Recent Developments in the  Treatment of Hypertension The Value of Facts 1999
Objectives <ul><li>To review recent clinical trial evidence of efficacy for antihypertensive agents </li></ul><ul><li>To p...
Documentation of Drug Safety and Efficacy <ul><li>Patients, clinicians and the health-care establishment expect adequate d...
Antihypertensive Drugs:  Documentation By the Time of Regulatory Approval <ul><li>BP lowering potential (N = 200-500 patie...
Antihypertensive Drugs:  Documentation By the Time of Regulatory Approval <ul><li>Effect on major CVD mortality/morbidity ...
Aim of Antihypertensive Therapy To prevent the cardiovascular complications of  hypertension -- stroke, acute myocardial i...
Eligibility criteria for meta-analysis <ul><li>Randomized placebo controlled trials </li></ul><ul><li>Treatment duration o...
Definition of Treatment Strategies <ul><li>Multiple agents used in most trials </li></ul><ul><li>Trials classified by firs...
Summary of Eligible Trials (n = 18) Low-dose diuretics   4 4,305   5,116 High-dose diuretics 11 7,768 12,075 Beta-blockers...
Meta-analysis:  Antihypertensives Event RR 95% CI High-dose diuretics Psaty et al., JAMA 1997 Stroke 0.49 0.39-0.62 CHF 0....
Meta-analysis:  Antihypertensives Event RR 95% CI Low-dose diuretics Psaty et al., JAMA 1997 Stroke 0.66 0.55-0.78 CHF 0.5...
Meta-analysis:  Antihypertensives Event RR 95% CI Beta-blockers Psaty et al., JAMA 1997 Stroke 0.71 0.59-0.85 CHF 0.58 0.4...
Summary of Major   Findings <ul><li>High-dose diuretic and ß-blocker therapies reduced the incidence of CHF and stroke </l...
Syst-Eur -- Nitrendipine in ISH <ul><li>Randomized, placebo-controlled, 2N = 4,695 </li></ul><ul><li>Baseline, mean age 70...
Concerns About Syst-Eur #  randomized 4,736 vs 4,695 # primary events (stroke)   262 vs   124 # lost-to-follow-up     10 v...
Captopril Prevention Project (CAPPP) Design Randomized, open Population 10,985 hypertensives, aged 25- 66 years, with DBP ...
Stroke, MI, CV death Stroke 0.33 0.5 1 2 Relative Risk MI Death Captopril better Conventional treatm. better Captopril Pre...
Limitations of CAPPP <ul><li>Captopril only given once or twice per day </li></ul><ul><li>Flawed randomization process (en...
Antihypertensive Treatment in Type 2 Diabetes <ul><li>1. Active treatment  vs  control (placebo) </li></ul><ul><li>2. More...
SHEP - CV Event Rate in ISH by Diabetes Status Curb et al., JAMA 1996 Annual cardiovascular event rate (%) No diabetes Dia...
Syst-Eur -- Diabetic Cohort No. of Events Tuomilento et al., NEJM 1999 Mortality   Stroke   Cardiac Events Nitrendipine Pl...
UK Prospective Diabetes Study 150/85 vs 180/105 mmHg BP  Target Endpoint   RR 95% CI Any endpoint   0.76 0.62-0.92 Diabete...
HOT - Rate of Major CV Events According to Randomized Groups BP goal mmHg p for trend 0.005 p for trend 0.5 Hansson et al....
<ul><li>FACET ABCD </li></ul><ul><li>UKPDS CAPPP </li></ul><ul><li>MIDAS </li></ul>Comparative Trials in Hypertensives wit...
FACET - Fosinopril versus Amlodipine Cardiovascular Events Trial <ul><li>Design Prospective randomized trial </li></ul><ul...
Tatti et al., Diabetes Care 1998 Cardiovascular Events in FACET Stroke AMI Rate per 100 person-years 0 1 2 3 4 5 10 14 13 ...
ABCD Trial <ul><li>Design   Double-blind randomized trial Enalapril  vs  nisoldipine Intensive  vs  moderate BP control  <...
Nisoldipine Enalapril 10 12 14 Intensive Moderate Number of Patients 4 1 13 12 0 2 4 6 8 ABCD Trial Risk of Myocardial Inf...
