Recent Developments in the Treatment of Hypertension by stephan2

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									Recent Developments in the
Treatment of Hypertension
     The Value of Facts


                          1999
                 Objectives
• To review recent clinical trial evidence of efficacy
  for antihypertensive agents
• To present new data on the treatment of
  hypertensive patients with type 2 diabetes
• To discuss the emerging evidence for use of
  ACE inhibitors in diabetes
• To review recent safety data on antihypertensive
  agents
      Documentation of Drug
       Safety and Efficacy
• Patients, clinicians and the health-care
 establishment expect adequate documentation
• A week-long treatment for an acute condition
 requires randomized trials that follow patients for
 > 1 week
• Lifelong treatments are ideally evaluated in lifelong
 trials, but evaluations in large populations over 4 to
 5 years are typically accepted.
Antihypertensive Drugs: Documentation
  By the Time of Regulatory Approval

                     Known
 • BP lowering potential (N = 200-500 patients)
 • Common side effects (symptoms)
 • Any common early drug complications (events)
 • Major changes in blood chemistry
 • Major animal toxicity
Antihypertensive Drugs: Documentation
  By the Time of Regulatory Approval
                    Unknown
  • Effect on major CVD mortality/morbidity
  • Optimal dose (risk-benefit balance)
  • Uncommon early side effects or clinical
      complications
  •   ADRs and complications of long-term drug use
  •   Efficacy or safety in various subgroups
  •   Effect on pregnancy
  •   Drug interactions
     Aim of Antihypertensive
             Therapy
To prevent the cardiovascular complications of
hypertension -- stroke, acute myocardial infarction,
congestive heart failure -- not just to lower an
elevated blood pressure.
Eligibility criteria for meta-analysis

• Randomized placebo controlled trials
• Treatment duration of > 1 year
• Assessment of major disease endpoints
• Unconfounded by other therapies

                       Psaty et al., JAMA 1997
Definition of Treatment Strategies
 • Multiple agents used in most trials
 • Trials classified by first-line strategy
       -- High-dose diuretic therapy
       -- Low-dose diuretic therapy
       -- Beta-blocker therapy
 •   No eligible trials evaluating CCBs or
     ACE inhibitors
                             Psaty et al., JAMA 1997
Summary of Eligible Trials (n = 18)

Therapy               Trial   Intervention    Control
Low-dose diuretics      4       4,305            5,116
High-dose diuretics   11        7,768           12,075
Beta-blockers           4       6,736           12,147
HDFP                    1       5,484            5,455


                                Psaty et al., JAMA 1997
Meta-analysis: Antihypertensives
High-dose diuretics
    Event             RR           95% CI
Stroke                0.49         0.39-0.62
CHF                   0.17         0.07-0.41
CHD                   0.99         0.83-1.18
Total mortality       0.88         0.75-1.03


                         Psaty et al., JAMA 1997
Meta-analysis: Antihypertensives
Low-dose diuretics
    Event            RR           95% CI
Stroke               0.66         0.55-0.78
CHF                  0.58         0.44-0.76
CHD                  0.72         0.61-0.85
Total mortality      0.90         0.81-0.99


                        Psaty et al., JAMA 1997
Meta-analysis: Antihypertensives
Beta-blockers
    Event         RR           95% CI
Stroke            0.71        0.59-0.85
CHF               0.58        0.40-0.84
CHD               0.93        0.80-1.09
Total mortality   0.95        0.84-1.07


                     Psaty et al., JAMA 1997
 Summary of Major Findings
• High-dose diuretic and ß-blocker therapies
 reduced the incidence of CHF and stroke
• Low-dose diuretic therapy reduced the
 incidence not only of CHF and stroke but also
 of CHD and total mortality
• High-dose versus low-dose diuretic comparison
 was confounded by patient age
                          Psaty et al., JAMA 1997
    Syst-Eur -- Nitrendipine in ISH
•   Randomized, placebo-controlled, 2N = 4,695
•   Baseline, mean age 70 yrs, BP 174/85 mm Hg
•   Median FU of 2 yrs, BP 10/5 mm Hg
•   Step-up drugs: enalapril (33%), HCTZ (20%)
•   237 randomized patients lost-to-follow-up
•   Reduction in stroke: RR 0.58, 95% CI 0.40 - 0.83
                  CHF: RR 0.71, 95% CI 0.47 - 1.10

