MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate

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MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
The cuRrent statE of Angina

   treatment in outpatient

 popuLation and heart rate

    monIToring surveY
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
Source: Fréquence des infarctus du myocarde
Meyer K. et al., Kardiovask, Med. 2007;10:279–284
                                                    http://www.obsandaten.ch/indikatoren/8_3_11/2004
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
CVD

Heart Disease

       CHD

     Stroke

Cooper et al., Circulation, 2000: 102
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
Qu’est qu’un facteur de risque
     cardiovasculaire ?

  “C’est une condition associée avec un risque augmenté de développer
  une maladie cardiovasculaire.
  L'association est au début toujours statistique. Ainsi le fait qu'une
  personne particulière ait un facteur particulier augmente simplement la
  probabilité de développer un certain type de maladie cardio-vasculaire.
  cela ne signifie en aucun cas qu’il ou elle soit sûre de développer la
  maladie cardiovasculaire.
  Réciproquement, le fait qu'un individu n'ait pas un facteur de risque
  cardio-vasculaire particulier ne garantit pas la protection contre une
  maladie cardiovasculaire”

                            Dr. William KanneI, premier directeur de l’étude Framingham
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
FCR et mortalité chez l’ Homme

                                                            Population générale

                                       Insuffisance cardiaque                                                        Mort subite

             70.0                                                                     6.0

                                                                      Evénements/1000 patients x 2 ans
Evénements/1000 patients x 2 ans

                                              66-94                                                                 35-84
             52.5                                                                     4.5

             35.0                                                                     3.0

             17.5                                                                     1.5

                                        15     25      48     63                                             1.1   2.5    3.1    4.7     5.9
                                   0                                                                     0
                                       < 64   65-74   75-84 >85/min                                          65          74-79         >88/min
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
Relationship between heart rate and cardiovascular mortality
        in the general and hypertensive population

                      J Clin Epidemiol 2006
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
Pouls et pression artérielle humérale
                                                  pendant examen final

                 Facteurs de risque CV
                  Syndrome
                 métabolique
                    Obésité
                 Diabète sucré       Dépôts
                 Hypertension      lipidiques
   Modifiables

                   artérielle
                 HDL, LDL, TGL

                    Diète
                    Tabac        Inflammation
                    Alcool
                   Exercice
                   physique

                     Âge
modifiables

                                 Contraintes de
                    Sexe
  Non-

                                  cisaillement
                   Hérédité

                                                   Uexküll T, Wick E: Arch Kreislaufforsch 39: 236-271; 1962
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
MonIToring surve Y - The cu Rrent stat E of Angina popuLation and heart rate
Coronary

                                                        Heart

                                                                Atherosclerotic                Plaque Rupture
                                                                   Plaque
                   Plaque Growth                                                           Risk Factors for Plaque Rupture

  Risk Factors for Plaque Growth                                                           Diabetes mellitus
                                                                                           Smoking
                      Metabolic                                                            Dyslipidemia
                      syndrome
                                                                                           Inflammation/Apoptosis
                        Obesity             Lipid
                    Diabetes mellitus     deposition                                       Endothelial dysfunction/Shear
  Can be changed

                     Hypertension                                                          stress
                    HDL,   LDL, TGL                                                        High heart rate
                     High-fat diet                                                         Hyperhomocysteinaemia/
                       Tobacco                                                             Lipoproteinaemia
                   Sedentary lifestyle   Inflammation                                      Genetic protein defiencies (ATIII,
                     High heart                                                            Protein C or S)
                         rate
                                                                                           Hypercoagulability/Fibrinolytic
                                                                                           state
Cannot be

                         Age                                                               Tissue factor activity
 changed

                       Gender            Shear stress
                       Heredity

                                                                                Coronary
                                                                                 Event
Cardiovascular events during Soccer
                                                     Coronary
                                 Worldcup in Germany
                                                        Heart

                                                                Atherosclerotic                Plaque Rupture
                                                                   Plaque
                   Plaque Growth                                                           Risk Factors for Plaque Rupture

  Risk Factors for Plaque Growth                                                           Diabetes mellitus
                                                                                           Smoking
                      Metabolic                                                            Dyslipidemia
                      syndrome
                                                                                           Inflammation/Apoptosis
                        Obesity             Lipid
                    Diabetes mellitus     deposition                                       Endothelial dysfunction/Shear
  Can be changed