10 15 20 25 30 35 40 45 Number of  Patients Nisoldipine Enalapril 5 5 20 43 25 22 0 5 Non-Fatal MI's All MI's All CV Event...
ABCD Trial <ul><li>The independent Data Safety Monitoring Committee recommended early termination of the hypertensive arm ...
UK Prospective Diabetes Study <ul><li>Design Randomized trial comparing  (a) less tight  vs  tight BP control and (b) two ...
UK Prospective Diabetes Study <ul><li>Endpoint   RR 95% CI </li></ul><ul><li>Any endpoint   1.10 0.86-1.41 </li></ul><ul><...
Stroke, MI, CV death Stroke 0.33 0.5 1 2 Relative Risk MI Death Captopril better Conventional treatm. better CAPPP - patie...
MIDAS Trial <ul><li>883 hypertensive patients randomized to isradipine or HCTZ and followed for 3 years </li></ul><ul><li>...
MIDAS Trial - Relative Risk of CV Events for Isradipine versus HCTZ   *p<.05 Byington et al., Diabetes Care 1998 HbA1c % R...
    Blood Pressure Changes in FACET mmHg * p    .05 amlodipine vs fosinopril.  Fosinopril  Amlodipine     Syst...
The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial Adapted from Estacio RO et al., NEJM 1998 Intensive-Treatm...
Systolic Blood Pressure Reduction and Cardiovascular Events in FACET  Amlodipine p<.05 p<.01 Fosinopril Pahor et al., J Ca...
One-year Diastolic BP Reduction and Cardiovascular Events in MIDAS  Isradipine p=.03 HCTZ p=.01 Byington et al.,  Diabetes...
Comparative Trials of Antihypertensive Agents in Diabetes <ul><li>Blood pressure alone is not a sufficient marker of drug ...
Other Benefits of ACE Inhibitors in Diabetes
0 10 20 30 40 50 60 70 Baseline 6 months 12 months Lisinopril (10-20mg o.d) Nifedipine (20-40 mg b.d) BRILLIANT Urinary Al...
ACE Inhibitors and Microvascular Disease in Diabetic Patients <ul><li>ACEIs delay the development and progression of diabe...
Short-term mortality benefit of ACE Inhibitors in Diabetic Patients with Acute MI % of pts Lisinopril Control NIDD IDD Zua...
Safety Documentation <ul><li>More than 100,000 person-years desired </li></ul><ul><li>Safety problems common across indica...
Safety Documentation for Slow-Release CAs in Hypertension Adalat CC   31   10 Procardia XL   56   36 Plendil   39   14 Nor...
Risk of Primary Cardiac Arrest 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 Thia...
CCBs in Hypertension Potential Serious Adverse Events <ul><li>Coronary events </li></ul><ul><li>Bleeding (GI and surgical)...
CAs safety - Non Randomized Studies and Meta-analysis CAs 10 5 4 6 2 5 1 0 0 0 2 4 6 8 10 12 CVD, death  Bleeding Cancer N...
Hypertensive Emergencies <ul><li>IR nifedipine widely used in hypertensive emergencies and even moderately elevated BP in ...
Hypertension Optimal Treatment Trial (HOT) <ul><li>18,790 hypertensives randomized to three DBP goals:  <  90,  <  85 and ...
Interpretation of HOT Results MRFIT 5.8 mm Hg lower DBP associated with lower stroke (44%) and CHD (25%) risks HDFP   Mean...
Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) <ul><li>Design Randomized, double-bli...
Conclusions <ul><li>ACEIs  appear to convey similar antihypertensive benefits as the established first-line agents low-dos...
