This document discusses combination drug therapy for treating hypertension. It notes that the majority of hypertensive patients require two or more drugs to control their blood pressure. Combination therapy is more effective than high doses of single drugs and has fewer side effects. Effective combinations include angiotensin receptor blockers or ACE inhibitors with diuretics or calcium channel blockers. Initial fixed-dose combination therapy improves medication adherence compared to free-drug combinations. Overall, rational combination therapy utilizing complementary drug classes is necessary to adequately control blood pressure for most hypertensive patients.

1. Antihypertensive drugs combinations
Muhamed Al Rohani

2. Hypertension (HTN) is a major public health concern, affecting
26% of adults worldwide1
Number of
people with HTN
worldwide in 20001
972 million
Increase in the
number of adults with
HTN globally by 20251
60%
Percent of all global
healthcare spending
attributable to high
blood pressure2
10%
Annual worldwide cost of
hypertension2 $370 billion
1.6 Billion
HTN patients estimated
by 2025
1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005 Jan 15-21;365(9455):217-23. Gaziano TA, Asaf B, S Anand, et.al. The
global cost of nonoptimal blood pressure. J Hypertens 2009; 27(7): 1472-1477.

4. Definition and classification
JNC 7

6. Historical Lessons on the Risks of Hypertension and
the Benefits of Treatment
CHD Incidence Rate/
1000 Person Years
50
40
30
20
10
0
Treatment Decreases
Morbidity and Mortality
Placebo Active
Treatment
Cumulative Fatal &
Nonfatal Endpoints
Hypertension Increases
Morbidity and Mortality
Normotension
Hypertension
The Framingham Study The Vet. Adm. Study II
Ann Intern Med. 1961; 55:33–50. JAMA. 1970; 213:1143–1152.
140
120
100
80
60
40
20
0
Men Women

7. Risk Factors for Cardiovascular Disease
• Smoking
• Hyperlipidaemia
• High salt intake
• Lack of exercise
• Obesity
• Diabetes
• Alcohol >4pints of beer/day
• Genetic

10. CV
mortality
risk
CV Mortality Risk Doubles With
Each 20/10 mm Hg BP Increment*
BP > 140/90 mmHg associated with:
 69% of pts in the 1st heart attack
 74% of pts with heart failure
 77% of pts in the 1st stroke
SBP/DBP (mm Hg)
8
7
6
5
4
3
2
1
0
115/75 135/85 155/95 175/105
*Individuals aged 40-69 years, starting at BP 115/75 mm Hg.
CV, cardiovascular; DBP, diastolic blood pressure; SBP, systolic blood pressure.
Lewington S et al. Lancet. 2002;360:1903-1913.
Chobanian AV et al. JAMA. 2003;289:2560-2572.

11. HTN leads to an increased risk of death from stroke and
heart disease
8x
4x
Systolic BP / Diastolic BP (mmHg)
2x
Cardiovascular Mortality Risk
CV mortality risk doubles for every 20 mmHg increase in systolic blood pressure.1,2
Chobanian et al. Hypertension 2003;42:1206-1252; 2Lancet 2002;360:1903-1913

12. BP Differences of 10 mmHg Are Associated With
Up to a 40% Effect on
CV Risk
• Meta-analysis of 61 prospective, observational studies
• 1 million adults
• 12.7 million person-years
30% reduction in
risk of IHD
mortality
10 mmHg
decrease in
mean SBP 40% reduction in
Lewington S et al. Lancet. 2002;360:1903–1913.
risk of stroke
mortality

13. Current Antihypertensive Therapy Reduces CV Events
Average Reduction in Events, %
0
–20
–40
–80
CV=cardiovascular.
Neal B et al. Lancet. 2000;356:1955–1964.
Major CV
Events
20%–30%
Stroke
30%–40%
CV Death
30%–40%
–60
–100
Can we do better?