                     Hypertension                                                          stress
                    HDL,   LDL, TGL                                                        High heart rate
                     High-fat diet                                                         Hyperhomocysteinaemia/
                       Tobacco                                                             Lipoproteinaemia
                   Sedentary lifestyle   Inflammation                                      Genetic protein defiencies (ATIII,
                     High heart                                                            Protein C or S)
                         rate
                                                                                           Hypercoagulability/Fibrinolytic
                                                                                           state
Cannot be

                         Age                                                               Tissue factor activity
 changed

                       Gender            Shear stress
                       Heredity

                                                                            Coronary
                                                                             Event
                                                                               NEJM 2008
Increased heart rate may contribute to coronary plaque
                      disruption

2002         2004           2004                          2009

                              Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482.
High resting heart rate: an independent predictor
  of mortality in the French general population

                   c a r d ia q u e é le v é e
        Fréquence
                       -
                        s . F a c te u r d e  r is q u e ?
  Marqueur de risque v

                                           Benetos A et al.Hypertension. 1999;33:44-52.
Ivabradine shifts the patients from
                                                      high risk to low risk

                            8

                                                                    HR >70 bpm in placebo
                                                                          (mean HR = 79 bpm)

                                                                                                         -36%*
 fatal or nonfatal MI (%)
   Hospitalization for

                            4                                        HR  70 bpm with Procoralan
                                                                    (mean HR = 66 bpm after treatment)

                            0                                                     *P=0.001
                                                                                 **P=0.0066

                                0   0.5    1          1.5       2
                                          Years

Fox K et al. Lancet. 2008;372:807-816.
Cascade                             Stabilité
ischémique                           de plaque

Contrôle des                     Contrôle des
symptômes                        événements
               Cook S & Hess OM, European Heart Journal, 2009
The cuRrent statE of

 Angina treatment in
outpatient popuLation

   and heart rate

 monIToring surveY
Objectives of REALITY

To characterize resting heart rate and
medication of the population with stable
angina pectoris in outpatient clinics

 To correlate angina pectoris events to heart
rate.

To evaluate the impact of angina pectoris on
quality of life
Study design

Cross-sectional epidemiological study

Data acquisition by 33 Swiss cardiologists in
clinical practice

Mock                  Sigwart                Grobéty

Gillard-Berguer                              Reynard
                      Bacchocchi-Suilen
                                             Jaussi
Koerfer               Burri                  Ricou
Pasquier              Perret                 Bérubé
Vulliemin            Bosquet                Fiori

Savcic               Goy                    Depeursinge
Baseline data:
                                   Cardiovascular risk factors

                   Total 283 coronary disease patients   (202 male, 81 female)

Mean heart rate at rest [bpm]                                 69
(min-max)                                                     (46-126)
Smoker                                                        45 (16%)
Mean systolic blood pressure [mmHg]                           140.0
(min-max)                                                     (98-202)
Mean diasolic blood pressure [mmHg]                           80.8
(min-max)                                                     (54-100)
Hypertension                                                  191 (67%)
Mean BMI [kg/m2]                                              26.8
(min-max)                                                     (17.9-39.5)
Diabetes Mellitus                                             74 (26%)
CAD

Mean time since diagnosis of a stable
                                        4.25 (0.02-36.7)
angina pectoris [years] (min-max)

Myocardial infarction                   84 (30%)
Coronary artery bypass graft (CABG)     35 (12%)
Percutaneous coronary intervention
                                        142 (50%)
(PCI)

PCI & CABG                              23 (8%)
Cardiovascular risk factors

Mean heart rate at rest [bpm]                69
(min-max)                                    (46-126)

       resting                         resting
      heart rate                      heart rate
      70 bpm
Association of resting heart rate with major
                                      cardiovascular risk factors
                                            70 bpm
                                           (n=157) (n=126)
  Atrial fibrillation %                    10            13             NS
  Heart failure %                          8             10             NS
  Cerebrovascular diseases %               9             17             p < 0.05
  Hypertension %                           62            74             p < 0.05
  Diabetes mellitus %                      21            33             p < 0.05
  Dyslipidemia %                           83            90             NS
  Obesity, BMI > 27 kg/m2 %                37            52             p < 0.01
Patients with heart rate >70 bpm suffer significantly more from additional
cardiovascular risks than patients with heart rate
FCR et mortalité chez      Physiopathologie -
     l’ Homme                   Acquis

      Coronary Artery Surgery Study
 24 913 patients avec maladie coronarienne
           suspecte ou prouvée

                                Diaz A, et al., European Heart Journal (2005) 26, 967–974
How do angina pectoris events and
                                         heart rate correlate?