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  • Recent Developments in the Treatment of Hypertension Recent Developments in the Treatment of Hypertension

    1. 1. Recent Developments in the Treatment of Hypertension The Value of Facts 1999
    2. 2. Objectives <ul><li>To review recent clinical trial evidence of efficacy for antihypertensive agents </li></ul><ul><li>To present new data on the treatment of hypertensive patients with type 2 diabetes </li></ul><ul><li>To discuss the emerging evidence for use of ACE inhibitors in diabetes </li></ul><ul><li>To review recent safety data on antihypertensive agents </li></ul>
    3. 3. Documentation of Drug Safety and Efficacy <ul><li>Patients, clinicians and the health-care establishment expect adequate documentation </li></ul><ul><li>A week-long treatment for an acute condition requires randomized trials that follow patients for > 1 week </li></ul><ul><li>Lifelong treatments are ideally evaluated in lifelong trials, but evaluations in large populations over 4 to 5 years are typically accepted . </li></ul>
    4. 4. Antihypertensive Drugs: Documentation By the Time of Regulatory Approval <ul><li>BP lowering potential (N = 200-500 patients) </li></ul><ul><li>Common side effects (symptoms) </li></ul><ul><li>Any common early drug complications (events) </li></ul><ul><li>Major changes in blood chemistry </li></ul><ul><li>Major animal toxicity </li></ul>Known
    5. 5. Antihypertensive Drugs: Documentation By the Time of Regulatory Approval <ul><li>Effect on major CVD mortality/morbidity </li></ul><ul><li>Optimal dose (risk-benefit balance) </li></ul><ul><li>Uncommon early side effects or clinical complications </li></ul><ul><li>ADRs and complications of long-term drug use </li></ul><ul><li>Efficacy or safety in various subgroups </li></ul><ul><li>Effect on pregnancy </li></ul><ul><li>Drug interactions </li></ul>Unknown
    6. 6. 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.
    7. 7. Eligibility criteria for meta-analysis <ul><li>Randomized placebo controlled trials </li></ul><ul><li>Treatment duration of > 1 year </li></ul><ul><li>Assessment of major disease endpoints </li></ul><ul><li>Unconfounded by other therapies </li></ul>Psaty et al., JAMA 1997
    8. 8. Definition of Treatment Strategies <ul><li>Multiple agents used in most trials </li></ul><ul><li>Trials classified by first-line strategy </li></ul><ul><li>-- High-dose diuretic therapy </li></ul><ul><li>-- Low-dose diuretic therapy </li></ul><ul><li>-- Beta-blocker therapy </li></ul><ul><li>No eligible trials evaluating CCBs or ACE inhibitors </li></ul>Psaty et al., JAMA 1997
    9. 9. Summary of Eligible Trials (n = 18) 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 Therapy Trial Intervention Control
    10. 10. Meta-analysis: Antihypertensives Event RR 95% CI High-dose diuretics Psaty et al., JAMA 1997 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
    11. 11. Meta-analysis: Antihypertensives Event RR 95% CI Low-dose diuretics Psaty et al., JAMA 1997 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
    12. 12. Meta-analysis: Antihypertensives Event RR 95% CI Beta-blockers Psaty et al., JAMA 1997 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
    13. 13. Summary of Major Findings <ul><li>High-dose diuretic and ß-blocker therapies reduced the incidence of CHF and stroke </li></ul><ul><li>Low-dose diuretic therapy reduced the incidence not only of CHF and stroke but also of CHD and total mortality </li></ul><ul><li>High-dose versus low-dose diuretic comparison was confounded by patient age </li></ul>Psaty et al., JAMA 1997
