Overall Goals

The overall goal of treating hypertension is to reduce hypertension-associated morbidity and mortality. This morbidity and mortality is related to hypertension-associated target-organ damage (e.g., ASCVD, retinopathies, cerebrovascular events, heart disease, kidney disease, and PAD etc.). Reducing CV risk is the primary purpose of hypertension therapy and the specific choice of drug therapy should be determined by evidence demonstrating such CV risk reduction.

Above overall target should be interpreted more deeper. According to JNC 7 guideline, hypertension patients can be divided into two groups, one with compelling indications, most of which are CV diseases but not necessarily due to hypertension (e.g., non-hypertension associated CKD, DM), one without compelling indications. For patients without compelling indications (no existed CV diseases or CV diseases non-detectable), the therapy is to reduce the risk of hypertension-associated CV (primary prevention). For patients with compelling indications which are non-hypertension-associated, for example, hypertension plus diabetes or non-hypertension-associated CKD, the therapy is to reduce the risk of hypertension-associated CV (primary prevention) and to reduce the morbidity and mortality of the compelling condition. For patients with compelling indications which are hypertension-associated,  the therapy is to slow the progression of hypertension and existed CV diseases or secondary prevention (e.g., Post-MI).

BP Goals

Because elevated BP level is related to CV risk/risk of hypertension-associated target-organ damage, which whereas involved with morbidity and mortality of hypertension, to achieve a desire target BP value is simply a surrogate goal of therapy. For primary prevention, reducing BP to goal does not guarantee prevention of hypertension-associated target-organ damage, but is associated with a lower risk of hypertension-associated target-organ damage.

The latest JNC 8 hypertension guideline category hypertension patients into four groups, including

  • Patients without diabetes or CKD >=60 years of age
  • Patients without diabetes or CKD <60 years of age
  • Patients with diabetes but no CKD
  • Patients with CKD

Each category has its target BP goal, as shown in the Figure 1 below.

In the general population aged 60 years or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 150 mm Hg or higher or diastolic blood pressure (DBP) of 90 mm Hg or higher and treat to a goal SBP lower than 150 mm Hg and goal DBP lower than 90 mm Hg (Strong recommendation – Grade A). In the general population aged 60 years or older, if pharmacologic treatment for high BP results in lower achieved SBP (for example, <140 mm Hg) and treatments is not associated with adverse effects on health or quality of life, treatment does not need to be adjusted (Expert opinion – Grade E).

In the general population younger than 60 years, initiate pharmacologic treatment to lower BP of 90 mm Hg or higher and treat to to a goal DBP of lower than 90 mm Hg (For ages 30 through 59 years, strong recommendation – Grade A; for ages 18 through 29 years, expert opinion – Grade E).

In the general population younger than 60 years, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher and treat to a goal SBP of lower than 140 mm Hg (Expert opinion – Grade E).

For more information about the JNC 8’s BP goals please visit the American Medical Association at http://jama.jamanetwork.com/article.aspx?articleid=1791497.

General Approach to Treatment

Most patients should be placed on both lifestyle modifications and drug therapy concurrently after a diagnosis of hypertension is made. Life-style modification alone is appropriate for most patients with prehypertension. However, lifestyle modifications alone may not be adequate for patients with either additional CV risk factors (in so, not adequate to reduced the CV risk) or hypertension-associated target-organ damage (secondary prevention/slow the progression of existed hypertension-associated target-organ damage).

Besides hypertension, other major and additional CV risk factors should be avoided if possible (e.g., smoking). Major and additional risk factors can be found at http://www.tomhsiung.com/wordpress/2014/07/the-management-of-dyslipidemia/

Choice of Initial Drug Therapy

The choice of initial drug therapy depends on the degree of BP elevation and presence of compelling indications (HFrEF, Post-MI, CAD, DM, CKD, and Recurrent Stroke Prevention). Most patients with stage 1 hypertension should be initially treat with a first-line antihypertensive drug or the combination of two agents. Combination drug therapy is recommended for patients with more severe BP elevation (stage 2 hypertension), using preferably two first-line antihypertensive drug.

It is important to remember that the general goal to treat hypertension patients without compelling is to reduce the risk or slow the progress of hypertension-associated target organ damage.


Nonpharmacologic Therapy

All patients with prehypertension and hypertension should be prescribed lifestyle modifications. Recommended modifications that have been shown to lower BP are list in Table 3-4. They can provide small to moderate reductions in SBP. Aside from lowering BP in patients with known hypertension, lifestyle modification can decrease the progression to hypertension in patients with prehypertension BP values.

