# Presentation: 103073

## WHEN SHOULD ONE INITIATE 

SUCCESSIVE ANTIHYPERTENSIVE  

DRUGS?

Henry R. Black M.D.
RUSH University Medical Center
Chicago, IL
June 15, 2005

**SUCCESSIVE ANTIHYPERTENSIVE  **
**DRUGS?**
**Henry R. Black M.D.**
**RUSH University Medical Center**
**Chicago, IL**
**June 15, 2005**

## 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***

## Animasa	Mistletoe
Benzyl Benzoate	“Natheim” Bath
Benzyl Succinate	Nitroscleran
Calcium Diuretin	Potassium Sulphocyanate
Calcium Salts and low Protein Diet	Radiation to the Skull
Corpus Luteum	Radium Water
Desecin	Subtonin
Diathermy	Sodium Sulphocyanate
Irradiation of the Suprarenal Region	Theominal
Liver Extract	Thyroid and Potassium
Lumbar Sympathectomy		Permanganate
Luminal	 Watermelon Extract

**Benzyl Benzoate****	****“Natheim” Bath**
**Benzyl Succinate****	****Nitroscleran**
**Calcium Diuretin****	****Potassium Sulphocyanate**
**Calcium Salts and low Protein Diet****	****Radiation to the Skull**
**Corpus Luteum****	****Radium Water**
**Desecin****	****Subtonin**
**Diathermy****	****Sodium Sulphocyanate**
**Irradiation of the Suprarenal Region****	****Theominal**
**Liver Extract****	****Thyroid and Potassium**
**Lumbar Sympathectomy****	****	****Permanganate**
**Luminal****	**** Watermelon Extract**

**TREATMENT OF ESSENTIAL HYPERTENSION: 1930**
**Drug or Method Used**

**Ayman, JAMA  1930; 95:246.**

## Development ofAntihypertensive Therapies

**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**
******-blo****ckers**

**ARBs**

***VPIs***
***Others***

**Peripheral****sympatholytics**
**Ganglion blockers**
**Veratrum****alkaloids**

**Central ********2**** agonists**
**Calcium****antagonists-non DHPs**
******-blockers**

**Thiazides****diuretics**

**Calcium****antagonists-****DHPs**

**	****1940’s****	****1950****	****1957****	****1960’s****	****1970’s****	****1980’s****	****1990’s****	****2001**

## Combination Antihypertensive Therapies

**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**
******blo****cker/****thiazide**
**Clonidine/****thiazide**

**ACE inhibitor****/thiazide**

**ACE inhibitor/****CCB**
**ARB/****thiazide**
**Low-dose ****	**
******blo****cker/****thiazide**

## KEY QUESTIONS

**How and when should you titrate or add additional agents?**
**When should you start with more than one drug?**

## 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.**
**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****).**

## Antihypertensive Treatment Regimen

| Step 1 | Dose 1 | Dose 2 | Dose 3 |
| --- | --- | --- | --- |
| Chlorthalidone | 12.5 mg | 12.5 mg | 25 mg |
| Amlodipine | 2.5 mg | 5 mg | 10 mg |
| Lisinopril | 10 mg | 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 |

## VALUE: Design

**VALUE: Design**
**Elective titration to target BP (<140/90 mmHg)**

**Month****	****0.5****	****0****	****1****	****2****	****3****	****4        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.**

## When should you start with more than one drug?

## JNC VI Treatment Algorithm

**JNC VI Treatment Algorithm**

**ACE = angiotensin-converting enzyme**
**LA DHP CCBs = long-acting****dihydropyridine calcium-channel**
**blockers **

## Monotherapy is Inadequate in 40%–60% of Hypertensive Patients

**0**

**20**

**40**

**60**

**80**

**Calcium**
**antagonist**

**Beta-**
**blocker**

**Diuretic**

**Alpha****1**
**antagonist**

**ACEI**

**Alpha****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**

## Initial Drug Choices

**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**

## Antihypertensive Therapy: Number of Agents Required to Achieve BP Goal 

- 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)

- 4

- 3

- 2

- 1

**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)

## Combination Therapy Needed to Achieve Target Blood Pressure

**Enrollment**

**Final**

**161/98**

**142/83**

**<90 mm Hg**

**144/85**

**<85 mm Hg**

**142/93**

**<80 mm Hg**

**140/81**

**SBP/DBP ****mm Hg**

**SBP/DBP****mm Hg**

**37%**

**63%**

**32%**

**68%**

**25%**

**75%**

**Monotherapy**
**Combination****Therapy**

**Combination Therapy Needed ****to Achieve Target Blood Pressure**

## CLINICAL TRIALS IN HYPERTENSIONHOT STUDY

**Hansson L et al, Lancet 1998;351:1755**

**DBP in mm Hg**

**Months**

## Significant Benefits From Intensive BP Reduction in Diabetic Patients

**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**

## 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.**** **

## Randomized Designof ALLHAT

**ALLHAT Collaborative Research Group. *****JAMA*****. 2002;288:2981-2997.**
**ALLHAT Collaborative Research Group. *****JAMA*****. 2000;283:1967-1975.**