    14. 14. Syst-Eur -- Nitrendipine in ISH <ul><li>Randomized, placebo-controlled, 2N = 4,695 </li></ul><ul><li>Baseline, mean age 70 yrs, BP 174/85 mm Hg </li></ul><ul><li>Median FU of 2 yrs, BP  10/5 mm Hg </li></ul><ul><li>Step-up drugs: enalapril (33%), HCTZ (20%) </li></ul><ul><li>237 randomized patients lost-to-follow-up </li></ul><ul><li>Reduction in stroke: RR 0.58, 95% CI 0.40 - 0.83 </li></ul><ul><li>CHF: RR 0.71, 95% CI 0.47 - 1.10 </li></ul>Staessen et al., Lancet 1997
    15. 15. Concerns About 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 SHEP Syst-Eur
    16. 16. 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
    17. 17. Stroke, MI, CV death Stroke 0.33 0.5 1 2 Relative Risk MI Death Captopril better Conventional treatm. better Captopril Prevention Project - CAPPP Diabetes Outcome Hansson et al., Lancet 1999
    18. 18. Limitations of CAPPP <ul><li>Captopril only given once or twice per day </li></ul><ul><li>Flawed randomization process (envelopes) </li></ul><ul><li>Baseline difference on BP unlikely explained by chance </li></ul><ul><li>Potential differential evaluation of incident diabetes in the 2 groups due to lack of blinding </li></ul>Cutler, Lancet 1999
    19. 19. Antihypertensive Treatment in Type 2 Diabetes <ul><li>1. Active treatment vs control (placebo) </li></ul><ul><li>2. More tight vs less tight BP control </li></ul><ul><li>3. Comparisons of active treatments </li></ul>
    20. 20. SHEP - CV Event Rate in ISH by Diabetes Status Curb et al., JAMA 1996 Annual cardiovascular event rate (%) No diabetes Diabetes 0 1 2 3 4 5 6 7 RR .66, 95%CI .55-.79 RR .66, 95%CI .46-.94 Active treatment Placebo
    21. 21. Syst-Eur -- Diabetic Cohort No. of Events Tuomilento et al., NEJM 1999 Mortality Stroke Cardiac Events Nitrendipine Placebo 0 5 10 15 20 25 30 26 16 15 5 15 NS p=0.02 7 NS
    22. 22. 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
    23. 23. HOT - Rate of Major CV Events According to Randomized Groups BP goal mmHg p for trend 0.005 p for trend 0.5 Hansson et al., Lancet 1998 0 5 10 15 20 25 30 All n=18790 Diabetic n=1501 Rate/1000 person-years < 90 < 85 < 80
    24. 24. <ul><li>FACET ABCD </li></ul><ul><li>UKPDS CAPPP </li></ul><ul><li>MIDAS </li></ul>Comparative Trials in Hypertensives with Type 2 Diabetes or Impaired Glucose Metabolism
    25. 25. FACET - Fosinopril versus Amlodipine Cardiovascular Events Trial <ul><li>Design Prospective randomized trial </li></ul><ul><li>Patients Hypertension and type 2 diabetes </li></ul><ul><li>Sample size 380 patients </li></ul><ul><li>Intervention Fosinopril / amlodipine open label </li></ul><ul><li>Outcomes - Primary: serum lipids </li></ul><ul><li>- Secondary: CV events, BP </li></ul><ul><li>Follow-up 2.5 to 3.5 years </li></ul>Tatti et al., Diabetes Care 1998
    26. 26. Tatti et al., Diabetes Care 1998 Cardiovascular Events in FACET Stroke AMI Rate per 100 person-years 0 1 2 3 4 5 10 14 13 27 10 4 p=.03 4 0 The figures at top of the bars indicate the number of events Any major CV event Hospit. Angina Fosinopril n=189 Amlodipine n=191
    27. 27. ABCD Trial <ul><li>Design Double-blind randomized trial Enalapril vs nisoldipine Intensive vs moderate BP control </li></ul><ul><li>Patients Type 2 diabetes, a normotensive and a hypertensive group </li></ul><ul><li>Outcomes - Primary: renal function - Secondary: CV events, BP </li></ul><ul><li>Follow-up 5 years </li></ul>Estacio et al., NEJM 1998
    28. 28. Nisoldipine Enalapril 10 12 14 Intensive Moderate Number of Patients 4 1 13 12 0 2 4 6 8 ABCD Trial Risk of Myocardial Infarction - Intensive and Moderate Groups Estacio et al., NEJM 1998 P= 0.03 P= 0.002
    29. 29. 10 15 20 25 30 35 40 45 Number of Patients Nisoldipine Enalapril 5 5 20 43 25 22 0 5 Non-Fatal MI's All MI's All CV Events ABCD Trial Cardiovascular Disease Estacio et al., NEJM 1998 P= 0.001 P= 0.001 P= 0.002