                          Staessen et al., Lancet 1997
     Concerns About Syst-Eur
                                 SHEP            Syst-Eur
# randomized                     4,736      vs     4,695
# primary events (stroke)          262      vs       124
# lost-to-follow-up                 10      vs       237

Case-fatality, stroke (%)          8.9      vs      27.3
Case-fatality, CHF (%)             6.4      vs      20.4

Questions in Syst-Eur: incomplete ascertainment?
                       level of medical care?
                       generalizable findings?

                                 Pahor et al., Lancet 1998
Captopril Prevention Project (CAPPP)
Design         Randomized, open
Population     10,985 hypertensives, aged 25-
               66 years, with DBP > 100 mm Hg
Intervention   Captopril (50-100 mg) vs clinician’s
               choice of a diuretic or a ß-blocker;
               diuretic or the other class as step-up
Follow-up      Average of 6.1 years

                         Hansson et al., Lancet 1999
Captopril Prevention Project - CAPPP
   Outcome           Captopril      Conventional
                     better         treatm. better
  Stroke, MI, CV death
  Stroke
  MI
  Death
  Diabetes
              0.33     0.5         1         2
                             Relative Risk
                     Hansson et al., Lancet 1999
         Limitations of CAPPP
• Captopril only given once or twice per day
• Flawed randomization process (envelopes)
• Baseline difference on BP unlikely explained
  by chance
• Potential differential evaluation of incident
  diabetes in the 2 groups due to lack of blinding

                              Cutler, Lancet 1999
Antihypertensive Treatment
    in Type 2 Diabetes
1.   Active treatment vs control (placebo)
2.   More tight vs less tight BP control
3.   Comparisons of active treatments
      SHEP - CV Event Rate in ISH
          by Diabetes Status
                 7      Placebo            RR .66, 95%CI .46-.94
                 6      Active treatment
                 5
                     RR .66, 95%CI .55-.79
   Annual        4
cardiovascular
                 3
  event rate
     (%)         2

                 1

                 0
                          No diabetes          Diabetes
                                      Curb et al., JAMA 1996
 Syst-Eur -- Diabetic Cohort
              Mortality     Stroke      Cardiac Events

         30          NS
                26         p=0.02
         25

                                                NS
Events




         20
No. of




                      16    15             15
         15

         10
                                                 7
                                    5
          5

          0

  Placebo
  Nitrendipine             Tuomilento et al., NEJM 1999
 UK Prospective Diabetes Study
150/85 vs 180/105 mmHg BP Target
Endpoint                 RR      95% CI
Any endpoint            0.76     0.62-0.92
Diabetes death          0.68     0.49-0.94
Any death               0.82     0.63-1.08
MI                      0.79     0.59-1.07
Stroke                  0.56     0.35-0.89
PAD                0.51      0.19-1.37
Microvascular dis.      0.63     0.44-0.89
n = 758 vs 390          UKPDS Group, BMJ 1998
  HOT - Rate of Major CV Events
 According to Randomized Groups
                         30                         p for trend
                                                    0.005         BP goal
                         25
Rate/1000 person-years




                                                                  mmHg
                         20
                                                                    <90
                         15   p for trend 0.5                       <85
                         10                                         <80
                          5
                          0
                              All n=18790       Diabetic n=1501
                                                Hansson et al., Lancet 1998
Comparative Trials in Hypertensives
 with Type 2 Diabetes or Impaired
       Glucose Metabolism

