)
                                                                                 •   1:1 ratio of Everolimus/PLA
                                                                                     matrix
                                                                                 •   Conformal Coating, 2-4 µm
                                                                                     thick
                       Drug/polymer matrix                                       •   Controlled drug release

                       Polymer backbone                                          •   PLLA Backbone
                                                                                 •   Highly crystalline
                                                                                 •   Provides device integrity
                                                                                 •   Processed for increased radial
                                                                                     strength


       © 2009 Abbott        Pipeline product. Currently in development at Abbott Vascular. Not
       Laboratories                                 available for sale.
SE 2928803 Rev C
© 2009 Abbott   Pipeline product. Currently in development at Abbott Vascular. Not
       Laboratories                            available for sale.
SE 2928803 Rev C
Clinical Study Design – Cohort A
                      Single,                                   3.0 mm
                   de-novo lesion                                n = 30                          BVS Device

  •     Sponsor: Abbott Vascular                            •         3.0 x 12mm device
                                                                    (3.0 x 18mm device available after
  •     Prospective, open label                                     enrolment start and used in 2 patients)
  •     PI: John Ormiston, MD
               Patrick Serruys, MD, PhD
                                                            •         6 sites EU, NZ
                                                                     Rotterdam, NL, Patrick Serruys
  •     DSMB: J. Tijssen PhD,
                                                                     Krakow, PL, Dariusz Dudek
        T. Lefèvre MD, P. Urban MD
                                                                     Auckland, NZ, John Ormiston
  •     CEC: C. Hanet MD,                                            Aarhus, DN, Leif Thuesen
        D. McClean MD, V. Umans MD                                   Aalst, BE, Bernard de Bruyne
                                                                     St Denis, F, Bernard Chevalier
  •     Angiographic and IVUS corelab:
        Cardialysis (Rotterdam, NL)                         •    Post-procedure clopidogrel for 6
                                                                 months, aspirin for 5 years

       © 2009 Abbott        Pipeline product. Currently in development at Abbott Vascular. Not
       Laboratories                                 available for sale.
SE 2928803 Rev C
ABSORB : Long term follow-up
                                                                5-Year Clinical Results
             ABSORB Cohort A Clinical Results at Each Phase: Intent to Treat
                                                                    RESTORATION                                     RESORPTION

        Hierarchical                                     6 Months                         12 Months                   24 Months                 60 Months
                                                        30 Patients                      29 Patients**               29 Patients**             29 Patients**
        Ischemia Driven MACE***                            1 (3.3%)*                          1 (3.4%)*                  1 (3.4%)*                 1 (3.4%)*
        Cardiac Death                                       0 (0.0%)                          0 (0.0%)                    0 (0.0%)                  0 (0.0%)
        MI                                                 1 (3.3%)*                          1 (3.4%)*                  1 (3.4%)*                 1 (3.4%)*
             Q-Wave MI                                      0 (0.0%)                          0 (0.0%)                    0 (0.0%)                  0 (0.0%)
             Non Q-Wave MI                                 1 (3.3%)*                          1 (3.4%)*                  1 (3.4%)*                 1 (3.4%)*
        Ischemia Driven TLR                                 0 (0.0%)                          0 (0.0%)                    0 (0.0%)                  0 (0.0%)
             by PCI                                         0 (0.0%)                          0 (0.0%)                    0 (0.0%)                   0 (0.%)
             by CABG                                        0 (0.0%)                          0 (0.0%)                    0 (0.0%)                   0 (0.%)

         Serruys, PW, TCT, 2011

  *     Same patient – this patient also underwent a TLR, not qualified as ID-TLR (DS = 42%)
  **    One patient missed the 9, 12, 18 month and 2, 3, and 4 year visits; one patient died from a non-cardiac cause 706 days post procedure
  ***   MACE –Abbott                       Pipeline product. Currently in development at Abbott Vascular. Not
        © 2009 Composite endpoint comprised of cardiac death, myocardial infarction (MI) and ischemia-driven target lesion revascularization (TLR) by PCI or CABG
        Laboratories                                                     available for sale.
        58
SE 2928803 Rev C
ABSORB :
                       Scaffold Thrombosis Out to 5 Years
                                                  Cohort A
                                           5-Year Clinical Results
                         Thrombosis Results Through All Phases


       Time                                                    % Patients                      N

       Acute (<1 day)                                             0 (0.0%)                     30

       Sub-Acute (1-30 days)                                      0 (0.0%)                     30

       Late (>30 days – 1 year)                                   0 (0.0%)                     29

       Very Late (>1 year)                                        0 (0.0%)                     29


       © 2009 Abbott      Pipeline product. Currently in development at Abbott Vascular. Not
       59
       Laboratories                               available for sale.
SE 2928803 Rev C
KM estimate of MACE rate in patients treated with BVS
                                           (Absorb Cohort B, n=101) vs. patients treated
                                    with a single 3x 18 mm metallic EES (Spirit I+II+III, n=227)
     M A C E (C -D e a t h , M I, ID -T L R )

