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					        Differing influence of hypertension on
      absolute and relative risk of stroke and MI
                           20

                                         Normotensives                           Hypertensives
         5 Year Risk (%)




                           15



                           10
                                              Stroke

                                              Myocardial
                            5
                                              Infarction


                            0
                                0   20   40   60    80   100   120   140   160   180   200   220   240   260   280   300

                                                   Systolic Blood Pressure (mmHg)

Brown, M.J. Lancet 2000; 355: 659 - 660
  Observational evidence for low threshold in curve relating
treated SBP to incidence of DM related endpoints in UKPDS
                      BMJ. 2000; 321: 412-419




                                                     *adjusted for age,
                                                     sex, and ethnic
                                                     group, expressed
                                                     for white men
                                                     aged 50-54 years
                                                     at diagnosis and
                                                     mean duration of
                                                     diabetes of 10
                                                     years


             Updated mean systolic blood pressure*
Blood Pressure Lowering
   Treatment Trialists’
      Collaboration
Second cycle of overview analyses




                                                   Institute
                                                      for
                                                 International
                                                    Health
       Turnbull, F. (2003) Lancet 362, 1527-35
                             STROKE
       Comparisons of different active
                treatments
                  BP
              difference      Favours      Favours
               (mm Hg)       first listed second listed      RR (95% CI)


ACE vs. D/BB    2/0                                        1.09 (1.00,1.18)
CA vs. D/BB     1/0                                        0.93 (0.86,1.01)
ACE vs. CA       1/1                                       1.12 (1.01,1.25)



                       0.5           1.0             2.0
                                 Relative Risk
  CORONARY HEART DISEASE
      Comparisons of different active
               treatments
                  BP
              difference          Favours         Favours
              (mm Hg)            first listed   second listed        RR (95% CI)


ACE vs. D/BB     2/0                                              0.98 (0.91,1.05)
CA vs. D/BB      1/0                                              1.01 (0.94,1.08)
ACE vs. CA       1/1                                              0.96 (0.88,1.05)


                           0.5             1.0              2.0
                                       Relative Risk
MAJOR CARDIOVASCULAR EVENTS
       Comparisons of different active
                treatments
                  BP
              difference          Favours        Favours
               (mm Hg)           first listed   second listed       RR (95% CI)


ACE vs. D/BB     2/0                                             1.02 (0.98,1.07)
CA vs. D/BB      1/0                                             1.04 (0.99,1.08)
ACE vs. CA       1/1                                             0.97 (0.92,1.03)


                           0.5             1.0             2.0
                                       Relative Risk
     Reduction in CV events in Hypertension Optimal
        Treatment (HOT) Study : DM vs. non-DM

                                25
                                                             p=0.005 (DM)

                                20                                 DM
         Events/1000 pt-years




                                                                   non-DM

                                15



                                10



                                5



                                0
                                     <90           <85            <80
                                           Target diastolic BP
Lancet1998; 351: 1755–
   Value of excellent vs. good blood pressure control in NIDDM
                                                       (144/82 vs. 154/87mmHg)



                                     40
                                                  Less tight control
          Patients With Events (%)



                                                  Tight control
                                     30


                                     20


                                     10


                                     0
                                          0   1       2     3   4    5     6     7    8
                                          9          Years From Randomisation




                                      Reduction in risk with tight control 32% (95% CI 6% to 51%) (P=0.019)

UKPDS, BMJ 1998;317:703-713.
Benefits of antihypertensive treatment is
proportional to reduction in blood pressure
              1.50

                                              ACE/CA
              1.25                                                ACE/DBB


              1.00
                                                  ARB/other
                                  ACE/plac
              0.75                                                 CA/DBB


                                         More/less
              0.50

                        CA/plac
              0.25
                  -10      -8       -6       -4      -2       0     2       4
                           Systolic blood pressure difference
                           between randomised groups (mmHg)

   Results of prospectively-designed overviews of randomised trials. Lancet 2003; 362:
   1527-35.
Coronary Heart Disease
       1.50

                                     ACE/CA
       1.25

                                                          ACE/DBB
       1.00
                          ACE/plac
                                                      CA/DBB
       0.75                               ARB/other

                                 More/less
       0.50     CA/plac


       0.25
              -10   -8      -6       -4      -2       0    2    4

                    Systolic blood pressure difference
                    between randomised groups (mmHg)
25


