Hypertension : A Multifactorial Entity

Hypertension is a multifactorial entity, it is therefore not surprising that there is heterogeneity in responsiveness to treatment. Today, there is no simple way of predicting which patients will respond to which class of antihypertensive agents.
- Journal of Human Hypertension 1995 ; 9 : S33-S36

Hypertension : A Multifactorial Entity

Hypertension even today is a triple paradox which is :
Easy to diagnose OFTEN remains undetected Simple to treat OFTEN remains untreated

Despite availability of potent drugs, treatment all too OFTEN is ineffective

Why combination therapy

Multiple mechanisms involved in the pathogenesis of hypertension Effectiveness of monotherapy limited by stimulation of counter-regulatory mechanisms Effective BP control seen in only 50% of patients on monotherapy; combination therapy results in a much higher responder rate (>80%) BP goals difficult to attain with monotherapy in patients with diabetes or target organ damage

American Heart Association

Starting with combination therapy may be the best way to get hypertensive patients blood pressure down to goal levels.

Multiple Antihypertensive Agents Are Needed to Achieve Target BP

Trial

Target BP (mm Hg)

Number of antihypertensive agents 1 4 2 3

ALLHAT SBP <140/DBP <90 UKPDS ABCD DBP <85 DBP <75

MDRD HOT
AASK IDNT

MAP <92 DBP <80

MAP <92 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.

Advantages of fixed-dose combination therapy

Better blood pressure control Lesser incidence of individual

drugs side-effects
Neutralization of side-effects Increased patient compliance Modification of risk factors Lesser cost of therapy

JNC 7 Treatment Guidelines recommend considering initiating therapy with two drugs when BP >20/10mmHg above goal
JNC7 recommends BP be reduced to < 140/90mmHg

For patients with diabetes or CKD: < 130/80mmHg

Consider initiating therapy with two drugs in patients whose BP is >20/10mmHg above goal (Stage 2 and Stage 1 patients at high risk)

thereby increasing the likelihood of achieving goal BP in a timely manner.Multi-drug combinations often produce greater BP reduction at lower doses of the component agents resulting in fewer side effects. The use of fixed dose combinations may be more convenient and simplify the treatment regimen.
More than 2/3 of patients will require two or more agents

Chobanian et al., JAMA 2003; 289:256072,

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: better adherence and potential for improved outcomes Economic benefits Fewer copayments health care costs reduced fewer office visits

Initial Fixed-Dose Combination Therapy

ADVANTAGES Many combinations of agents with complementary MOA available, e.g. RAS blocker/diuretic RAS blocker/CCB Patient response to fixed dose combinations predictable FDCs well studied and efficacy and tolerability data available in package inserts and publications Similar data not always available for ad hoc free combinations

Combination therapy for hypertension Recommended by JNC-VI guidelines and 1999 WHO-ISH guidelines

With any single drug, not more than 2550% of hypertensives achieve adequate blood pressure control
J Hum. Hypertens 1995; 9:S33S36

For patients not responding adequately to low doses of monotherapy

Substitute with another Increase the dose of drug. Add a second drug from a This, however, may lead to drug from a different class different class increased side effects (Combination therapy)

If inadequate response obtained

Add second drug from different class (Combination therapy)

Guidelines for initial combination therapy. Committee BP levels requiring initial combination therapy
JNC-7 Stage 2 (160/100 mmHg) SBP > 20 mmHg or DBP > 10 mmHg above the goal

NKF

SBP >20 mmHg above the goal according to the stage of CKD and CVD risk
BP >130/80 mmHg and type II diabetes High risk patients according to total CVD risk

ADA ESH

Benefits of combination therapy in hypertension.

Better adherence to therapy and simplification of the therapeutic regimen. Better BP control than monotherapy. Avoidance of dose dependent adverse effects seen with higher doses of single agents. Attenuation of the adverse effects of some agents when used alone. Complementary/synergistic vasculoprotective or pleiotropic effects.

Conclusions
Controlling hypertension reduces CV outcomes
Doubling of CV risk with BP increases of 20/10mmHg Relationship between BP and CV risk is continuous: lower is better

Majority of patients require >2 drugs to achieve BP goal JNC 7 recommends initial combination therapy in patients > 20/10 mm Hg over goal BP

Conclusions
Multiple combinations have been well studied in patients with Stage 2 hypertension Patient response to fixed dose combinations is predictable Incremental efficacy with good tolerability achieved with combinations representative of several antihypertensive classes, not just thiazide combinations as referenced in JNC7 Benefit/risk profile of these agents can be determined from clinical studies to support appropriate clinical use