                                                25.0%
                                                                   B V S ( B 1 + B 2 )
                                                                   X V ( S P I + S P I I + S P I I I R C T )
                                                20.0%                                                              393-day HR
                                                                                                                 0.93 [0.38,2.24]
                                                                                                                    p=0.8678
                                                15.0%



                                                10.0%
                                                                                                                                               7.5%
                                                                                                                                                 ∆ 0.6%
                                                5.0%                                                                                           6.9%

                                                                                                             XV Includes only patients with single 3.0 x 18mm stent
                                                                                                             BVS Includes all patients
                                                0.0%
                                                        0   1      2    3        4    5    6      7     8    9     10     11      12      13     14

                                                                T im        e        P o s t I n d e x                   P r o c e d u r e
Patients at risk                                            0 days     37 days         194 days       284 days      365 days             393 days
                                                             101            99            96            96              95                 94
BVS(B1+B2) Abbott
      © 2009                                                Pipeline product. Currently in development at Abbott Vascular. Not
                       Laboratories
                                                             227          224       available for sale. 211
                                                                                         219                          209                  208
XV(SPI+SPII+SPIII RCT)
 SE 2928803 Rev C
ABSORB Extend
              • N = up to 1,000 patients at up to 100 sites
                (Europe, Australia, New Zealand)
                Device sizes:
                       – 2.5 & 3 x 18 & 28 mm
                                           (overlap of two 18 mm long devices also permitted)
                       – Lesion length treatable: ≤ 28 mm

              • Clinical follow up only
                       – ID-MACE, ID-TVF, ID-TLR, ID-TVR, ‘stent’
                         thrombosis
       © 2009 Abbott
       Laboratories
                       – 30 days, 6 months,forand annually 1-3 years
                             Pipeline product. Currently in development at Abbott Vascular. Not
                                                     available     sale.
SE 2928803 Rev C
First ABSORB EXTEND Follow-up
                                        6-Month Clinical Results in the first 200 patients

                                            ABSORB Extend Clinical Results –
                                                    Intent to Treat


                                                                              30 Days            6 Months

                            Non-hierarchical                                   N = 200            N = 200
                              Cardiac Death % (n)                                   0              0.5 (1)*
                            Myocardial Infarction % (n)                         2.0 (4)            2.0 (4)
                              Q-wave MI                                         1.0 (2)            1.0 (2)
                              Non Q-wave MI                                     1.0 (2)            1.0 (2)
                            Ischemia driven TLR % (n)                           0.5 (1)            0.5 (1)
                              CABG                                                  0                 0
                              PCI                                               0.5 (1)            0.5 (1)
                            Hierarchical MACE % (n)                             2.0 (4)            2.5 (5)
                            Hierarchical TVF % (n)
                              Abizaid, A., TCT, 2011                            2.0 (4)           3.0 (6)**
                        *     Patient was treated with a metallic DES, not ABSORB
       © 2009 Abbott                    Pipeline product. Currently in development at Abbott Vascular. Not
       Laboratories    **                                               available for
                                                                              sale.
                             One additional ischemia driven non-TL TVR treated by CABG

SE 2928803 Rev C
So far…
       • Bioabsorbable active stent keeps promise
                – As good as DES
                – Positive effect on late healing (vasoreactivity,
                  conformability, positive remodeling, no trigger
                  for neo-atherosclerosis)
       • A slow & relatively long resorption process
         is necessary to obtain these results
       • Future trials are mandatory to evaluate the
         role of this technology
       © 2009 Abbott    Pipeline product. Currently in development at Abbott Vascular. Not
       Laboratories                             available for sale.
SE 2928803 Rev C
Trans-catheter Aortic Valve
   Implantation (TAVI)
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
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.
Mortality in Aortic Valve Replacement

                     n = 1.984




Burr et al, Annals Thor Surg, 1995;60:S264-269
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.
Landmark PARTNER TRAIL
Baseline Characteristics
of the patients and
Echocardiographic
findings
Primary End Point
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
Vitamin D
a Novel Cardiovascular risk factor
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.
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
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
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
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.
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
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*)
What is adequate supplementation
      in the Indian context ?
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
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
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
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.
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.
Role of Vit D.
in CVD/ CV risk factors
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
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
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.
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
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
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.
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.
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
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
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
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.
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.
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.
• 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.
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
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
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
NIH Recommendations of Vit D
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
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
Dr. neeraj-presentation-23-des