                                Biochemical Results –
        ALLHAT                 Fasting Glucose – mg/dL
                                Chlorthalidone      Amlodipine      Lisinopril
     Total
                  Baseline           123.5 (58.3)   123.1 (57.0)   122.9 (56.1)
                  4 Years            126.3 (55.6)   123.7 (52.0)   121.5 (51.3)*
     Among baseline nondiabetics with baseline <126 mg/dL
                  Baseline           93.1 (11.7)    93.0 (11.4)     93.3 (11.8)
                  4 Years            104.4 (28.5)   103.1 (27.7)   100.5 (19.5)*
     Diabetes Incidence (follow-up fasting glucose  126 mg/dL)
                  4 Years              11.6%           9.8%*          8.1%*




 *p<.05 compared to chlorthalidone
    LIFE: New Onset Diabetes
                            0.10                         Intention-to-Treat
                            0.09
                                                                                    Atenolol
                            0.08

                            0.07
            Endpoint Rate




                            0.06

                            0.05                                                                  Losartan
                            0.04

                            0.03

                            0.02
                                                          Adjusted Risk Reduction 25%, p<0.001
                            0.01                          Unadjusted Risk Reduction 25%, p<0.001
                            0.00
     Study Day                     0   180   360   540    720   900   1080   1260   1440   1620    1800   1980
7   B Dahlof et al. Lancet 2002;359:995-1003
         Percentages of Patients whose
           Hypertension is Controlled
        < 140/90 mmHg                                    < 160/95 mmHg
        USA      Canada                            Finland     Spain  Australia
                                 13                       20.5                20              19
                 27



     England              France                 Germany Scotland                          India
             6                    24                                         17.5            9
                                                          22.5

                                                    > 65 years


USA: JNC VI. Arch Intern Med 1997            Marques-
                                             Marques-Vidal P et al. J Hum Hypertens 1997
Canada: Joffres et al. Am J Hypertens 2001

England: Colhoun et al. J Hypertens 1998                              Adapted from G. Mancia / L.
France: Chamontin et al. Am J Hypertens                                                 Ruilope
1998
Target blood pressure – new levels for
                 DM




For ambulatory (mean daytime) or home BP monitoring,
reducing these targets by ~10/5 is recommended.
BP Thresholds for treatment
                 Drugs acting on the
              renin-angiotensin system
 Brown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120.

                                                    arteries



Angiotensinogen           AI               AII



                Renin
                                             adrenal glands




                                                              Aldosterone
                                  kidneys
                      Na+                         Na+
                 Drugs acting on the
              renin-angiotensin system
 Brown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120.

                                                    arteries



Angiotensinogen           AI               AII



                Renin
                                             adrenal glands




                                                              Aldosterone
                                  kidneys
                      Na+                         Na+
                   Drugs acting on the
                renin-angiotensin system
   Brown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120.


                                 ACE Inhibitors        arteries



 Angiotensinogen            AI                AII
                                                                  AIIRA


                   Renin
                                                  adrenal glands

Calcium Blockers
Diuretics

Beta-blockers
                                                                Aldosterone
                                      kidneys       Spironolactone
              Design of Rotation

• 56 untreated patients with EHT, aged 21-49
• 8 month, open-label rotation through 4 classes, alternating
  RX and washout
• Drugs: Lisinopril 10-20 mg (ACE inhibitor)
           – Bisoprolol 5 mg (Beta blocker)
           – Dyazide one daily (Diuretic)
           – Nifedipine LA 30 mg (Calcium Blocker)
• Best drug repeated at end of rotation
• Evidence of variability:
   – Number at target higher on best > first treatment
   – Lack of correlation between pairs of drugs
                                                                                                            200

                     Influence of rotation on                                                               190
                                                                                                                    FIRST TREATMENT




                                                                                    SYSTO LIC BP (m m Hg)
                                                                                                            180


                     success of monotherapy                                                                 170
                                                                                                            160
                                                                                                            150
                                                                                                            140
                     200
                                                                                                            130
                     190
                                       PRE-TREATMENT
                                                                                                            120
SYSTOLIC BP (mmHg)




                     180                                                                                    110
                                                                                                               65   70   75   80    85    90    95       100   105   110   115
                     170
                                                                                                                              DIAST OL IC BP (m m Hg )
                     160

                     150

                     140
                                                                                                            200
                     130
                                                                                                            190               BEST TREATMENT
                     120




                                                                                      SYSTOLIC BP (mmHg)
                                                                                                            180
                     110
                        65   70   75   80   85   90   95   100   105   110   115                            170

                                       DIASTOLIC BP (mmHg)                                                  160

                                                                                                            150

                                                                                                            140

                                                                                                            130

                                       ACE INHIBITOR                                                        120
                                       BETA BLOCKER                                                         110
                                                                                                               65   70   75   80    85     90    95      100   105   110   115
                                       CALCIUM BLOCKER
                                       DIURETIC                                                                               DIASTOLIC BP (mmHg)


