Chronic hypertension medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [6]; Assistant Editor-In-Chief: Taylor Palmieri

Overview

There are many classes of medications for treating hypertension, together called antihypertensives, which by varying means act by lowering blood pressure. Evidence suggests that reduction of the blood pressure by 5-6 mmHg can decrease the risk of stroke by 40%, of coronary heart disease by 15-20%, and reduces the likelihood of dementia, heart failure, and mortality from vascular disease.

Medical Therapy

Goals of Therapy

In addition to alleviating symptoms of hypertension, such as headache and blurry vision, the ultimate long term goals of the management of hypertension are to reduce cardiovascular risk, prevent cardiovascular events, and reverse or ameliorate target organ damage. According to “Blood Pressure Lowering Treatment Trialists’ Collaboration” in 2000, lowering blood pressure decreases the incidence of stroke by an average of 30%, MI by an average of 20%, major cardiovascular events by an average of 21%, and heart failure by an average of more than 50%.

A set target blood pressure anticipated from medical therapy is required to steer the management and follow-up of patients with hypertension. However, a lot of debate exists on how low should physicians target blood pressure in their patients especially in light of studies that have shown a J or U-shaped curve phenomenon associated with hypertension treatment where low and very high blood pressure values are associated with increased risk of cardiovascular events. Along those lines, a new trend has recently surfaced advocating a less strict target in diabetic and elderly patients seen in the new ADA and ESH/ESC 2013 guidelines respectively. This rationale is supported by the fact that lower SBP targets in diabetic patients have not been shown to generate better outcomes. Similarly, treatment of stage 1 hypertension in elderly patients and targeting SBP values to <140 mmHg have not been well substantiated and may sometimes carry more risk than benefit. Still it is agreed that in the general population at low to moderate cardiovascular risk a target BP below 140/90 mmHg is recommended. A more detailed discussion about targets in special populations is available below.

Approach to Medical Therapy

Pharmacologic therapy is normally initiated based on the cardiovascular risk. Failure to achieve BP goals in patients with low and moderate cardiovascular risk after three to six months of non-pharmacologic measures necessitates the initiation of pharmacologic therapy. Medical management should be reserved to patients with BP>140/90 mmHg (except in certain cases discussed below). A lot of debate exists on the optimal approach to the medical management of hypertension. With the multitude of classes and agents that can be used, several questions arise about the single best agent, the optimal combination of agents, and the best step-wise approach to medical management. Although JNC7 tried to address these issues, almost a decade has passed since the release of their recommendations, with a myriad of studies and trials presenting newer compelling evidence to update the current recommendations. The 2013 ESH/ESC guidelines for the management of hypertension have dwelled into these issues and have outlined the rationale behind adopting a new approach. Below are the algorithms for the approach to the medical therapy of hypertension presented by JNC7 in 2004 and ESH/ESC in 2013.

JNC7 Guidelines. Approach to medical therapy of hypertension.

JNC7 Guidelines. Approach to medical therapy of hypertension.

ESH/ESC 2013 Guidelines. Approach to medical therapy of hypertension.

ESH/ESC 2013 Guidelines. Approach to medical therapy of hypertension.

Antihypertensive Agents & Indications

Common Antihypertensive Agents

Several classes of medications are used in the treatment of hypertension namely diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers, alpha-blockers, and direct vasodilators. Below is a list of common oral agents used in the treatment of hypertension.