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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
  • 2.
  • 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
  • 14. Incidence of Stroke or Systemic Embolism RR 0.90 (95% CI: 0.74–1.10) P<.001 (NI) RR 0.65 (95% CI: 0.52–0.81) 1.8 Stroke/systemic embolism (%/yr) P<.001 (Sup) 1.71 1.5 RRR 1.54 35% 1.2 1.11 0.9 0.6 0.3 0.0 Dabigatran Dabigatran Warfarin 110 mg BID 150 mg BID Events/n: 183/6015 134/6076 202/6022 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.
  • 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.
  • 21. Significantly Lower Intracranial Bleeding with Dabigatran RR 0.30 (95% CI: P<.001 (Sup) 0.9 0.19–0.45) RR 0.41 (95% CI: 0.28–0.60) 0.8 P<.001 (Sup) 0.7 Intracranial bleeding (%/yr) 0.76 0.6 RRR 0.5 59% RRR 0.4 70% 0.3 0.32 0.2 0.23 0.1 0 Dabigatran Dabigatran Warfarin 110 mg BID 150 mg BID 27/6015 38/6076 90/6022 Events/n: BID, twice daily; RR, relative risk; RRR, relative risk reduction; Sup, superiority
  • 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
  • 30.
  • 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.
  • 33.
  • 34.
  • 35.
  • 36.
  • 37.
  • 38.
  • 39.
  • 40.
  • 41.
  • 42.
  • 43.
  • 44.
  • 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
  • 46. Bioabsorbable stent: The 4th Step…
  • 47. Balloon Bare metal Stent Drug Eluting Stent Angioplasty Decade 1980s 1990s 2000s Acute Success rate 70-85% >95% >95% Restenosis 40-45% 20-30% <10% Early Thrombosis 3-5% 1-2% 1-2% <30 days Late Thrombosis NA <0.5% 1% >30 days Very Late Thrombosis NA ≈0% 0.6%per yr (>1y) © 2009 Abbott Pipeline product. Currently in development at Abbott Vascular. Not Laboratories available for sale. SE 2928803 Rev C
  • 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.
  • 54. Poly Lactide - Hydrolysis PLA PLA – Poly Lactic Acid H2O ↓ Molecular Weight Hydrolysis Lactide O O Mass Loss R + H2O R + HO R′ O R′ OH carboxylic acid alcohol Mass Transport CO2 + H2O Krebs Cycle © 2009 Abbott Pipeline product. Currently in development at Abbott Vascular. Not Laboratories available for sale. SE 2928803 Rev C
  • 55. Bioresorbable Polymer: ABSORB • Everolimus/PDLLA Matrix Coating • Thin coating layer • Amorphous (non-crystalline) • 1:1 ratio of Everolimus/PLA matrix • Conformal Coating, 2-4 µm thick Drug/polymer matrix • Controlled drug release Polymer backbone • PLLA Backbone • Highly crystalline • Provides device integrity • Processed for increased radial strength © 2009 Abbott Pipeline product. Currently in development at Abbott Vascular. Not Laboratories available for sale. SE 2928803 Rev C
  • 56. © 2009 Abbott Pipeline product. Currently in development at Abbott Vascular. Not Laboratories available for sale. SE 2928803 Rev C
  • 57. Clinical Study Design – Cohort A Single, 3.0 mm de-novo lesion n = 30 BVS Device • Sponsor: Abbott Vascular • 3.0 x 12mm device (3.0 x 18mm device available after • Prospective, open label enrolment start and used in 2 patients) • PI: John Ormiston, MD Patrick Serruys, MD, PhD • 6 sites EU, NZ Rotterdam, NL, Patrick Serruys • DSMB: J. Tijssen PhD, Krakow, PL, Dariusz Dudek T. Lefèvre MD, P. Urban MD Auckland, NZ, John Ormiston • CEC: C. Hanet MD, Aarhus, DN, Leif Thuesen D. McClean MD, V. Umans MD Aalst, BE, Bernard de Bruyne St Denis, F, Bernard Chevalier • Angiographic and IVUS corelab: Cardialysis (Rotterdam, NL) • Post-procedure clopidogrel for 6 months, aspirin for 5 years © 2009 Abbott Pipeline product. Currently in development at Abbott Vascular. Not Laboratories available for sale. SE 2928803 Rev C
  • 58. ABSORB : Long term follow-up 5-Year Clinical Results ABSORB Cohort A Clinical Results at Each Phase: Intent to Treat RESTORATION RESORPTION Hierarchical 6 Months 12 Months 24 Months 60 Months 30 Patients 29 Patients** 29 Patients** 29 Patients** Ischemia Driven MACE*** 1 (3.3%)* 1 (3.4%)* 1 (3.4%)* 1 (3.4%)* Cardiac Death 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) MI 1 (3.3%)* 1 (3.4%)* 1 (3.4%)* 1 (3.4%)* Q-Wave MI 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Non Q-Wave MI 1 (3.3%)* 1 (3.4%)* 1 (3.4%)* 1 (3.4%)* Ischemia Driven TLR 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) by PCI 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.