       FACET        ABCD
       UKPDS        CAPPP
       MIDAS
FACET - Fosinopril versus Amlodipine
    Cardiovascular Events Trial
Design         Prospective randomized trial
Patients       Hypertension and type 2 diabetes
Sample size    380 patients
Intervention   Fosinopril / amlodipine open label
Outcomes       - Primary: serum lipids
               - Secondary: CV events, BP
Follow-up      2.5 to 3.5 years
                       Tatti et al., Diabetes Care 1998
   Cardiovascular Events in FACET
                            Amlodipine n=191
                            Fosinopril n=189        p=.03
                                                    27
                   5
                   4
          Rate                                        14
                   3             13
        per 100        10             10
      person-years 2
                   1        4               4
                   0
                                                0
                       Stroke    AMI       Hospit. Any major
The figures at top
of the bars indicate
                                           Angina CV event
the number of events

                                 Tatti et al., Diabetes Care 1998
            ABCD Trial
Design      Double-blind randomized trial
            Enalapril vs nisoldipine
            Intensive vs moderate BP control
Patients    Type 2 diabetes, a normotensive
            and a hypertensive group
Outcomes    - Primary: renal function
            - Secondary: CV events, BP
Follow-up   5 years
                         Estacio et al., NEJM 1998
            ABCD Trial
   Risk of Myocardial Infarction -
  Intensive and Moderate Groups
                                  P= 0.03            P= 0.002
                        14                         13
                             12
                        12
   Number of Patients




                        10
                        8
                        6
                                         4
                        4
                        2                                       1
                        0
                             Intensive             Moderate
Nisoldipine                  Enalapril
                                             Estacio et al., NEJM 1998
                             ABCD Trial
                       Cardiovascular Disease
                                                              P= 0.002
                      45                                    43
                      40
 Number of Patients




                      35     P= 0.001        P= 0.001
                      30
                            22               25
                      25                                          20
                      20
                      15
                      10            5               5
                       5
                       0
                           Non-Fatal MI's     All MI's     All CV Events

Nisoldipine                      Enalapril
                                                  Estacio et al., NEJM 1998
                ABCD Trial
• The independent Data Safety Monitoring
 Committee recommended early termination of
 the hypertensive arm because of the 5-fold
 increase in risk of fatal and non-fatal AMI in the
 nisoldipine group compared to the enalapril
 group
• Those receiving the calcium antagonist were
 reassigned to the ACE inhibitor
                            Estacio et al., NEJM 1998
UK Prospective Diabetes Study
Design         Randomized trial comparing (a) less
               tight vs tight BP control and (b) two
               forms of tight control
Patients       Hypertensives with type 2 diabetes
Intervention   Furosemide-based vs captopril- or
               atenolol-based
Outcomes       Fatal and nonfatal CV events
Follow-up      8.4 years

                           UKPDS Group, BMJ 1998
UK Prospective Diabetes Study
 Captopril vs Atenolol (reference group)
 Endpoint               RR     95% CI
 Any endpoint          1.10    0.86-1.41
 Diabetes death        1.27    0.82-1.97
 Any death             1.14    0.81-1.61
 MI                    1.20    0.82-1.76
 Stroke                1.12    0.59-2.12
 PAD                   1.48    0.35-6.19
 Microvascular dis.    1.29    0.80-2.10
n = 400 vs 358        UKPDS Group, BMJ 1998
CAPPP - patients with diabetes
  Outcome              Captopril         Conventional
                       better            treatm. better
Stroke, MI, CV death
 Stroke
MI
Death
               0.33      0.5         1          2
                               Relative Risk
                       Hansson et al., Lancet 1999
               MIDAS Trial
• 883 hypertensive patients randomized to
 isradipine or HCTZ and followed for 3 years
• No difference in carotid intimal medial thickness,
 the primary outcome
• Increased risk of major CV events by 78%
 (p=0.07) and all CV events and procedures by
 63% (p=0.02) in the isradipine group

                          Borhani et al., JAMA 1996
 MIDAS Trial - Relative Risk of CV
Events for Isradipine versus HCTZ
     4
                                          3.22*
     3                  2.71*
                                                      *p<.05
RR   2   1.81
                 1.16              1.25
     1