14. Multiple Antihypertensive Agents
Are Needed to Achieve Target BP
Target BP (mm Hg)
Number of antihypertensive agents
Trial 1 2 3 4
ALLHAT SBP <140/DBP <90
UKPDS DBP <85
ABCD DBP <75
MDRD MAP <92
HOT DBP <80
AASK MAP <92
IDNT SBP <135/DBP <85
DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.
Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.
Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Cushman WC et al. J Clin Hypertens. 2002;4:393-405.

15. ALLHAT study:
42,418 patients with hypertension
 SBP >140mmHg and/or DBP >90 mmHg OR
 Took medication for hypertension and had at least one additional risk factor for CHD
 Age >55 years
 Diuretics vs. ACEi
 Stage 1 and 2
 only 26% the BP controlled by single drug
 30% required 3 drugs
The LIFE Trial
9,200 patients with hypertension
 SBP 160 – 200 mmHg and/or DBP 95- 115 mmHg with LVH
 ARBs vs. BB
 Stage 2
 90% had 2 drugs
 50% BP achieved

18. Poor Compliance and Persistence with
Antihypertensive Treatment

19. Definition of resistant hypertension:
uncontrolled BP despite adherence to a
regimen with at least three antihypertensive
agents including a diuretic.
The percentage of patients in this category is
estimated at approximately 10–15% of the
hypertensive population.

26. Value of low dose combination treatment with blood pressure
lowering drugs: analysis of 354 randomized trials (2003 BMJ)
Objective To determine the average reduction in BP, prevalence of adverse effects,
and reduction in risk of stroke and IHD events produced by the five main categories
of antihypertensive drugs, singly and in combination.
Design Meta-analysis of 354 randomized double blind placebo controlled trials.
40 000 treated patients and 16 000 patients given placebo
Results All five categories of drug produced similar reductions in BP.
The standard dose average reduction was 9.1 mm Hg systolic and 5.5 mm Hg
diastolic .
The half standard dose was 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower)
The BP lowering effects of different categories of drugs were additive.
Symptoms attributable to thiazides, BB, and CCB were strongly dose related; but by
ACEi (mainly cough) were not dose related. ARBs caused no excess of symptoms.
The prevalence of symptoms with two drugs in combination was less than additive.
Adverse metabolic effects (such as changes in cholesterol or potassium) were
negligible at half standard dose.
Conclusions Combination low dose drug treatment increases efficacy
and reduces adverse effects. From the average blood pressure in people
who have strokes (150/90 mm Hg) three drugs at half standard dose are
estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg
diastolic and thereby reduce the risk of stroke by 63% and IHD events by
46% at age 60-69.

28. Rational of combination therapy
1. The heterogeneity of the hypertensive population.
2. Initial falls in BP from monotherapy are also opposed by reflex responses in
counter-regulatory mechanisms that are activated following BP reduction.1
3. Combining selected classes of antihypertensive therapy with different
modes of action.
4. RAAS blockers tolerability is the best in comparison.
5. ARBs or ACEi + duiretics reduce the incidence of hypokalemia
6. ARBs or ACEi + CCB reduce the incidence and severity of edema
1. Sever P, Messerli FH. Eur Heart J 2011;32:2499-506.
2. Law M et al. BMJ 2003;326:1427-31.
3. Alan Grdman. Current opinion nephrol hyoetens 2012,21:486-491

30. Drug combination (AHS)
Preferred :
ARBs/diuretics
ARBs/CCB
ACEi/diuretics
ACEi/CCB
Acceptable:
BB/diuretics
Thiazide/K+ sparing
CCB/diuretics
CCB/BB
BB/diuretics
Less effective:
ACEi/BB
ARB/BB
CCB(nondihydropyridine)/BB
Central acting agent/BB
1. Reduces risk of hypokalemia
2. Ameliorates diuretic-induced activation
of RAAS
3. Ameliorates CCB edema
4. Reduction of mortality
5. Option for CKD
1. BB ameliorate thiazide-induced activation
of RAAS
2. Side effect sexual dysfunction and
glucose intolerance
3. BB less effect as anti-HTN
4. Carvedilol
1. BB with CCB increase the risk of
bradycardia and heart block
2. the combination of ACE inhibitor/CCB
was associated with a 20% reduction in
major CV endpoints compared with ACE
inhibitor/HCTZ. (ACCOMPLISH)
3. Abrupt discontinuation cause
hypertensive crisis
New combinations
Valsartan/amlodipine/HCT
Olmesartan/amlodipine/HCT
Aliskiren/amlodipine/HCT