Table 3-4 Lifestyle Modifications to Prevent and Manage Hypertension

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Pharmacotherapy – No Compelling Indications

First line antihypertensive agents include thiazide, ACEI, ARB, and CCB. They should be used to treat the majority of patients with hypertension because evidence from outcome data have demonstrated CV risk reduction benefits with these classes. As we discussed earlier, the overall goal of management of hypertension is to reduce hypertension-associated morbidity and mortality. This morbidity and mortality is related to hypertension-associated target-organ damage (e.g., CV events, retinopathies, cerebrovascular events, heart failure, kidney disease, and PAD etc.) and therefore reducing CV risk is the primary purpose of hypertension therapy and the specific choice of drug therapy should be determined by evidence demonstrating such CV risk reduction. So the efficacy (clinical outcome) of antihypertensive agents could be measured by comparing the reduction of the CV risk of each drug.

Evidence from ALLHAT trial showed that therapeutic arm of chlorthalidone, compared with lisinopril or amlodipine, respectively, are of no significant differences in the primary end point (fatal CHD and nonfatal MI). However, chlorthalidone had statistically fewer secondary end points than amlodipine (heart failure) and lisinopril (combined CV disease, heart failure, and stroke).

Figure 1 Patient Criteria for ALLHAT Trial 

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PS: Detail information for ALLHAT trail could be found at https://clinicaltrials.gov/ct2/show/study/NCT00000542?term=allhat&rank=3. Note that 36 percent of all patients enrolled were diabetics.

Clinical trial data cumulatively demonstrate that ACEI-, CCB-, or ARB-based antihypertensive therapy reduces CV events. These agents may be used for patients without compelling indications as a first-line therapy.

Clinical trial data cumulatively suggest that beta-blockers may not reduce CV events to the extent that ACEIs, ARBs, or thiazide diuretics do. Available data from meta-analyses demonstrated fewer reductions in CV events with beta-blocker-based antihypertensive therapy compared mostly with ACEI-, and CCB-based therapy. However, it is important for clinicians to remember that beta-blocker-based antihypertensive therapy does not increase risk of CV events; beta-blocker-based therapy reduces risk of CV event compared with no antihypertensive therapy. Using a beta-blocker as a primary antihypertensive agent is optimal when an ACEI, ARB, or thiazide diuretic cannot be used as the primary agent. Besides, beta-blocker still have an important add-on role after first-line agents to reduce BP in patients with hypertension but without compelling indications.

Pharmacotherapy – With Compelling Indications

The JNC 7 report identifies six compelling indications. Compelling indications represent specific comorbid conditions where evidence from clinical trials supports using specific antihypertensive classes to treat both the compelling indiction and hypertension. Drug therapy recommendations typically consist of combination drug therapies. Data from these clinical trials have demonstrated reduction in CV morbidity and/or mortality that justify use for patients with hypertension and with such a compelling indication.

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  • HFrEF (ACEI or ARB + Diuretic, then add Beta-Blocker. Aldosterone receptor antagonist is add-on therapy).

Five drug classes are list as compelling indications for HFrEF. An evidence-based pharmacotherapy regimen for HFrEF, sometimes called standard pharmacotherapy, consists of three to four drugs: an ACEI or ARB plus diuretic therapy, followed by the addition of an appropriate beta-blocker, and possibly an aldosterone receptor antagonist. Evidence from clinical trials shows that ACEIs significantly modify disease progression by reducing morbidity and mortality. Although HFrEF was the primary disease in these studies, ACEI therapy will also control BP in patient with HFrEF and hypertension. ARBs are acceptable as an alternative therapy for patients who cannot tolerate ACEIs based on data from the CHARM studies (https://clinicaltrials.gov/ct2/show/NCT00634309?term=assessment+of+reduction+in+mortality+and+morbidity&rank=1). An ACEI or ARB should be started with low doses for patients with HFrEF, especially those in acute exacerbation. Heart failure induces a compensatory high-rennin condition, and starting ACEI inhibitors or ARBs under these conditions can cause a pronounced first-dose effect and possible orthostatic hypotension.

Diuretics are also a part standard pharmacotherapy primarily to control symptoms. They provide symptomatic relief of edema by inducing diuresis. Loop diuretics are often needed, especially for patients with more advanced heart failure. However, some patients with well-controlled heart failure and without significant CKD may be managed with a thiazide diuretic.

