2. WHEN SHOULD ONE INITIATE SUCCESSIVE ANTIHYPERTENSIVE DRUGS? Henry R. Black M.D. RUSH University Medical Center Chicago, IL June 15, 2005

3. Treatment of Hypertension 1937 “The treatment of hypertension itself is a difficult and almost hopeless task in the present state of knowledge, and in fact for aught we know...the hypertension may be an important compensation mechanism which should not be tampered with, even were it certain that we could control it.” —Paul Dudley White, 1937

4. AnimasaMistletoe Benzyl Benzoate“Natheim” Bath Benzyl SuccinateNitroscleran Calcium DiuretinPotassium Sulphocyanate Calcium Salts and low Protein DietRadiation to the Skull Corpus LuteumRadium Water DesecinSubtonin DiathermySodium Sulphocyanate Irradiation of the Suprarenal RegionTheominal Liver ExtractThyroid and Potassium Lumbar SympathectomyPermanganate Luminal Watermelon Extract TREATMENT OF ESSENTIAL HYPERTENSION: 1930 Drug or Method Used Ayman, JAMA 1930; 95:246.

5. Development of Antihypertensive Therapies Effective but poorly tolerated As effective and better tolerated As effective and even better tolerated More effective for SBP Direct vasodilators ACE inhibitors  -blockers ARBsVPIsOthers Peripheral sympatholytics Ganglion blockers Veratrum alkaloids Central  2 agonists Calcium antagonists- non DHPs  -blockers Thiazides diuretics Calcium antagonists- DHPs 1940’s195019571960’s1970’s1980’s1990’s2001

6. Combination Antihypertensive Therapies 1950’s 1960’s 1970’s 1980’s 1990’s -2000s Butiserpine (reserpine/butalbital) Hyphex (hexamethonium/hydralazine) Hypotensin A, B, & C (pentolinium/hydralazine/resperine) Renir (reserpine/ephedrine) Verapene (rauwolfia/veratrum) Ser-Ap-Es (reserpine/hydralazine/ hydrochlorothiazide) Methyldopa/thiazide Thiazide/K + -sparing diuretic  blocker/thiazide Clonidine/thiazide ACE inhibitor/thiazide ACE inhibitor/CCB ARB/thiazide Low-dose  blocker/thiazide

7. KEY QUESTIONS 1. How and when should you titrate or add additional agents? 2. When should you start with more than one drug?

8. How and when should you titrate or add additional agents? Any schedule for dose titration is arbitrary and based on the pharmacodynamics and pharmacokinetics of the individual drugs used. Any schedule for dose titration is arbitrary and based on the pharmacodynamics and pharmacokinetics of the individual drugs used. We would generally recommend titration of drugs that are not given at full dose after 1-4 weeks, or adding additional drugs for those patients not at goal blood pressure. We would generally recommend titration of drugs that are not given at full dose after 1-4 weeks, or adding additional drugs for those patients not at goal blood pressure. The speed with which this is undertaken depends on the stage of BP (relative risk) and the clinician’s judgment of the impact of co- morbidity and other CV risk factors (absolute risk). The speed with which this is undertaken depends on the stage of BP (relative risk) and the clinician’s judgment of the impact of co- morbidity and other CV risk factors (absolute risk).

9. Antihypertensive Treatment Regimen Step 1 Dose 1 Dose 2 Dose 3 Chlorthalidone 12.5 mg 25 mg Amlodipine 2.5 mg 5 mg 10 mg Lisinopril 20 mg 40 mg Step 2 Reserpine 0.05 mg qd 0.1 mg qd 0.2 mg qd Clonidine 0.1 mg bid 0.2 mg bid 0.3 mg bid Atenolol 25 mg qd 50 mg qd 100 mg qd Step 3 Hydralazine 25 mg bid 50 mg bid 100 mg bid ALLHAT

10. VALUE: Design Elective titration to target BP (<140/90 mmHg) Month0.501234 6 *72 A 10 mg + HCTZ 25 mg A 5 mg A 10 mg + HCTZ 12.5 mg A 10 mg V 80 mg V 160 mg V 160 mg + HCTZ 12.5 mg V 160 mg + HCTZ 25 mg Amlodipine - based regimen V 160 mg + HCTZ 25 mg + "Free" add-on A 10 mg + HCTZ 25 mg + "Free" add-on Valsartan- based regimen Screening Randomisation End of treatment adjustment period Rollover from previous therapy (92%) *Patient visits every 6 months for months 6–72. Julius S et al. Lancet. June 2004;363.