    30. 30. ABCD Trial <ul><li>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 </li></ul><ul><li>Those receiving the calcium antagonist were reassigned to the ACE inhibitor </li></ul>Estacio et al., NEJM 1998
    31. 31. UK Prospective Diabetes Study <ul><li>Design Randomized trial comparing (a) less tight vs tight BP control and (b) two forms of tight control </li></ul><ul><li>Patients Hypertensives with type 2 diabetes </li></ul><ul><li>Intervention Furosemide-based vs captopril- or atenolol-based </li></ul><ul><li>Outcomes Fatal and nonfatal CV events </li></ul><ul><li>Follow-up 8.4 years </li></ul>UKPDS Group, BMJ 1998
    32. 32. UK Prospective Diabetes Study <ul><li>Endpoint RR 95% CI </li></ul><ul><li>Any endpoint 1.10 0.86-1.41 </li></ul><ul><li>Diabetes death 1.27 0.82-1.97 </li></ul><ul><li>Any death 1.14 0.81-1.61 </li></ul><ul><li>MI 1.20 0.82-1.76 </li></ul><ul><li>Stroke 1.12 0.59-2.12 </li></ul><ul><li>PAD 1.48 0.35-6.19 </li></ul><ul><li>Microvascular dis. 1.29 0.80-2.10 </li></ul>n = 400 vs 358 UKPDS Group, BMJ 1998 Captopril vs Atenolol (reference group)
    33. 33. Stroke, MI, CV death Stroke 0.33 0.5 1 2 Relative Risk MI Death Captopril better Conventional treatm. better CAPPP - patients with diabetes Outcome Hansson et al., Lancet 1999
    34. 34. MIDAS Trial <ul><li>883 hypertensive patients randomized to isradipine or HCTZ and followed for 3 years </li></ul><ul><li>No difference in carotid intimal medial thickness, the primary outcome </li></ul><ul><li>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 </li></ul>Borhani et al., JAMA 1996
    35. 35. MIDAS Trial - Relative Risk of CV Events for Isradipine versus HCTZ *p<.05 Byington et al., Diabetes Care 1998 HbA1c % RR Serum insulin  U/ml 1.81 1.16 2.71* 1.25 3.22* 0 1 2 3 4 All <6.7 6.7+ <9.8 9.8+
    36. 36.     Blood Pressure Changes in FACET mmHg * p  .05 amlodipine vs fosinopril.  Fosinopril  Amlodipine     Systolic Diastolic *         Tatti et al., Diabetes Care 1998 Baseline 1 2 3 Follow-up time (years) 60 80 100 120 140 160 180
    37. 37. The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial Adapted from Estacio RO et al., NEJM 1998 Intensive-Treatment Group 70 90 110 130 150 0 6 12 18 24 30 36 42 48 54 60 Month No. of patients 237 189 199 176 166 137 Nisoldipine Enalapril Systolic Diastolic Blood Pressure (mm Hg)
    38. 38. Systolic Blood Pressure Reduction and Cardiovascular Events in FACET Amlodipine p<.05 p<.01 Fosinopril Pahor et al., J Cardiovasc Pharmacol 1998 -20 -23 -20 -32 -35 -30 -25 -20 -15 -10 -5 0 mm Hg No events Events
    39. 39. One-year Diastolic BP Reduction and Cardiovascular Events in MIDAS Isradipine p=.03 HCTZ p=.01 Byington et al., Diabetes Care 1998 -20 -15 -10 -5 0 mm Hg No events Events
    40. 40. Comparative Trials of Antihypertensive Agents in Diabetes <ul><li>Blood pressure alone is not a sufficient marker of drug efficacy </li></ul><ul><li>Pronounced reductions may be harmful in diabetics </li></ul><ul><li>Health benefits may differ among antihypertensive agents </li></ul><ul><li>ACE inhibitors appear to be most beneficial; calcium antagonists least beneficial </li></ul>Demonstrate that:
    41. 41. Other Benefits of ACE Inhibitors in Diabetes
    42. 42. 0 10 20 30 40 50 60 70 Baseline 6 months 12 months Lisinopril (10-20mg o.d) Nifedipine (20-40 mg b.d) BRILLIANT Urinary Albumin Excretion Urinary albumin excretion (microg/min) * *p=0.0006 Agardh et al., J Human Hypertens 1996
    43. 43. ACE Inhibitors and Microvascular Disease in Diabetic Patients <ul><li>ACEIs delay the development and progression of diabetic nephropathy* </li></ul><ul><li>ACEIs markedly slow progression of retinopathy** </li></ul><ul><li>ACEIs appear to improve peripheral neuropathy*** </li></ul>* Ahmad et al., Diabetes Care 1997 * Maschio et al., NEJM 1996 ** Chaturvedi et al., Lancet 1998 *** Malik et al., Lancet 1998
