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 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 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 discuss the emerging evidence for use of ACE inhibitors in diabetes To review recent safety data on antihypertensive agents To review recent safety data on antihypertensive agents

Documentation of Drug Safety and Efficacy Patients, clinicians and the health-care establishment expect adequate documentation 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 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. 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 = patients) BP lowering potential (N = patients) Common side effects (symptoms) Common side effects (symptoms) Any common early drug complications (events) Any common early drug complications (events) Major changes in blood chemistry Major changes in blood chemistry Major animal toxicity Major animal toxicity Known

Antihypertensive Drugs: Documentation By the Time of Regulatory Approval Effect on major CVD mortality/morbidity Effect on major CVD mortality/morbidity Optimal dose (risk-benefit balance) Optimal dose (risk-benefit balance) Uncommon early side effects or clinical complications Uncommon early side effects or clinical complications ADRs and complications of long-term drug use ADRs and complications of long-term drug use Efficacy or safety in various subgroups Efficacy or safety in various subgroups Effect on pregnancy Effect on pregnancy Drug interactions Drug interactions Unknown

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 Randomized placebo controlled trials Treatment duration of > 1 year Treatment duration of > 1 year Assessment of major disease endpoints Assessment of major disease endpoints Unconfounded by other therapies Unconfounded by other therapies Psaty et al., JAMA 1997

Definition of Treatment Strategies Multiple agents used in most trials Multiple agents used in most trials Trials classified by first-line strategy 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 No eligible trials evaluating CCBs or ACE inhibitors Psaty et al., JAMA 1997

Summary of Eligible Trials (n = 18) Low-dose diuretics 44,305 5,116 High-dose diuretics117,76812,075 Beta-blockers 46,73612,147 HDFP 15,484 5,455 TherapyTrialInterventionControl Psaty et al., JAMA 1997

Meta-analysis: Antihypertensives EventRR 95% CI High-dose diuretics Psaty et al., JAMA 1997 Stroke CHF CHD Total mortality

Meta-analysis: Antihypertensives EventRR 95% CI Low-dose diuretics Psaty et al., JAMA 1997 Stroke CHF CHD Total mortality

Meta-analysis: Antihypertensives EventRR 95% CI Beta-blockers Psaty et al., JAMA 1997 Stroke CHF CHD Total mortality

Summary of Major Findings High-dose diuretic and ß-blocker therapies reduced the incidence of CHF and stroke 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 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 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 Randomized, placebo-controlled, 2N = 4,695 Baseline, mean age 70 yrs, BP 174/85 mm Hg Baseline, mean age 70 yrs, BP 174/85 mm Hg Median FU of 2 yrs, BP  10/5 mm Hg Median FU of 2 yrs, BP  10/5 mm Hg Step-up drugs: enalapril (33%), HCTZ (20%) Step-up drugs: enalapril (33%), HCTZ (20%) 237 randomized patients lost-to-follow-up 237 randomized patients lost-to-follow-up Reduction in stroke:RR 0.58, 95% CI Reduction in stroke:RR 0.58, 95% CI CHF: RR 0.71, 95% CI CHF: RR 0.71, 95% CI Staessen et al., Lancet 1997

Concerns About Syst-Eur # randomized4,736vs4,695 # primary events (stroke) 262vs 124 # lost-to-follow-up 10vs 237 Case-fatality, stroke (%) 8.9vs 27.3 Case-fatality, CHF (%) 6.4vs 20.4 Questions in Syst-Eur:incomplete ascertainment? level of medical care? generalizable findings? SHEPSyst-Eur Pahor et al., Lancet 1998

Captopril Prevention Project (CAPPP) DesignRandomized, open Population10,985 hypertensives, aged years, with DBP > 100 mm Hg InterventionCaptopril ( 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 Relative Risk MI Death CaptoprilbetterConventional treatm. better Captopril Prevention Project - CAPPP Diabetes Outcome Hansson et al., Lancet 1999