11. When should you start with more than one drug?

12. Adapted from Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413-2446. JNC VI Treatment Algorithm Uncomplicated Hypertension Compelling Indications Diuretics Type 1 diabetes ISH Beta blockers-ACE inhibitors-Diuretics CHF-LA DHP CCBs -ACE inhibitorsMI -Diuretics-Beta blockers -ACE inhibitors Begin or continue lifestyle modifications Not at goal BP (<140/90 mm Hg) Not at goal BP No response or troublesome side effectsInadequate response but well tolerated Substitute another drug from different class Add second agent from different class (diuretic if not already used) Not at goal BP Continue adding agents from other classes Consider referral to hypertension specialist Initial Drug Choices ACE = angiotensin-converting enzyme LA DHP CCBs = long-acting dihydropyridine calcium-channel blockers

13. Materson et al. Am J Hypertens. 1993;8:189-192. 0 20 40 60 80 Calcium antagonist Beta- blocker DiureticAlpha 1 antagonist ACEIAlpha 2 agonist Placebo 50% response Response defined as DBP < 95 mm Hg after one year of treatment Percent response Monotherapy is Inadequate in 40%–60% of Hypertensive Patients

14. Not at Goal Blood Pressure Initial Drug Choices Uncomplicated Compelling Indications Not at Goal Blood Pressure TREATMENT OF HYPERTENSION – JNC VI – – Start at low dose and titrate upward. – – Low-dose combinations may be appropriate. Specific Indications

15. MAP=mean arterial pressure. Adapted from Bakris et al, Brenner et al, and Lewis et al. Number of BP Medications Antihypertensive Therapy: Number of Agents Required to Achieve BP Goal UKPDS (<85 mm Hg, diastolic) 4321 MDRD (92 mm Hg, MAP) HOT (<80 mm Hg, diastolic) AASK (<92 mm Hg, MAP) RENAAL (<140/90 mm Hg) IDNT (  135/85 mm Hg)

16. Adapted from Hansson L et al for the HOT Study Group. Lancet. 1998;351:1755-1762. EnrollmentFinal 161/98142/83 <90 mm Hg 144/85 <85 mm Hg 142/93 <80 mm Hg 140/81 SBP/DBP mm Hg 37% 63% 32% 68% 25% 75% 60% 40% 32% 68% Monotherapy Combination Therapy Combination Therapy Needed to Achieve Target Blood Pressure

17. CLINICAL TRIALS IN HYPERTENSION HOT STUDY Hansson L et al, Lancet 1998;351:1755 DBP in mm Hg Months

18. Major CV Events/1000 Patient-yr  90 mm Hg  85 mm Hg  80 mm Hg (target DBP) Hansson et al. Lancet 1998;351:1755 P = 0.005 for trend Significant Benefits From Intensive BP Reduction in Diabetic Patients

19. PROGRESS Combination (ACEI + Diuretic) lowered BP by12/5 mm Hg Single-drug (ACEI) lowered BP by 5/3 mm Hg) Tests for homogeneity (combination vs single drug): both <0.001. PROGRESS Collaborative Group. Lancet. 2001;358:1033-1041. Events (No.) Risk reduction (95% CI)ActivePlacebo Stroke Single drug2272374% (-15%-20%) Favors active Favors placebo 0.5 2.0 Hazard ratio 1.0 Combination15025543% (30%-54%) Combination23136740% (29%-49%) Total45860426% (16%-34%) Single drug1571655% (-19%-23%) Total30742028% (17%-38%) Major vascular events

20. Randomized Design of ALLHAT ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997. ALLHAT Collaborative Research Group. JAMA. 2000;283:1967-1975. High-risk hypertensive patients Consent/ Randomize (42,418) Amlodipine 2.5-10 mg (n=9048) Chlorthalidone 12.5-25 mg (n=15,255) Doxazosin 2-8 mg (n=9067) Lisinopril 10-40 mg (n=9054) Amlodipine 2.5-10 mg (n=9048) Chlorthalidone 12.5-25 mg (n=15,255) Doxazosin 2-8 mg (n=9067) Lisinopril 10-40 mg (n=9054) Eligible for lipid-lowering Not eligible for lipid-lowering Consent/Randomize (10,355) Pravastatin Usual care Follow for CHD and other outcomes until death or end of study (up to 8 years). ALLHAT

