1. Pre-ALLHAT Drug Use IMS Health NDTI, 1978-1992 0 10 20 30 40 50 60 1978 Year % of Treated Patients on Medication CCBs Beta Blockers Diuretics ACE Inhibitors CCBs ß-Blockers Diuretics 1980198219841986198819901992

2. Background In addition to their BP lowering potential all antihypertensive agents have other important mechanisms of action, indications, and side effects.In addition to their BP lowering potential all antihypertensive agents have other important mechanisms of action, indications, and side effects. These actions may convey benefits or risks independent of BP loweringThese actions may convey benefits or risks independent of BP lowering By having a common BP goal for all treatment arms, ALLHAT aimed to evaluate the health effects of these non-BP actionsBy having a common BP goal for all treatment arms, ALLHAT aimed to evaluate the health effects of these non-BP actions ALLHAT

3. Overall Purpose To determine whether the newer, more costly antihypertensive drugs - CCBs, ACE inhibitors and alpha-blockers - are superior to the older, less expensive diuretics in preventing CV complications of hypertension. ALLHAT

4. Health Effects of Diuretics Low-dose thiazide-type diuretic-based treatment in large clinical trials has been shown to reduce the risks of: Event reduction % Stroke 34 Heart failure 42 CHD 28 CVD mortality 24 Total mortality 10 ALLHAT Psaty et al., JAMA 1997;277:739-45

5. Strengths Largest hypertension trial ever (n=42,418); practice-basedLargest hypertension trial ever (n=42,418); practice-based Diverse study populationDiverse study population High methodologic standardsHigh methodologic standards Independent sponsorship and conductIndependent sponsorship and conduct Conclusions based on 10,834 cardiovascular eventsConclusions based on 10,834 cardiovascular events ALLHAT

6. Implications 1.Selection of first-line drug 2.Selecting treatments for particular patients 3.Drug cost and health benefit ● To patients ● To society 4.Design of future hypertension trials 5.Impact on treatment guidelines ALLHAT

7. Selection of 1 st -line Drug - Conclusions Among antihypertensive drugs, thiazide- like diuretics were unsurpassed in: long-term drug adherencelong-term drug adherence controlling elevated blood pressurecontrolling elevated blood pressure and were superior to other therapies in preventing one or more forms of cardiovascular eventspreventing one or more forms of cardiovascular events having lower drug costhaving lower drug cost ALLHAT Implications

8. Selection of 2 nd -line Drug(s) - Type of Add-on Large proportion of hypertensive patients require additional drug(s) for BP controlLarge proportion of hypertensive patients require additional drug(s) for BP control No direct comparison of 2 nd -line drugs in ALLHATNo direct comparison of 2 nd -line drugs in ALLHAT Optimal type of add-on agent unknownOptimal type of add-on agent unknown Need for large trials comparing different classes of agents added to diureticsNeed for large trials comparing different classes of agents added to diuretics ALLHAT Implications

9. Source: NDTI -- IMS HEALTH 2002 Use of Antihypertensive Medications, Proportion of Drug-Treated Patients by Drug Class 0% 10% 20% 30% 40% ACE- Inhibitors Calcium Channel Blockers DiureticsBeta- Blockers ARBs % Patients 37% 27% 20% 20% 19%

10. Selecting Treatments for Particular Patients I Benefits of diuretics generalizable to: Men and womenMen and women Age group 65 yrsAge group 65 yrs Blacks and non-blacksBlacks and non-blacks Diabetics and non-diabeticsDiabetics and non-diabetics Presence and absence of other co- morbidityPresence and absence of other co- morbidity ALLHAT Implications

11. Diuretics are better than: -ACEIs (lisinopril) for patients at high risk of CVD events, especially heart failure, as well as for African-Americans at risk of stroke -Alpha-blockers (doxazosin) for patients at high risk of heart failure, stroke, angina and coronary revascularizations -CCBs (amlodipine) for patients at high risk of developing heart failure ALLHAT Implications Selecting Treatments for Particular Patients II

12. Selecting Treatments for Patients - Conclusions Thiazide-type diuretics should be considered for nearly all patients with hypertension: Untreated patientsUntreated patients Inadequately controlled patients on non-diuretic agent(s)Inadequately controlled patients on non-diuretic agent(s) Controlled patients on non-diuretic agent(s) unless compelling indication exists for another agentControlled patients on non-diuretic agent(s) unless compelling indication exists for another agent ALLHAT Implications

13. Drug Cost to Patient (U.S. 2002) Chlorthalidone$ 36 Amlodipine$679 Lisinopril- branded$533 - generic**$280 *Drugstore.com (exclusive of dispensing fee) **available 3 rd quarter 2002 Annual Implications ALLHAT

14. Drug Cost to Society ACEIs$280-12.7$3,556- 533 6,769 533 6,769 CCBs$679 9.3$6,315 Diuretics$ 36 6.9$ 248 ALLHAT Average Annual AnnualDrugCost/Pt* No. of AnnualUsers** TotalDrugCost** *price of largest selling drug/class (2002) **in million Implications

15. Excess CV Events ACEIs Comb CV 2.3%12.7 48,700 EventsCCBs CHF 2.5% 9.3 38,800 ALLHAT 6-yrExcess TotalUsers* Excessevents/yr** *in million**concomitant use of diuretics may reduce these numbers by up to 20% Implications

16. Design of Hypertension Trials Thiazide-like diuretics, in low to moderate dose, should be the treatment control group of future comparative trials in patients with hypertension. ALLHAT Implications

17. Treatment Guidelines Thiazide-like diuretics, in low to moderate dose, should be the guideline-recommended first-line drug treatment for nearly all patients with hypertension. ALLHAT Implications

18. Conclusions I The benefit of diuretics as first-line therapy applies to nearly all patients with hypertensionThe benefit of diuretics as first-line therapy applies to nearly all patients with hypertension Diuretics are superior or unsurpassed in reducing the risks of cardiovascular complicationsDiuretics are superior or unsurpassed in reducing the risks of cardiovascular complications Diuretics are the least expensive agents for treating hypertensionDiuretics are the least expensive agents for treating hypertension ALLHAT Implications

19. Conclusions II Translating the ALLHAT findings into practice will reduce the financial cost of antihypertensive drugs and reduce the societal burden of CV complicationsTranslating the ALLHAT findings into practice will reduce the financial cost of antihypertensive drugs and reduce the societal burden of CV complications Future comparative hypertension trials should use diuretics as the control group or base therapyFuture comparative hypertension trials should use diuretics as the control group or base therapy Treatment guidelines are being revised to reflect the ALLHAT findingsTreatment guidelines are being revised to reflect the ALLHAT findings ALLHAT Implications