31. From: An Effective Approach to High Blood Pressure Control: A Science Advisory From the American Heart Association, the
American College of Cardiology, and the Centers for Disease Control and Prevention
Figure Legend:
Date of download:
9/2/2014
Copyright © The American College of Cardiology.
All rights reserved.
J Am Coll Cardiol. 2014;63(12):1230-1238. doi:10.1016/j.jacc.2013.11.007
Appendix

33. Persistence with antihypertensive therapy regimens; single-pill combination therapy
vs free-drug combinations.

35. Initial Fixed-Dose Combination Therapy
ADVANTAGES
• 2 drugs needed for control of Stage 2 BP
• Low (therapeutic) dose of 2 drugs
– more effective than higher dose of single drug
– usually well tolerated
– adverse effects can be reduced
• Simplified treatment regimen: adherence improved by 26% compare to free
combination
• and potential for improved outcomes
• Economic benefits
– Fewer copayments
– health care costs reduced
– fewer office visits

38. Reduced discontinuation of antihypertensive treatment by two-drug
combination as first step. Evidence from daily life practice
OBJECTIVES:
To measure persistence with antihypertensive drug therapy in patients
initiating treatment with mono or combination therapy.
METHODS:
Data were limited to patients aged 40-80 years who received their first
antihypertensive drug prescription (n = 433,680 and 41,199, respectively)
CONCLUSION:
Initiating treatment with a combination of two drugs is associated with a
reduced risk of treatment discontinuation.
Corrao G1, et al, J Hypertens. 2010 Jul;28(7):1584-90.
MILANO ITALY

39. Strategies for Combination Therapy in Hypertension
Conclusion
Combination therapy is necessary in
approximately 75% of patients with
hypertension. Rational combination therapy
begins with the selection of two-drug
combinations that exhibit additive BP
reduction, excellent tolerability and a
demonstrated ability to reduce CV endpoints
in long-term clinical trials. The latter include
ACE inhibitors, ARBs, CCBs and low-dose
diuretics. More than 25% of patients need at
least three drugs. Strategies for clinical use of
combination therapy continue to evolve.
Current guidelines recommend routine initiation
of a combination in patients with Stage 2
hypertension. More recent studies suggests a
potential for hastening goal attainment and
improving long-term outcomes through the
use of initial combination therapy in a
broader spectrum of patients with
hypertension.
• In a meta-analysis of nine studies comparing
administration of SPCs or their separate
components, the adherence rate was
improved by 26% in patients receiving SPCs
• initial combination treatment consistently
reduces the time taken to reach target BP
compared with initial monotherapy. After 8
weeks, 48% of patients achieved their target
compared with 75% begun on a combination.
• Initial combination therapy was associated
with a 33% reduction in major CV events
compared with patients initiated on
monotherapy and later switched to a
combination treatment by their treating
physician.
• Initial combination treatment should be used
sparingly in frail or very elderly patients (the
presence of orthostatic hypotension)
Alan H. Gradman, Curr Opin Nephrol Hypertens. 2012;21(5):486-491