Limitations of CAPPP Captopril only given once or twice per day Captopril only given once or twice per day Flawed randomization process (envelopes) Flawed randomization process (envelopes) Baseline difference on BP unlikely explained by chance Baseline difference on BP unlikely explained by chance Potential differential evaluation of incident diabetes in the 2 groups due to lack of blinding 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 by Diabetes Status Curb et al., JAMA 1996 Annual cardiovascular event rate (%) No diabetes Diabetes Active treatment RR.66, 95%CI RR.66, 95%CI Placebo

Syst-Eur -- Diabetic Cohort No. of Events Tuomilento et al., NEJM 1999 Mortality Stroke Cardiac Events Mortality Stroke Cardiac Events Nitrendipine Placebo NS p= NS

UK Prospective Diabetes Study 150/85 vs 180/105 mmHg BP Target Endpoint RR95% CI Any endpoint Diabetes death Any death MI Stroke PAD Microvascular dis n = 758 vs 390 UKPDS Group, BMJ 1998

HOT - Rate of Major CV Events According to Randomized Groups BP goal mmHg p for trend p for trend 0.5 Hansson et al., Lancet All n=18790Diabetic n=1501 Rate/1000 person-years <90 <85 <80

FACETABCD UKPDSCAPPP MIDAS Comparative Trials in Hypertensives with Type 2 Diabetes or Impaired Glucose Metabolism

FACET - Fosinopril versus Amlodipine Cardiovascular Events Trial Design DesignProspective randomized trial Patients PatientsHypertension and type 2 diabetes Sample size Sample size380 patients Intervention Intervention Fosinopril / amlodipine open label Outcomes Outcomes- Primary: serum lipids - Secondary: CV events, BP Follow-up Follow-up2.5 to 3.5 years Tatti et al., Diabetes Care 1998

Cardiovascular Events in FACET StrokeAMI Rate per 100 person-years p= 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 Design Double-blind randomized trial Enalapril vs nisoldipine Intensive vs moderate BP control Patients Patients Type 2 diabetes, a normotensive and a hypertensive group Outcomes Outcomes- Primary: renal function - Secondary: CV events, BP Follow-up Follow-up5 years Estacio et al., NEJM 1998

NisoldipineEnalapril IntensiveModerate Number of Patients ABCD Trial Risk of Myocardial Infarction - Intensive and Moderate Groups Estacio et al., NEJM 1998 P= 0.03 P= 0.002

Number of Patients NisoldipineEnalapril Non-Fatal MI'sAll MI'sAll CV Events ABCD Trial Cardiovascular Disease Estacio et al., NEJM 1998 P= 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

UK Prospective Diabetes Study DesignRandomized trial comparing (a) less tight vs tight BP control and (b) two forms of tight control PatientsHypertensives with type 2 diabetes InterventionFurosemide-based vs captopril- or atenolol-based OutcomesFatal and nonfatal CV events Follow-up8.4 years UKPDS Group, BMJ 1998

UK Prospective Diabetes Study Endpoint RR95% CI Any endpoint Diabetes death Any death MI Stroke PAD Microvascular dis n = 400 vs 358 UKPDS Group, BMJ 1998 Captopril vs Atenolol (reference group)

Stroke, MI, CV death Stroke 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 883 hypertensive patients randomized to isradipine or HCTZ and followed for 3 years No difference in carotid intimal medial thickness, the primary outcome 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 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 *p<.05 Byington et al., Diabetes Care 1998 HbA1c % RR Serum insulin  U/ml * * All< <

Blood Pressure Changes in FACET mmHg *p .05 amlodipine vs fosinopril. Baseline123 Follow-up time (years) Fosinopril Amlodipine Systolic Diastolic * Tatti et al., Diabetes Care 1998

The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial Adapted from Estacio RO et al., NEJM 1998 Intensive-Treatment Group Month No. of patients 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 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 mm Hg No events Events