     0
         All     <6.7 6.7+         <9.8 9.8+
                  HbA1c %       Serum insulin U/ml

                Byington et al., Diabetes Care 1998
Blood Pressure Changes in FACET
             180
                      
                      
                              Systolic
             160                                   Fosinopril
                                          
                                            
             140                            *        Amlodipine
    mmHg     120

             100
                              Diastolic
                      
                             
                                          
                                           
              80

              60
                   Baseline   1      2       3
                           Follow-up time (years)
*p .05 amlodipine vs fosinopril. Tatti et al., Diabetes Care 1998
The Appropriate Blood Pressure
Control in Diabetes (ABCD) Trial
                           Intensive-Treatment Group
        Blood Pressure


                         150
                                                                              Nisoldipine
                                                     Systolic
                                                                              Enalapril
          (mm Hg)



                         130

                         110

                         90                      Diastolic

                         70
                               0   6   12    18 24    30 36     42 48 54 60

                                                     Month
No. of patients            237         189     199       176      166   137

                                       Adapted from Estacio RO et al., NEJM 1998
 Systolic Blood Pressure Reduction
and Cardiovascular Events in FACET
                 Fosinopril           Amlodipine
             0
            -5
           -10
           -15                                     No events
   mm Hg




           -20                                     Events
                  -20   -20
           -25                         -23
           -30
           -35                              -32
                                         p<.05
                              p<.01

                 Pahor et al., J Cardiovasc Pharmacol 1998
One-year Diastolic BP Reduction and
  Cardiovascular Events in MIDAS
                HCTZ        Isradipine
            0


           -5

                                         No events
  mm Hg




          -10
                                         Events

          -15
                 p=.03

          -20
                               p=.01

                  Byington et al., Diabetes Care 1998
       Comparative Trials of
Antihypertensive Agents in Diabetes
Demonstrate that:
• Blood pressure alone is not a sufficient marker of
    drug efficacy
•   Pronounced reductions may be harmful in diabetics
•   Health benefits may differ among antihypertensive
    agents
•   ACE inhibitors appear to be most beneficial;
    calcium antagonists least beneficial
Other Benefits of ACE
Inhibitors in Diabetes
                                        BRILLIANT
                            Urinary Albumin Excretion
                            70
Urinary albumin excretion




                                                                     *
                            60
       (microg/min)




                            50
                                                                         *p=0.0006
                            40

                            30

                            20
                                              Lisinopril (10-20mg o.d)
                            10
                                              Nifedipine (20-40 mg b.d)
                             0

                            Baseline          6 months         12 months

                                       Agardh et al., J Human Hypertens 1996
 ACE Inhibitors and Microvascular
   Disease in Diabetic Patients
• ACEIs delay the development and progression of
 diabetic nephropathy*

• ACEIs markedly slow progression of retinopathy**
• ACEIs appear to improve peripheral neuropathy***
                  * Ahmad et al., Diabetes Care 1997
                  * Maschio et al., NEJM 1996
                 ** Chaturvedi et al., Lancet 1998
                *** Malik et al., Lancet 1998
 Short-term mortality benefit of ACE
 Inhibitors in Diabetic Patients with
               Acute MI
                                           p <0.05
  %      25
of pts                                           21.1
         20
                      p <0.05
         15
                                       11.8
                            10.6
         10       8

         5

         0
              Lisinopril   Control   Lisinopril   Control
                   NIDD                      IDD
              Zuanetti & Latini, J Diabetes Complications 1997
       Safety Documentation
• More than 100,000 person-years desired
• Safety problems common across indications
• Extensive safety documentation for diuretics,
  beta-blockers and ACE inhibitors
• Inadequate documentation of long-term safety
  for calcium antagonists, alpha-blockers,
  angiotension II blockers
Safety Documentation for Slow-Release
         CAs in Hypertension
                     Person-years
  Drugs          Active       Control
Adalat CC          31             10
Procardia XL       56             36
Plendil            39             14
Norvasc           269            158
Cardene            53             22
Cardizem SR       138            115
Dilacor XR         24              7
Isoptin             1              1
Verelan             5              2
 Total            616 (x = 68)   365 (x = 41)
   Risk of Primary Cardiac Arrest
Therapy            K-sparing    RR          95% CI
ß-blocker                       1.0        reference
Thiazide, 100 mg     No         2.4        0.7-8.8
Thiazide, 50 mg      No         1.1        0.5-2.5
Thiazide, 25 mg      No         0.7        0.2-2.5
Thiazide, 50 mg      Yes        0.5        0.1-2.2
Thiazide, 25 mg      Yes        0.3        0.1-1.0