                                            Angina pectoris events per week
Angina pectoris events/ week

                               4

                               3                                          3.8
                                                               3.3
                                      2.8
                                                  2.7
                               2
                                     n=86        n=71         n=62       n=62
                                     ≤60       61-69        70-77        ≥77

                                                 Subgroups by bpm
FCR et mortalité chez                              Fréquence cardiaque et
                l’ Homme                                      Espérance de vie après
                                                              infarctus du myocarde

    Analyse de l’étude GUSTO-I
                                               *   ECG à l’admission
    Admission pour infarctus aigu du               41’021 patients
    myocarde                                       Mortalité à 30 jours

*
                                                                          Hathaway WR,et al. Jama. 1998;279(5):387-391.
GUSTO-I: Global Utilization of Streptokinase
and t-PA (alteplase) for Occluded Coronary
Arteries
Classification of severity of angina by the
                      CCS: Canadian Cardiology Society Scale

                                                CCS IV = Inability to perform any
                                                         activity without angina or
                                                         angina at rest, i.e., severe
100%                                                     limitation

                                                CCS III = Symptoms with everyday
75%
                                                         living activities, i.e.,
                                                         moderate limitation
50%
                                                CCS II = Slight limitation, with
                                                         angina only during vigorous
25%
                                                         physical activity

 0%                                             CCS I = Angina only during
       ≤60    61-69     70-77     ≥77                    strenuous or prolonged
                                                         physical activity

         Subgroups by bpm
Objective 2

How does angina pectoris influence
  habits and quality of life of CD
            patients?
Restenosis and Quality
Bénéfices des DES                                             of Life

             Functional Status
                       No Revasc              Repeat Revasc

                 P=0.03                 P=
Limitation of everyday living activities
                                                             Whole              p
                                70 bpm
                                                           population      difference
                                (n=157 )     (n=126 )
                                                            (n=283 )       70

 Fear of angina pectoris
events leads to limitation
                                  26%           38%           31%           p < 0.05
  of physical activity
   (despite treatment)

Regular physical activity         60%           47%           54%           p < 0.05

•Fear from angina pectoris events leads to limitation of everyday living activities in many CD
patients.
Subgroup heart rate >70 bpm significantly more affected than subgroup 70 bpm are significantly less physically active than
patients of the subgroup heart rate
Evaluation of CAD treatments in
                             Switzerland
                                                  Whole
                              70 bpm                p Difference
                                                  population
                              (n=157)   (n=126)                70
                                                  (n=283)
Invasive treatments           75%       67%       72%          NS
Nitrates                      51%       51%       51%          NS
Calcium antagonists           30%       40%       34%          NS
Coronary therapy              24%       25%       25%          NS

Beta-blockers                 81%       67%       75%          p < 0.01

No Beta-blockers because of
                              7%        18%       13%          NS
contraindication

Antianginal therapy per
                              4.26      4.51      4.37         NS
patient (11 months)

Increase of heart rate
                              3%        17%       9%           p < 0.001
since diagnosis
Heart rate reduction is associated with
a decrease of post-MI cardiac deaths

                           Meta-regression of 12 controlled studies

                 2.0

                 1.0
    Odds ratio

                 0.5

                 0.2

                           β-Blockers                                                         P
Comparison Europe wide –
                                                        cardiovascular risk factors

                         EUROASPIRE II1                     2000/2001                 EUROASPIRE III1                   REALITY CH
 Risk factors              1999-2000                       Survey CH2                   2006-2007                          2008
                            n = 2975                          n=565                      n = 2392                         n=283

  Age (years)                       59                            68                              60                            69
Angioplasty %                       28                            62                              50                            72
  Smoker %                          21                            18                              18                            16
  Obesity %                         33                             -                              38                            44
Hypertension %                      58                            65                              61                            67
Dyslipidemia %                      75                            71                              46                            87
 Diabetes %                         20                            22                              28                            26

       1 Wood DA et coll. Abst. 316. Hot Line I, ESC 2007, Vienne, Autriche - 2 National survey on prescription of cardiovascular drugs among
                              outpatients with coronary artery disease in switzerland. Swiss Med Wkly 2003;133:88-92
Comparison Europe wide - treatment