Comparative Trials of Antihypertensive Agents in Diabetes Blood pressure alone is not a sufficient marker of drug efficacy Blood pressure alone is not a sufficient marker of drug efficacy Pronounced reductions may be harmful in diabetics Pronounced reductions may be harmful in diabetics Health benefits may differ among antihypertensive agents Health benefits may differ among antihypertensive agents ACE inhibitors appear to be most beneficial; calcium antagonists least beneficial ACE inhibitors appear to be most beneficial; calcium antagonists least beneficial Demonstrate that:

Other Benefits of ACE Inhibitors in Diabetes

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= 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 delay the development and progression of diabetic nephropathy* ACEIs markedly slow progression of retinopathy** ACEIs markedly slow progression of retinopathy** ACEIs appear to improve peripheral neuropathy*** ACEIs appear to improve peripheral neuropathy*** * Ahmad et al., Diabetes Care 1997 * Ahmad et al., Diabetes Care 1997 * Maschio et al., NEJM 1996 * Maschio et al., NEJM 1996 ** Chaturvedi et al., Lancet 1998 ** Chaturvedi et al., Lancet 1998 *** Malik et al., Lancet 1998

Short-term mortality benefit of ACE Inhibitors in Diabetic Patients with Acute MI % of pts LisinoprilControl NIDDIDD Zuanetti & Latini, J Diabetes Complications LisinoprilControl p <0.05

Safety Documentation More than 100,000 person-years desired More than 100,000 person-years desired Safety problems common across indications Safety problems common across indications Extensive safety documentation for diuretics, beta-blockers and ACE inhibitors Extensive safety documentation for diuretics, beta-blockers and ACE inhibitors Inadequate documentation of long-term safety for calcium antagonists, alpha-blockers, angiotension II blockers Inadequate documentation of long-term safety for calcium antagonists, alpha-blockers, angiotension II blockers

Safety Documentation for Slow-Release CAs in Hypertension Adalat CC Procardia XL Plendil Norvasc Cardene Cardizem SR Dilacor XR 24 7 Isoptin 1 1 Verelan 5 2 Total616 (x = 68)365 (x = 41) Drugs ActiveControl Person-years

Risk of Primary Cardiac Arrest ß-blocker1.0reference Thiazide, 100 mgNo Thiazide, 50 mgNo Thiazide, 25 mgNo Thiazide, 50 mgYes Thiazide, 25 mgYes Therapy K-sparing RR 95% CI Siscovick et al., N Engl J Med 1994

CCBs in Hypertension Potential Serious Adverse Events Coronary events Coronary events Bleeding (GI and surgical) Bleeding (GI and surgical) Cancer (blocking apoptosis) Cancer (blocking apoptosis) Cerebral white matter lesions (MRI) Cerebral white matter lesions (MRI) Others Others Strong association to drug dose and duration of exposure support causation Strong association to drug dose and duration of exposure support causation

CAs safety - Non Randomized Studies and Meta-analysis CAs CVD, deathBleedingCancer 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 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 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 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” “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 MRFIT5.8 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 HOTMean 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) DesignRandomized, double-blind clinical trial Patients42,451 hypertensives; 15,290 diabetics InterventionLisinopril, amlodipine and doxazosin compared to chlorthalidone Same BP goal /90 mm Hg EndpointsFatal and nonfatal CV events Follow-upApproximately 6 years

Conclusions ACEIs appear to convey similar antihypertensive benefits as the established first-line agents low-dose diuretics and beta-blockers 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 the antihypertensive drugs of choice in hypertensives with type 2 diabetes ACEIs are recommended in diabetic patients with nephropathy and myocardial infarction ACEIs are recommended in diabetic patients with nephropathy and myocardial infarction CCBs should be 4th-line agents in diabetics CCBs should be 4th-line agents in diabetics

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