21. SBP Distribution at Baseline and 36 Months of Follow-up Baseline: 31% < 140 mm Hg 14%  160 mm Hg 36 Months: 64% < 140 mm Hg 8%  160 mm Hg 8%  160 mm Hg SBP (mm Hg) Percent ALLHAT Cushman, et al. J Clinical Hypertens 2002; 4:393-404

22. Blood Pressure Control ALLHAT 1.4 1.6 1.7 1.8 2.0 1.6 = mean number of drugs

23. Cumulative Combined CVD Event Rate Years to Combined CVD Event 01234567 0.1.2.3.4.5 Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group RR (95% CI)p value A/CA/C1.04 (0.99-1.09)0.12 L/CL/C1.10 (1.05-1.16)<0.001 ALLHAT Chlorthalidone Amlodipine Lisinopril

24. Cumulative Stroke Rate Years to Stroke 01234567 0.02.04.06.08.1 Cumulative Event Rates for Stroke by ALLHAT Treatment Group RR (95% CI)p value A/CA/C0.93 (0.81-1.06)0.28 L/CL/C1.15 (1.02-1.30)0.02 ALLHAT Chlorthalidone Amlodipine Lisinopril

25. Stroke – Subgroup Comparisons – RR (95% CI) ALLHAT P =.01 for interaction

26. BP Results by Treatment Group Compared to chlorthalidone: SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg). Compared to chlorthalidone: DBP significantly lower in the amlodipine group (~1 mm Hg). ALLHAT

27. Algorithm for Treatment of Hypertension Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Lifestyle Modifications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist. Stage 2 Hypertension (SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications

28. VALUE: Fatal and Non-fatal Stroke Julius S et al. Lancet. June 2004;363. Number at risk Valsartan Amlodipine 7596 7649 7499 7494 7455 7448 7334 7312 7195 7170 6918 6877 7055 7022 6744 6692 6163 6093 3846 3859 1532 1516 6587 6515 65432106543210 Time (months) 0612182430364248546066 Proportion of Patients With First Event (%) Valsartan-based regimen Amlodipine-based regimen HR = 1.15; 95% CI = 0.98–1.35; P = 0.08

29. VALUE: Outcome and SBP Differences at Specific Time Periods: Stroke Julius S et al. Lancet. June 2004;363. Odds Ratios and 95% CIs favors valsartan favors amlodipine 1.02.00.5 Time Interval (months) Overall study 36–48 24–36 12–24 6–12 0–3 Study end  SBP (mmHg) 1.4 1.6 1.8 2.0 3.8 1.7 2.2 3–62.3 0.25 4.0 STROKE

30. VALUE: Systolic Blood Pressure in Study Julius S et al. Lancet. June 2004;363. Valsartan (N= 7649) Amlodipine (N = 7596) 135 140 145 150 155 mmHg Months (or final visit) Sitting SBP by Time and Treatment Group Baseline 1244823461218303642546066 0 1.0 2.0 3.0 4.0 12448 mmHg 23461218303642546066 Months (or final visit) 5.0 Difference in SBP Between Valsartan and Amlodipine –1.0

31. VALUE: Analysis of Results Based on Immediate Response Outcomes were compared in: Immediate responders – –patients not on previous treatment, with BP response of ≥10 mmHg SBP at 1 month, OR – –patients on previous treatment, with BP ≤ baseline at 1 month WITH: Non-immediate responders – –those who failed to meet above criteria Weber MA et al. Lancet. 2004;363:2047–49.

32. VALUE: Analysis of Results Based on Immediate Response* Fatal/Non-fatal cardiac events Fatal/Non-fatal stroke All-cause death Myocardial infarction Heart failure hospitalizations 0.40.60.81.01.21.4 Immediate responders* (n = 9336) Non-immediate responders (n = 5663) Odds Ratio 95% CI *Those not on previous tx: SBP  ≥10 mmHg at one month; those on previous tx: SBP ≤ baseline at one month. **P < 0.05; † P < 0.01. Pooled Treatment Groups ** † 0.88 (0.79–0.97) 0.83 (0.71–0.98) 0.90 (0.81–0.99) 0.89 (0.76–1.04) 0.87 (0.75–1.01) Odds Ratio Weber MA et al. Lancet. 2004;363:2047–49.