                    Siscovick et al., N Engl J Med 1994
     CCBs in Hypertension
Potential Serious Adverse Events
•   Coronary events
•   Bleeding (GI and surgical)
•   Cancer (blocking apoptosis)
•   Cerebral white matter lesions (MRI)
•   Others

• Strong association to drug dose and duration
    of exposure support causation
                        CAs safety - Non Randomized
                         Studies and Meta-analysis
                12                                              increase risk
                          10                          CAs
                10                                              neutral
                                                                reduce risk
Number of reports




                    8
                               6
                    6                  5                          5
                                                            4
                    4
                                             2
                    2              1
                                                  0                   0
                    0
                         CVD, death    Bleeding             Cancer
                                           Pahor et al., (to be published)
      Hypertensive Emergencies
• IR nifedipine widely used in hypertensive
  emergencies and even moderately elevated BP in
  asymptomatic patients
• Never approved by the FDA for this indication;
  complete lack of outcome data
• Unpredictable BP fall associated with stroke,
  acute MI, severe hypotension and death
• “Routine use of IR nifedipine in hypertensive
  emergencies and pseudoemergencies should be
  abandoned”
                         Grossman et al., JAMA 1996
        Hypertension Optimal
        Treatment Trial (HOT)
 18,790 hypertensives randomized to three DBP
  goals: < 90, < 85 and < 80 mm Hg.
 Achieved mean DBP: 85.2, 83.2 and 81.1 mm Hg.
 No difference in incidence of major CV events:
  9.9, 10.0 and 9.3/1,000 pt. years.
 Post-hoc analysis suggested benefit of lower DBP
  among diabetics. Offset by increase in events
  among non-diabetics.
                         Hansson et al., Lancet 1998
     Interpretation of HOT Results
MRFIT 5.8 mm Hg lower DBP associated with lower stroke
       (44%) and CHD (25%) risks
HDFP Mean 5.4 mm Hg reduction in DBP translated into
       17% mortality and 35% stroke benefit
HOT    Mean 4.0 mm Hg reduction in DBP between < 90
       and < 80 target groups translated into a 7% lower
       CV event rate (N.S.)
Explanations (1) Null hypothesis true (unlikely)
               (2) Higher doses of felodipine
               increased CV event offsetting
               benefit of BP lowering itself (likely)
               (3) Insufficient power
     Antihypertensive and Lipid
   Lowering Treatment to Prevent
    Heart Attack Trial (ALLHAT)
Design         Randomized, double-blind clinical
               trial
Patients       42,451 hypertensives; 15,290 diabetics
Intervention   Lisinopril, amlodipine and doxazosin
               compared to chlorthalidone
               Same BP goal -- 140/90 mm Hg
Endpoints      Fatal and nonfatal CV events
Follow-up      Approximately 6 years
                 Conclusions
• ACEIs appear to convey similar antihypertensive
 benefits as the established first-line agents low-dose
 diuretics and beta-blockers

• ACEIs are the antihypertensive drugs of choice in
 hypertensives with type 2 diabetes

• ACEIs are recommended in diabetic patients with
 nephropathy and myocardial infarction

• CCBs should be 4th-line agents in diabetics
     Ordering of Slide Set
If you wish to order an electronic copy
of this slide set, “Recent Developments in
the Treatment of Hypertension,” please
contact Ms. Sarah Hutchens, Wake Forest
University School of Medicine at:

shutchen@rc.phs.wfubmc.edu

The slide set is in PowerPoint Version 4.0.

								
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