Beta-blocker therapy is appropriate to further modify disease in HFrEF and is a component of standard therapy for these patients. For patients on an initial regimen of diuretics and ACEIs, beta-blockers have been shown to reduce CV morbidity and mortality. It is of paramount importance that beta-blockers be doses appropriately due to the risk of including an acute exacerbation of heart failure. They must be started in very low doses, does much lower than that used to treat hypertension, and titrated slowly to high doses based on tolerability. Bisoprolol, carvedilol, and sustained-release metoprolol succinate are the only beta-blockers proven to be beneficial in HFrEF.

After implementation of a standard three-drug regimen (diuretic, ACEI or ARB, and beta-blocker), other agents may be added to further reduce CV morbidity and mortality, and reduce BP if needed. The addition of an aldosterone antagonist can reduce CV morbidity and mortality in HFrEF. Spironolactone has been studied in severe HFrEF and has shown benefit in addition to diuretic and ACEI therapy.

  • Post-MI (Beta-Blocker, then add ACEI or ARB)

Beta-blockers (those without intrinsic sympathomimetic activity [ISA]) and ACEI inhibitor or ARB therapy are recommended in the AHA/ACC Foundation and JNC 7 guidelines. Beta-blockers decrease cardiac adrenergic stimulation and have been shown in clinical trials to reduce the risk of a subsequent MI or sudden cardiac death. ACEIs have been shown to improve cardiac remodeling and cardiac function and to reduce CV events post-MI. These two drug classes, with beta-blockers first, are considered the first drugs of choice for patients who have experienced an MI. One study, the VALIANT trial, demonstrated that ARB therapy is similar to ACEI therapy for patients post-MI heart failure and/or left ventricular systolic dysfunction.

  • Coronary Artery Disease (Beta-Blocker, then add ACEI or ARB. CCB or Thiazide Diuretic are add-on agents)

Beta-blocker therapy has been considered a standard of care for treating patients with coronary artery disease and hypertension. Beta-blockers are first-line therapy in chronic stable angina and have the ability to reduce BP and improve ischemic symptoms by decreasing myocardial oxygen consumption and demand. Beta-blockers therapy seems to be most effective in reducing the risk of CV events in patients with recent MI and/or ischemic symptoms. Long-acting CCBs may considered alternatives to beta-blockers (diltiazem and verapamil) or as add-on therapy (dihydropyridine CCBs) in chronic stable angina for patients with ischemic symptoms.

For acute coronary syndromes, first-line therapy should consist of a beta-blocker and ACEI. An ARB is a reasonable alternative to an ACEI.

  • Diabetes Mellitus (ACEI or ARB, CCB, Thiazide Diuretic, or Beta-Blocker might be add-on agents)

All patients with diabetes and hypertension should ideally be treated with an ACEI or an ARB. The reason is that, pharmacologically, both of these agents should provide nephroprotection due to vasodilation in the efferent arteriole of the kidney. CCBs are the most appropriate add-on agents for BP control for patients with diabetes.

  • CKD (ACEI or ARB)

Patients with hypertension may develop damage to either the renal tissue or the renal arteries. The rate of kidney function deterioration is accelerated when both hypertension and diabetes are present. Once patients have an estimated GFR <60 mL/min/1.73 m2 or albuminuria, they have significant CKD and risk of CV disease and progression to severe CKD increases. BP Control can slow the decline in kidney function.

In addition to lowering BP, ACEIs and ARBs reduce intraglomerular pressure, which can theoretically provide additional benefits by further reducing the decline in kidney function. ACEIs and ARBs have been shown to reduce progression of CKD in diabetes and in those without diabetes. However, it is difficult to differentiate whether the kidney protection benefits are from RAAS blockade versus BP lowering.

  • Recurrent Stroke Prevention (Thiazide with/without ACEI)

Ischemic stroke (not hemorrhagic stroke) and transient ischemic attack are considered a form of hypertension-associated target-organ damage. Attaining goal BP values in patients who have experienced an ischemic stroke is considered a primary modality to reduce risk of a second stroke. A thiazide diuretic, either in combination with an ACEI or as monotherapy, is considered an evidence-based antihypertensive regimen for patients with a history of stroke or transient ischemic attack. Antihypertensive drug therapy should only be implemented after patients have stabilized following an acute cerebrovascular event.

Combination Therapy

Initial therapy with a combination of two drugs is highly recommended for patients with stage 2 hypertension and is an option of retreating patients with stage 1 hypertension. Also initial two-drug combination therapy may be appropriate for patients with multiple compelling indications for different antihypertensive agents. Clinicians should anticipate the need for combination drug to control BP in most patients. Besides, using low-dose combinations provides greater reductions in BP compared with high doses of single agents and appropriately increasing the number of antihypertensive medications to attain goal BP values does not increase the risk of adverse effects.