40. Initial Fixed-Dose Combination Therapy
DISADVANTAGES
• BP may be controlled with 1 drug in some patients
– However, majority of patients require 2 drugs
• Combination ‘too potent’ causing hypotension
– Benefit risk profile for each combination should be assessed in appropriate
patient population
– Individualize therapy
• Additive risk for dose independent adverse effects
– However, mono components likely to be taken as part of a multi drug regimen
– Balance against risk of dose dependent side effects with high dose monotherapy
and risk of inadequate BP control (stroke, heart failure and MI)
• If adverse effects
– must discontinue both drugs:
– more office visits
– more lab tests

41. Cost-effectiveness analysis of cardiovascular disease prevention
with a multidrug regimen
Sanz G and Fuster V (2008) Fixed-dose combination therapy and secondary cardiovascular prevention: rationale,
selection of drugs and target population
Nat Clin Pract Cardiovasc Med doi:10.1038/ncpcardio1419

42. Thank you for
Patience and Sacrifice

43. 1.5 Initiating and monitoring antihypertensive drug treatment, including blood pressure
targets
Initiating treatment
1.5.1 Offer antihypertensive drug treatment to people aged under 80 years with stage 1
hypertension who have one or more of the following:
target organ damage
established cardiovascular disease
renal disease
diabetes
a 10-year cardiovascular risk equivalent to 20% or greater. [new 2011]
1.5.2 Offer antihypertensive drug treatment to people of any age with stage 2 hypertension.
[new 2011]
1.5.3 For people aged under 40 years with stage 1 hypertension and no evidence of target organ
damage, cardiovascular disease, renal disease or diabetes, consider seeking specialist evaluation
of secondary causes of hypertension and a more detailed assessment of potential target organ
damage. This is because 10-year cardiovascular risk assessments can underestimate the lifetime
risk of cardiovascular events in these people. [new 2011]

44. .6 Choosing antihypertensive drug treatment
1.6.1 Where possible, recommend treatment with drugs taken only once a day. [2004]
1.6.2 Prescribe non-proprietary drugs where these are appropriate and minimise cost. [2004]
1.6.3 Offer people with isolated systolic hypertension (systolic blood pressure 160 mmHg or more)
the same treatment as people with both raised systolic and diastolic blood pressure. [2004]
1.6.4 Offer people aged 80 years and over the same antihypertensive drug treatment as people
aged 55–80 years, taking into account any comorbidities. [new 2011]
1.6.5 Offer antihypertensive drug treatment to women of child-bearing potential in line with the
recommendations on Management of pregnancy with chronic hypertension and Breastfeeding in
'Hypertension in pregnancy' (NICE clinical guideline 107). [2010]
Step 1 treatment
1.6.6 Offer people aged under 55 years step 1 antihypertensive treatment with an angiotensin-converting
enzyme (ACE) inhibitor or a low-cost angiotensin-II receptor blocker (ARB). If an ACE
inhibitor is prescribed and is not tolerated (for example, because of cough), offer a low-cost ARB.
[new 2011]
1.6.7 Do not combine an ACE inhibitor with an ARB to treat hypertension. [new 2011]
1.6.8 Offer step 1 antihypertensive treatment with a calcium-channel blocker (CCB) to people
aged over 55 years and to black people of African or Caribbean family origin of any age. If a CCB is
not suitable, for example because of oedema or intolerance, or if there is evidence of heart failure
or a high risk of heart failure, offer a thiazide-like diuretic. [new 2011]
1.6.9 If diuretic treatment is to be initiated or changed, offer a thiazide-like diuretic, such as
chlortalidone (12.5–25.0 mg once daily) or indapamide (1.5 mg modified-release once daily or
2.5 mg once daily) in preference to a conventional thiazide diuretic such as bendroflumethiazide
or hydrochlorothiazide. [new 2011]