                        EUROASPIRE II1                     2000/2001                  EUROASPIRE III1                   REALITY CH
  Treatment               1999-2000                       Umfrage CH2                   2006-2007                          2008
                           n = 2975                          n=565                       n = 2392                         n=283

Antithrombotic
  agents %                          84                            84                              93                            99

Beta blockers %                     69                            71                              85                            75
ACE-blockers &
  Sartans %                         49                            47                              74                            65

   Statins %                        57                              -                             87                            84

       1 Wood DA et coll. Abst. 316. Hot Line I, ESC 2007, Vienne, Autriche - 2 National survey on prescription of cardiovascular drugs among
                              outpatients with coronary artery disease in switzerland. Swiss Med Wkly 2003;133:88-92
Latéral
Inférieur   Latéral    Inférieur

  Latéral             Antérieur
Aspirine 100 mg/d
CK 3250 U/l       Plavix 75 mg/d
LVEF @ D3: 45 %   Coversum 5 mg/d
                   Torem 5mg/d
Medicaments ?     Concor 5mg/d
                   Crestor 10 mg/d
FCR 74 bpm        Concor 10mg ou
                   Procoralan 5mg/d ?
Merci
Multiple cardiac effects of heart rate

                    MVO       Neurohormonal
     Myocardial                  systems
     perfusion                           Ion fluxes

 Autonomous                                   Myocardial
nervous system         Heart rate
                                              relaxation

     Arterial                            Myocardial
   compliance                            contraction
                  Plaque       Myocardial
                  rupture    gene expression
The Bowditch phenomenon

                               Contractile force of frog heart increases
                               when paced at increasing frequency.

Henry Pickering Bowditch
     (1840 – 1911)

Bowditch HP. Ueber die Eigenthuemlichkeiten der Reizbarkeit, welche die Muskelfasern
des Herzens zeigen.
Ber Sachs Ges Akad Wiss 1871; 23: 652-689.                               Courtesy of R. Lerch, MD
Effect of long-term therapy with β-blocker on EF

       1936 patients enrolled in 15 placebo-controlled trials

                            Packer et al, Am Heart J 2001; 141: 899-907
                                                           Courtesy of R. Lerch, MD
Force-Frequency relationship
              in normal and failing myocardium
   Trabecula from human hearts
                                                       Stimulation frequency (/min)

                                                     "negative staircase"

Schillinger, Hasenfuss et al, Basic Res Cardiol 1998; 93 (Suppl. 1): 38-45
                                                                 Courtesy of R. Lerch, MD
Ivabradine shifts the patients from
                                                      high risk to low risk

                            8

                                                                    HR >70 bpm in placebo
                                                                          (mean HR = 79 bpm)

                                                                                                         -36%*
 fatal or nonfatal MI (%)
   Hospitalization for

                            4                                        HR  70 bpm with Procoralan
                                                                    (mean HR = 66 bpm after treatment)

                            0                                                     *P=0.001
                                                                                 **P=0.0066

                                0   0.5    1          1.5       2
                                          Years

Fox K et al. Lancet. 2008;372:807-816.
IVA
Fréquence cardiaque et Espérance de vie après
infarctus du myocarde
432 patients avec infarctus aigu   ECG à l’admission et Holter 24 heures fin hosp.
343 hommes, 89 femmes;58           “Endpoints”: Mortalité et événements arrythmiques
±11 ans                            (Mort subite, fibrillation ventriculaire, tachycardie
                                   ventriculaire soutenue).
Suivi: 41 mois
                                   Mortalité à 30 jours

                                                                      Mauss O, et al. J
                                                                    Electrocardiol. 2005;
                                                                        38_106-112
The effects of a reduction in heart rate
Lower oxygen consumption
Improved diastolic coronary flow
Anti-ischemic effects
Increased ventricular fibrillation threshold
Antithromboatherosclerotic effects
Prevention of plaque rupture
Prevention of cardiomyopathy
Slower development and progression of IHD
Prevention of acute and chronic ischemic events
(CV death, sudden death, angina, AMI, CHF)
Implication of heart rate as a simple tool for
          mortality risk estimation

Simple (part of routine clinical examination)
Predictive (demonstrated in large number of
epidemiological trials)
Cheap (does not request special equipment)
Easily interpreted
Useful to monitor improvement of management
Conclusions
  CAD patients suffer from angina pectoris despite intensive
treatments. Number and severity of angina pectoris events in
patients with heart rate >70 is significantly higher than in subgroup
heart rate 70 suffering significantly more the patients with 70 than
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