    44. 44. Short-term mortality benefit of ACE Inhibitors in Diabetic Patients with Acute MI % of pts Lisinopril Control NIDD IDD Zuanetti & Latini, J Diabetes Complications 1997 0 5 10 15 20 25 8 10.6 11.8 21.1 Lisinopril Control p <0.05 p <0.05
    45. 45. Safety Documentation <ul><li>More than 100,000 person-years desired </li></ul><ul><li>Safety problems common across indications </li></ul><ul><li>Extensive safety documentation for diuretics, beta-blockers and ACE inhibitors </li></ul><ul><li>Inadequate documentation of long-term safety for calcium antagonists, alpha-blockers, angiotension II blockers </li></ul>
    46. 46. Safety Documentation for Slow-Release CAs in Hypertension 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) Drugs Active Control Person-years
    47. 47. Risk of Primary Cardiac Arrest 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 Therapy K-sparing RR 95% CI Siscovick et al., N Engl J Med 1994
    48. 48. CCBs in Hypertension Potential Serious Adverse Events <ul><li>Coronary events </li></ul><ul><li>Bleeding (GI and surgical) </li></ul><ul><li>Cancer (blocking apoptosis) </li></ul><ul><li>Cerebral white matter lesions (MRI) </li></ul><ul><li>Others </li></ul><ul><li>Strong association to drug dose and duration of exposure support causation </li></ul>
    49. 49. CAs safety - Non Randomized Studies and Meta-analysis CAs 10 5 4 6 2 5 1 0 0 0 2 4 6 8 10 12 CVD, death Bleeding Cancer Number of reports increase risk neutral reduce risk Pahor et al., (to be published)
    50. 50. Hypertensive Emergencies <ul><li>IR nifedipine widely used in hypertensive emergencies and even moderately elevated BP in asymptomatic patients </li></ul><ul><li>Never approved by the FDA for this indication; complete lack of outcome data </li></ul><ul><li>Unpredictable BP fall associated with stroke, acute MI, severe hypotension and death </li></ul><ul><li>“ Routine use of IR nifedipine in hypertensive emergencies and pseudoemergencies should be abandoned” </li></ul>Grossman et al., JAMA 1996
    51. 51. Hypertension Optimal Treatment Trial (HOT) <ul><li>18,790 hypertensives randomized to three DBP goals: < 90, < 85 and < 80 mm Hg. </li></ul><ul><li>Achieved mean DBP: 85.2, 83.2 and 81.1 mm Hg. </li></ul><ul><li>No difference in incidence of major CV events: 9.9, 10.0 and 9.3/1,000 pt. years. </li></ul><ul><li>Post-hoc analysis suggested benefit of lower DBP among diabetics. Offset by increase in events among non-diabetics . </li></ul>Hansson et al., Lancet 1998
    52. 52. 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
    53. 53. Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) <ul><li>Design Randomized, double-blind clinical trial </li></ul><ul><li>Patients 42,451 hypertensives; 15,290 diabetics </li></ul><ul><li>Intervention Lisinopril, amlodipine and doxazosin compared to chlorthalidone Same BP goal -- 140/90 mm Hg </li></ul><ul><li>Endpoints Fatal and nonfatal CV events </li></ul><ul><li>Follow-up Approximately 6 years </li></ul>
    54. 54. Conclusions <ul><li>ACEIs appear to convey similar antihypertensive benefits as the established first-line agents low-dose diuretics and beta-blockers </li></ul><ul><li>ACEIs are the antihypertensive drugs of choice in hypertensives with type 2 diabetes </li></ul><ul><li>ACEIs are recommended in diabetic patients with nephropathy and myocardial infarction </li></ul><ul><li>CCBs should be 4th-line agents in diabetics </li></ul>
    55. 55. 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: [email_address] The slide set is in PowerPoint Version 4.0.

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