33. VALUE: Analysis of Results Based on BP Control at 6 Months Fatal/Non-fatal cardiac events Fatal/Non-fatal stroke All-cause death Myocardial infarction Heart failure hospitalizations 0.40.60.81.01.21.4 Controlled patients* (n = 10755) Non-controlled patients (n = 4490) Hazard Ratio 95% CI *SBP < 140 mmHg at 6 months. Pooled Treatment Groups ** **P < 0.01. 0.75 (0.67–0.83) 0.55 (0.46–0.64) 0.79 (0.71–0.88) 0.86 (0.73–1.01) 0.64 (0.55–0.74) Odds Ratio Weber MA et al. Lancet. 2004;363:2047–49.

34. VALUE: Analysis of Results Based on BP Control at 6 Months Fatal/Non-fatal cardiac events Fatal/Non-fatal stroke All-cause death Myocardial infarction Heart failure hospitalizations *SBP < 140 mmHg at 6 months. **P < 0.01. Patients Treated With ValsartanPatients Treated With Amlodipine Hazard Ratio 95% CI 0.40.60.81.01.2 Controlled patients* (n = 5253) Non-controlled patients (n = 2396) ** 0.40.60.81.01.2 Controlled patients* (n = 5502) Non-controlled patients (n = 2094) Hazard Ratio 95% CI ** 0.76 (0.66–0.88) 0.60 (0.48–0.74) 0.79 (0.69–0.91) 0.83 (0.66–1.03) 0.62 (0.50–0.77) Odds Ratio 0.73 (0.63–0.85) 0.50 (0.39–0.64) 0.79 (0.69–0.92) 0.91 (0.71–1.17) 0.64 (0.52–0.79) Odds Ratio Weber MA et al. Lancet. 2004;363:2047–49.

35. ASCOT: Primary Objectives To assess and compare the long-term effects on nonfatal MI and fatal CHD of the standard antihypertensive regimen (  -blocker +/- diuretic) with a more contemporary regimen (CCB +/- ACEI)

36. BP Control at 3 years One drug27% Two or more drugs73%

37. ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; MI = myocardial infarction; CHD = cardiovascular heart disease; CV = cardiovascular. Sever PS, Dahlöf B. American College of Cardiology 2005 Scientific Sessions; March 6-9, 2005; Orlando, FL. ASCOT: Primary and Secondary End Points – Amlodipine/Perindopril vs Atenolol/Bendroflumethiazide Favors Amlodipine/Perindopril Favors Atenolol/Bendroflumethiazide Hazard Ratio All-cause mortality Primary end point: nonfatal MI and fatal CHD Total coronary end point: primary end point + new- onset angina + fatal and nonfatal heart failure Fatal and nonfatal stroke All CV events and revascularization procedures CV mortality 0.511.5 End point P Value 0.005 0.12 0.0048 0.0007 <0.0001 0.0017

38. Blood Pressure Overall, BP was lowered by 28/16 mm Hg. Early differences in BP were observed between treatment groups with lower levels on amlodipine/perindopril. BP differences reduced over time and mean trial differences were 2.9 mm Hg systolic and 1.8 mm Hg diastolic. PRELIMINARY DATA - ACC – March 8, 2005

39. BP Reductions as Small as 2 mmHg Reduce the Risk of CV Events by Up to 10% Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years Prospective Studies Collaboration. Lancet. 2002;360:1903-1913. 2 mmHg decrease in mean SBP 10% reduction in risk of stroke mortality 7% reduction in risk of IHD mortality

40. Odds Ratio for CV Events and Systolic BP Difference: Recent and Older Trials Staessen et al. J Hypertens. 2003;21:1055-1076.

41. BP-Lowering Treatment Trialists Stroke Systolic BP Difference Between Randomized Groups (mm Hg) Relative Risk of Stroke 0.25 0.50 0.75 1.00 1.25 1.50 -10-8-6-4-2024 Systolic BP Difference Between Randomized Groups (mm Hg) Relative Risk of CHD 0.25 0.50 0.75 1.00 1.25 1.50 -10-8-6-4-202 4CHD Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.

42. JNC – VI, 7 and ?(8) S.O.C.O.s Go For Goal And Don’t Settle For Less Go For Goal And Don’t Settle For Less It’s not BEYOND the Blood Pressure, IT IS THE BLOOD PRESSURE! It’s not BEYOND the Blood Pressure, IT IS THE BLOOD PRESSURE! AND IT’S ALSO HOW FAST YOU GET TO GOAL AND IT’S ALSO HOW FAST YOU GET TO GOAL S.O.C.O. = Single Overriding Communications Objective