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Recent Developments in the Treatment of Hypertension

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

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Recent Developments in the Treatment of Hypertension

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  1. Recent Developments in the Treatment of Hypertension The Value of Facts 1999

  2. 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

  3. Documentation of DrugSafety 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.

  4. Antihypertensive Drugs: DocumentationBy 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

  5. Antihypertensive Drugs: DocumentationBy 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

  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. 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

  8. 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

  9. Therapy Trial Intervention Control 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

  10. 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

  11. 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

  12. 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

  13. Summary of MajorFindings • 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

  14. 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

  15. SHEP Syst-Eur 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

  16. Captopril Prevention Project (CAPPP) DesignRandomized, 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. Captopril Prevention Project - CAPPP Outcome Captopril better Conventional treatm. better Stroke, MI, CV death Stroke MI Death Diabetes 0.5 0.33 1 2 Relative Risk Hansson et al., Lancet 1999

  18. 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

  19. 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

  20. Placebo Active treatment SHEP - CV Event Rate in ISH by Diabetes Status 7 RR .66, 95%CI .46-.94 6 5 RR .66, 95%CI .55-.79 Annualcardiovascular event rate (%) 4 3 2 1 0 No diabetes Diabetes Curb et al., JAMA 1996

  21. Syst-Eur -- Diabetic Cohort Mortality Stroke Cardiac Events NS 30 p=0.02 26 25 NS 20 16 15 15 No. of Events 15 10 7 5 5 0 Placebo Tuomilento et al., NEJM 1999 Nitrendipine

  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 UKPDS Group, BMJ 1998 n = 758 vs 390

  23. HOT - Rate of Major CV Events According to Randomized Groups p for trend 0.005 30 BP goal mmHg 25 20 <90 p for trend 0.5 15 <85 Rate/1000 person-years <80 10 5 0 All n=18790 Diabetic n=1501 Hansson et al., Lancet 1998

  24. Comparative Trials in Hypertensives with Type 2 Diabetes or Impaired Glucose Metabolism FACET ABCD UKPDS CAPPP MIDAS

  25. 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

  26. Amlodipine n=191 Fosinopril n=189 Cardiovascular Events in FACET p=.03 27 5 4 Rateper 100person-years 14 13 3 10 10 2 4 4 1 0 0 Stroke AMI Hospit. Angina Any major CV event The figures at top of the bars indicate the number of events Tatti et al., Diabetes Care 1998

  27. 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

  28. ABCD Trial Risk of Myocardial Infarction - Intensive and Moderate Groups P= 0.002 P= 0.03 13 14 12 12 10 8 Number of Patients 6 4 4 1 2 0 Intensive Moderate Nisoldipine Enalapril Estacio et al., NEJM 1998

  29. ABCD Trial Cardiovascular Disease P= 0.002 43 45 40 P= 0.001 P= 0.001 35 30 25 22 25 20 Number of Patients 20 15 10 5 5 5 0 Non-Fatal MI's All MI's All CV Events Nisoldipine Enalapril Estacio et al., NEJM 1998

  30. 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

  31. 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

  32. 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 UKPDS Group, BMJ 1998 n = 400 vs 358

  33. CAPPP - patients with diabetes Outcome Captopril better Conventional treatm. better Stroke, MI, CV death Stroke MI Death 0.5 0.33 1 2 Relative Risk Hansson et al., Lancet 1999

  34. 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

  35. MIDAS Trial - Relative Risk of CV Events for Isradipine versus HCTZ 4 3.22* 2.71* 3 *p<.05 RR 1.81 2 1.25 1.16 1 0 All <6.7 6.7+ <9.8 9.8+ Serum insulin U/ml HbA1c % Byington et al., Diabetes Care 1998

  36. 180 160 140 120 100 80 60 Baseline 1 2 3 Follow-up time (years) Blood Pressure Changes in FACET Systolic   Fosinopril        Amlodipine *  mmHg Diastolic         Tatti et al., Diabetes Care 1998 *p.05 amlodipine vs fosinopril.

  37. The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial Intensive-Treatment Group Nisoldipine 150 Systolic Enalapril 130 BloodPressure (mm Hg) 110 Diastolic 90 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

  38. Systolic Blood Pressure Reduction and Cardiovascular Events in FACET Fosinopril Amlodipine 0 -5 -10 No events -15 -20 Events mm Hg -20 -20 -25 -23 -30 -32 -35 p<.05 p<.01 Pahor et al., J Cardiovasc Pharmacol 1998

  39. One-year Diastolic BP Reduction and Cardiovascular Events in MIDAS HCTZ Isradipine 0 -5 No events -10 Events mm Hg -15 p=.03 -20 p=.01 Byington et al., Diabetes Care 1998

  40. 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

  41. Other Benefits of ACE Inhibitors in Diabetes

  42. BRILLIANT Urinary Albumin Excretion 70 * 60 *p=0.0006 50 40 (microg/min) Urinary albumin excretion 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

  43. 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

  44. Short-term mortality benefit of ACE Inhibitors in Diabetic Patients with Acute MI p <0.05 % of pts 25 21.1 20 p <0.05 15 11.8 10.6 8 10 5 0 Lisinopril Control Lisinopril Control NIDD IDD Zuanetti & Latini, J Diabetes Complications 1997

  45. 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

  46. Safety Documentation for Slow-ReleaseCAs 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)

  47. 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

  48. CCBs in HypertensionPotential 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

  49. CAs safety - Non Randomized Studies and Meta-analysis increase risk 12 CAs 10 neutral 10 reduce risk 8 6 5 5 6 4 Number of reports 4 2 1 2 0 0 0 CVD, death Bleeding Cancer Pahor et al., (to be published)

  50. 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

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