## 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**

**SBP (mm Hg)**

**Percent**

**Cushman, et al. J Clinical Hypertens 2002; 4:393-404**

## Blood Pressure Control

**1.4**

**1.6**

**1.7**

**1.8**

**2.0**

## Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group 

**Cumulative Event Rates for ****Combined CVD**** by ALLHAT Treatment Group**

|  | RR (95% CI) | p value |
| --- | --- | --- |
| A/C | 1.04 (0.99-1.09) | 0.12 |
| L/C | 1.10 (1.05-1.16) | <0.001 |

**Chlorthalidone**
**Amlodipine**
**Lisinopril**

## Cumulative Event Rates for Stroke by ALLHAT Treatment Group 

**Cumulative Event Rates for Stroke by ALLHAT Treatment Group**

|  | RR (95% CI) | p value |
| --- | --- | --- |
| A/C | 0.93 (0.81-1.06) | 0.28 |
| L/C | 1.15 (1.02-1.30) | 0.02 |

**Chlorthalidone**
**Amlodipine**
**Lisinopril**

## Stroke – Subgroup Comparisons – RR (95% CI)

**Stroke – Subgroup Comparisons – RR (95% CI)**

**P = .01 for interaction**

## BP Results by Treatment Group

## Algorithm for Treatment of Hypertension

**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**

**Lifestyle Modifications**

## 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

**6**
**5**
**4**
**3**
**2**
**1**
**0**

**Time (months)**

**0****	****6****	****12****	****18****	****24****	****30****	****36****	****42****	****48****	****54****	****60****	****66**

**Proportion of Patients With First Event (%)**

**Valsartan-based regimen**

**Amlodipine-based regimen**

**HR = ****1.15; 95% CI = 0.98–1.35; *****P***** ****= 0.08**** **

## 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**

**1.0**

**2.0**

**0.5**

**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**

**3–6**

**2.3**

**0.25**

**4.0**

**STROKE**

## 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**

**1**

**24**

**48**

**2**

**3**

**4**

**6**

**12**

**18**

**30**

**36**

**42**

**54**

**60**

**66**

**0**

**1.0**

**2.0**

**3.0**

**4.0**

**1**

**24**

**48**

**mmHg**

**2**

**3**

**4**

**6**

**12**

**18**

**30**

**36**

**42**

**54**

**60**

**66**

**Months**

**(or final visit)**

**5.0**

**Difference in SBP Between Valsartan and Amlodipine**

**–****1.0**

## 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.**

## 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**

**0.4**

**0.6**

**0.8**

**1.0**

**1.2**

**1.4**

**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.**

## 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**

**0.4**

**0.6**

**0.8**

**1.0**

**1.2**

**1.4**

**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.**

## 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 Valsartan**

**Patients Treated With Amlodipine**

**Hazard Ratio 95% CI**

**0.4**

**0.6**

**0.8**

**1.0**

**1.2**

**Controlled patients***
**(n = 5253)**

**Non-controlled patients**
**(n = 2396)**

******

******

******

******

**0.4**

**0.6**

**0.8**

**1.0**

**1.2**

**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.**

## ASCOT: Primary Objectives

**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)**

## BP Control at 3 years

**One drug****	****	****	****27%**
**Two or more drugs****	****73%**

## ASCOT: Primary and Secondary End Points –Amlodipine/Perindopril vs Atenolol/Bendroflumethiazide

- 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

**0.5**

**1**

**1.5**

**End point**

***P***** Value **

- 	0.005
- 	0.12
- 	0.0048
- 	0.0007
- 	<0.0001
- 	0.0017

## 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.

- 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

## 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**

## Odds Ratio for CV Events and Systolic BP Difference: Recent and Older Trials

**Staessen et al. *****J Hypertens*****. 2003;21:1055-1076.**

## BP-Lowering Treatment Trialists

**Blood Pressure Lowering Treatment Trialists’ Collaboration. *****Lancet*****. 2003;362:1527-1535.**

## JNC – VI, 7 and ?(8)S.O.C.O.s

**Go For Goal And Don’t Settle For Less**
**It’s not ****BEYOND**** the Blood Pressure, IT**** IS ****THE BLOOD PRESSURE!**
**AND IT’S ALSO HOW ****FAST**** YOU GET TO GOAL**

**S.O.C.O. = Single Overriding Communications Objective**