%) by CABG 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.%) Serruys, PW, TCT, 2011 * Same patient – this patient also underwent a TLR, not qualified as ID-TLR (DS = 42%) ** One patient missed the 9, 12, 18 month and 2, 3, and 4 year visits; one patient died from a non-cardiac cause 706 days post procedure *** MACE –Abbott Pipeline product. Currently in development at Abbott Vascular. Not © 2009 Composite endpoint comprised of cardiac death, myocardial infarction (MI) and ischemia-driven target lesion revascularization (TLR) by PCI or CABG Laboratories available for sale. 58 SE 2928803 Rev C
  • 59. ABSORB : Scaffold Thrombosis Out to 5 Years Cohort A 5-Year Clinical Results Thrombosis Results Through All Phases Time % Patients N Acute (<1 day) 0 (0.0%) 30 Sub-Acute (1-30 days) 0 (0.0%) 30 Late (>30 days – 1 year) 0 (0.0%) 29 Very Late (>1 year) 0 (0.0%) 29 © 2009 Abbott Pipeline product. Currently in development at Abbott Vascular. Not 59 Laboratories available for sale. SE 2928803 Rev C
  • 60. KM estimate of MACE rate in patients treated with BVS (Absorb Cohort B, n=101) vs. patients treated with a single 3x 18 mm metallic EES (Spirit I+II+III, n=227) M A C E (C -D e a t h , M I, ID -T L R ) 25.0% B V S ( B 1 + B 2 ) X V ( S P I + S P I I + S P I I I R C T ) 20.0% 393-day HR 0.93 [0.38,2.24] p=0.8678 15.0% 10.0% 7.5% ∆ 0.6% 5.0% 6.9% XV Includes only patients with single 3.0 x 18mm stent BVS Includes all patients 0.0% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 T im e P o s t I n d e x P r o c e d u r e Patients at risk 0 days 37 days 194 days 284 days 365 days 393 days 101 99 96 96 95 94 BVS(B1+B2) Abbott © 2009 Pipeline product. Currently in development at Abbott Vascular. Not Laboratories 227 224 available for sale. 211 219 209 208 XV(SPI+SPII+SPIII RCT) SE 2928803 Rev C
  • 61. ABSORB Extend • N = up to 1,000 patients at up to 100 sites (Europe, Australia, New Zealand) Device sizes: – 2.5 & 3 x 18 & 28 mm (overlap of two 18 mm long devices also permitted) – Lesion length treatable: ≤ 28 mm • Clinical follow up only – ID-MACE, ID-TVF, ID-TLR, ID-TVR, ‘stent’ thrombosis © 2009 Abbott Laboratories – 30 days, 6 months,forand annually 1-3 years Pipeline product. Currently in development at Abbott Vascular. Not available sale. SE 2928803 Rev C
  • 62. First ABSORB EXTEND Follow-up 6-Month Clinical Results in the first 200 patients ABSORB Extend Clinical Results – Intent to Treat 30 Days 6 Months Non-hierarchical N = 200 N = 200 Cardiac Death % (n) 0 0.5 (1)* Myocardial Infarction % (n) 2.0 (4) 2.0 (4) Q-wave MI 1.0 (2) 1.0 (2) Non Q-wave MI 1.0 (2) 1.0 (2) Ischemia driven TLR % (n) 0.5 (1) 0.5 (1) CABG 0 0 PCI 0.5 (1) 0.5 (1) Hierarchical MACE % (n) 2.0 (4) 2.5 (5) Hierarchical TVF % (n) Abizaid, A., TCT, 2011 2.0 (4) 3.0 (6)** * Patient was treated with a metallic DES, not ABSORB © 2009 Abbott Pipeline product. Currently in development at Abbott Vascular. Not Laboratories ** available for sale. One additional ischemia driven non-TL TVR treated by CABG SE 2928803 Rev C
  • 63. So far… • Bioabsorbable active stent keeps promise – As good as DES – Positive effect on late healing (vasoreactivity, conformability, positive remodeling, no trigger for neo-atherosclerosis) • A slow & relatively long resorption process is necessary to obtain these results • Future trials are mandatory to evaluate the role of this technology © 2009 Abbott Pipeline product. Currently in development at Abbott Vascular. Not Laboratories available for sale. SE 2928803 Rev C
  • 64. Trans-catheter Aortic Valve Implantation (TAVI)
  • 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.
  • 69.
  • 71. Baseline Characteristics of the patients and Echocardiographic findings
  • 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
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  • 103. Vitamin D a Novel Cardiovascular risk factor
  • 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*)
  • 111. What is adequate supplementation in the Indian context ?
  • 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.
  • 117. Role of Vit D. in CVD/ CV risk factors
  • 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