45. Display Settings:
•Abstract
A2absb0trasctt (rteaxtc) t
J Hypertens. 2010 Jul;28(7):1584-90. doi: 10.1097/HJH.0b013e328339f9fa.
Reduced discontinuation of antihypertensive treatment by two-drug combination as first step. Evidence
from daily life practice.
Corrao G1, Parodi A, Zambon A, Heiman F, Filippi A, Cricelli C, Merlino L, Mancia G.
Author information
•1Department of Statistics, Unit of Biostatistics and Epidemiology, University of Milano-Bicocca, Milan, Italy.
giovanni.corrao@unimib.it
Abstract
OBJECTIVES:
To measure persistence with antihypertensive drug therapy in patients initiating treatment with mono or
combination therapy.
METHODS:
Data analysis was based on two cohorts of patients, that is, a cohort derived from the registration of drug
prescriptions in all residents of the Lombardy region receiving Public Health Service and a cohort of patients
followed by general practitioners throughout the Italian territory. Data were limited to patients aged 40-80 years
who received their first antihypertensive drug prescription (n = 433,680 and 41,199, respectively) in whom
persistency of treatment was examined over 9 months. A proportional hazards model was fitted to estimate the
association between the pattern of initial antihypertensive drug therapy and risk of treatment discontinuation. Data
were adjusted for available potential confounders.
RESULTS:
Taking patients starting with diuretic monotherapy as reference, the adjusted risk of treatment discontinuation was
progressively lower in patients starting with monotherapy other than a diuretic, a two-drug combination, including a
diuretic and a two-drug combination without a diuretic. No significant difference in the risk of discontinuation was
seen between extemporaneous and fixed dose combinations, including a diuretic, that is, the only combination
reimbursable by Public Health Service and, thus, available in the database. Data were similar for the two cohorts.
CONCLUSION:
Initiating treatment with a combination of two drugs is associated with a reduced risk of treatment discontinuation.

54. There is great concern over the impact of patients not achieving BP goals. Poor BP control is
associated with a marked increase in the risk of CV fatal and non-fatal events.1 A meta-analysis
of 1 million patients in 61 prospective studies demonstrated that the relationship
between BP and cardiovascular disease events is continuous, consistent and age-dependent
– each 20 mmHg increase in SBP or 10 mmHg increase in DBP is associated with at least a
twofold increase in the risk of death from stroke, ischaemic heart disease or other vascular
cause.2
The US study using NHANES III data (Third National Health and Nutrition Examination
Survey) highlighted in this slide shows that uncontrolled and untreated hypertension is
associated with an increased risk of total and CV mortality in the general hypertensive
population.3 Relative to treated controlled hypertensive patients, treated uncontrolled
patients had a 57% and 74% increased risk of all-cause and CVD mortality, with untreated
hypertensives having a 34% and 37% increased risk, respectively. This association was
persistent and remained significant after excluding subjects with hypertension co-morbidities
at baseline.3
1. Grassi G et al. Eur Heart J 2011;32:218-25.
2. Lewington S et al. Lancet 2002;360:1903-13.
3. Gu Q et al. Am J Hypertens 2010;23:38-45.

55.  69% 1st heart attack
 74% Heart failure
 77% 1st stroke
Too low BP may leads to cardiac events
The J-CurvThe J-curve effect describes an inverse relation
between low blood pressure (BP) and cardiovascular
complications. This effect is more pronounced in
patients with preexisting coronary artery disease (CAD),
hypertension or left ventricular hypertrophy (LVH). e
phenomenon The recent large clinical outcomes trials
have observed a J-curve effect between a diastolic BP of
70-80 mmHg as well as a systolic BP <130 mmHg. The J-curve
phenomenon does not appear in stroke or renal
disease. This is because the coronary arteries are
perfused during diastole, but the cerebral and renal
perfusion mainly occurs in systole. Therefore, caution
should be taken to maintain the diastolic blood pressure
(DBP) at minimum of 70 mmHg and possibly to maintain
the DBP between 80-85 mmHg in patients with severe
LVH, CAD or vascular diseases. BP control in high-risk
elderly patients should be carefully done as undergoing
aggressive therapy to lower the systolic blood pressure
below 140 mmHg can cause cardiovascular
complications due to the severely reduced DBP and
increased pulse pressure.