                                                                                   Dickerson et al. Lancet 353:2008-13, 1999
Delta Diastolic Blood Pressure (mmHg)                CI
                                                    AE
                                                          Correlations between drug pairs
                                                =. , =. 2
                                                   5    0
                                                r 0 0 p0 0 1
                                          4                           _ LC
                                                                     B B OK

                                        -16
                                        -36

                                        14                                               IU E IC
                                                                                        D RT


                                         -2
                                        -18
                                        18                                           6    0
                                                                                  =. , =. 0
                                                                                  r 0 1 p0 0 9                A B OK
                                                                                                              C_ L C

                                         -2
                                        -22

                                              -36   -10   12                      -18     -2       14
                                                                                                        -22    -2      18
                                                               -36    -16     4

                                                      Delta Diastolic Blood Pressure (mmHg)
              ADLiB: Design
• Double-blind Latin-square placebo-controlled
  randomised crossover rotation through
  –   Amlodipine 5 mg         Calcium blocker
  –   Doxazosin 4 mg          Alpha blocker
  –   Lisinopril 10 mg        ACE inhibitor
  –   Bisoprolol 5 mg         Beta blocker
  –   Bendrofluazide 2.5 mg   Diuretic
• Placebo run-in then 6 x 6 week cycles
• Most effective, best tolerated drug repeated
                                       Distribution of best drugs
                                     (& 24 h BP readings on these)
                                     14                               135/86
Number choosing for best treatment




                                     12                      136/89
                                     10

                                      8
                                          144/95                       13
                                      6            154/102    10
                                      4                                        148/99
                                            5
                                      2              4
                                                                                    2
                                      0
                                           A        D        Li        B        b
        AB/CD Rule for optimisation of
         antihypertensive treatment
        ( AB/CD =ACEi, Beta-blocker Ca++-blocker, Diuretic)
                                    AGE

             Younger                 Renin                     Older
STEP:         (<55)                                            (>55)
        1:    A or B                                           C or D

             2:         C or D                A or B

                  3:    A or B        +       C or D

 Resistant HT / 4: Add / substitute alpha blocker
 Intolerance    5: Re-consider 20 causes  trial of spironolactone
                                 Dickerson et al. Lancet 353:2008-11;1999
   BHS on fixed dose combos

• The UK has by far the lowest rate of fixed-
  dose combination therapy use in Europe
  and BP control rates lag substantially
  behind those of North America.
• All four of the possible permutations of
  {A or B}+{C or D} have been approved by
  regulatory authorities as fixed-dose
  combinations.
      BHS on fixed dose combos

• The most widely used combinations which
  are undoubtedly effective in terms of BP
  reduction are those of  blockade and
  thiazide-like diuretics, ACE inhibitor or ARB
  and thiazide-like diuretics, and -blocker and
  CCB.
• When fixed-dose combinations replicate the
  desired treatment plan for a patient and when
  there is no cost disadvantage, the BHS
  recommends their use to reduce the number
  of medications and thereby improve
  adherence with therapy.
   Probable indications for statin

All patients up to the age of at least 80 with
  total cholesterol >3.5 mmol/L and
• active CHD, or
• peripheral arterial disease, or
• history of ischaemic stroke, or
• diabetes, or
• 10 yr CVD risk  20%
        Changes in autoregulation in Benign and
              Accelerated Hypertension


                                                                                   Hypertensive
        Cerebral Blood Flow




                                                         Normotensive




                                                                    Accelerated Hypertension




                              0    50             100                150               200
                                  DIASTOLIC BLOOD PRESSURE (mm Hg)

Laurence DR, Bennett PN, Brown MJ. Arterial hypertension, angina pectoris, myocardial infarction;
Clinical Pharmacology, 8th Edition, Churchill Livingston, 1997.
                                            Encephalopathy
                                            (Eclampsia)
                    Severe Hypertension
                                            LVF
                                            Dissection


      Accelerated Hypertension     Urgent Hypertension


Rx:                                         Rx:
-blockade                                  Nitroprusside
                                            GTN
                                            Labetalol
                       Summary
• Hypertension is the commonest cause of major
 morbidity, but less than a quarter of patients are
 adequately treated.

• A reduction in cardiovascular disease mortality and
 morbidity can be achieved through improved treatment
 and control of hypertension.

• A greater choice of drugs are available for hypertension
 than for other chronic diseases

• Rational choice of single and combination drugs
 facilitated by understanding their effects on the renin
 system, but systematic trial and error may still be
 necessary

				
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posted:8/16/2010
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