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

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 .

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 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 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 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 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

Randomized placebo controlled trials

Treatment duration of > 1 year

Assessment of major disease endpoints

Unconfounded by other therapies

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 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

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

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 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

FACET ABCD UKPDS CAPPP MIDAS 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

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 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

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

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

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

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

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

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

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

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

UK Prospective Diabetes Study 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 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

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

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

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

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+

    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

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)

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

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

Comparative Trials of Antihypertensive Agents in Diabetes 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 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

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

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

ACEIs delay the development and progression of diabetic nephropathy*

ACEIs markedly slow progression of retinopathy**

ACEIs appear to improve peripheral neuropathy***

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

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

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 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

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

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

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 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)

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

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”

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

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 .

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

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

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: [email_address] The slide set is in PowerPoint Version 4.0.