JNC7: Common oral antihypertensive agents

Class	Drug	Usual Dose Range (mg/day)
Thiazide Diuretics	Chlorothiazide	125-500
	Chlorthalidone	12.5-25
	Hydrochlorothiazide	12.5-50
	Polythiazide	2-4
	Indapamide	1.25-2.5
	Metolazone	0.5-5
Loop Diuretics	Bumetanide	0.5-2
	Furosemide	20-80
	Torsemide	2.5-10
Potassium-sparing Diuretics	Amiloride	5-10
	Triamterene	50-100
Aldosterone Receptor Diuretics	Spironolactone	25-50
	Eplerenone	50-100
Beta-Blockers	Atenolol	25-100
	Betaxolol	5-20
	Bisoprolol	2.5-10
	Metoprolol	50-100
	Metoprolol extended release	50-100
	Nadolol	40-120
	Propranolol	40-160
	Propranolol long-acting	60-180
	Timolol	20-40
Beta-Blockers with intrinsic sympathomimetic activity	Acebutolol	200-800
	Penbutolol	10-40
	Pindolol	10-40
Combined Alpha- and Beta-Blockers	Carvedilol	12.5-50
	Labetalol	200-800
ACE Inhibitors	Benazepril	10-40
	Captopril	25-100
	Enalapril	5-40
	Fosinopril	10-40
	Lisinopril	10-40
	Moexipril	7.5-30
	Perindopril	4-8
	Quinapril	10-80
	Ramipril	2.5-20
	Trandolapril	1-4
Angiotensin Receptor Blockers	Candesartan	8-32
	Eprosartan	400-800
	Irbesartan	150-300
	Losartan	25-100
	Olmesartan	20-40
	Telmisartan	20-80
	Valsartan	80-320
Nondihydropyridine Calcium Channel Blockers	Diltiazem extended release	120-540
	Verapamil immediate release	80-320
	Verapamil long acting	120-480
	Verapamil	120-360
Dihydropyridine Calcium Channel Blockers	Amlodipine	2.5-10
	Felodipine	2.5-10
	Isradipine	2.5-10
	Nicardipine sustained release	60-120
	Nifedipine long-acting	30-60
	Nisoldipine	10-40
Alpha-1 Blockers	Doxazosin	1-16
	Prazosin	2-20
	Terazosin	1-20
Centrally Acting Drugs	Clonidine	0.1-0.8
	Methyldopa	250-1000
	Reserpine	0.1-0.25
	Guanfacine	0.5-2
Direct Vasodilators	Hydralazine	25-100
	Minoxidil	2.5-80

JNC7: Compelling Indications and Choice of Antihypertensive Agents

Clinical trials and basis for compelling indications for individual drug classes

Compelling Indication	Recommended Drugs	Clinical Trial Basis
Heart failure	Diuretics, Beta blockers, ACEIs, ARBs, Aldosterone antagonist	ACC/AHA Heart Failure Guideline ; MERIT-HF ;COPERNICUS ; CIBIS ; SOLVD ; AIRE ; TRACE ; ValHEFT ; RALES
Post-Myocardial infarction	Beta blockers, ACEIs, Aldosterone antagonist	ACC/AHA Post-MI Guideline ; BHAT ; SAVE ; Capricorn ; EPHESUS
High coronary disease risk	Diuretics, Beta blockers, ACEIs, CCBs,	ALLHAT ; HOPE; ANBP2 ; LIFE ; CONVINCE
Diabetes	Diuretics, Beta blockers, ACEIs, ARBs, CCBs	NKF-ADA Guideline ;UKPDS ; ALLHAT
Chronic kidney disease	ACEIs, ARBs	NFK Guideline ; Captopril Trial ; RENAAL ; IDNT ; REIN ; AASK
Recurrent stroke prevention	Diuretics, ACEIs	PROGRESS

ESH/ESC 2013 Guidelines: Drugs to be Preferred in Specific Conditions

Condition	Drug
Asymptomatic organ damage
LVH	ACE inhibitor, calcium antagonist, ARB
Asymptomatic atherosclerosis	Calcium antagonist, ACE inhibitor
Microalbuminuria	ACE inhibitor, ARB
Renal dysfunction	ACE inhibitor, ARB
Clinical CV event
Previous stroke	Any agent effectively lowering BP
Previous myocardial infarction	BB, ACE inhibitor, ARB
Angina pectoris	BB, calcium antagonist
Heart failure	Diuretic, BB, ACE inhibitor, ARB, mineralocorticoid receptor antagonists
Aortic aneurysm	BB
Atrial fibrillation, prevention	Consider ARB, ACE inhibitor, BB or mineralocorticoid receptor antagonist
Atrial fibrillation, ventricular rate control	BB, non-dihydropyridine calcium antagonist
ESRD/proteinuria	ACE inhibitor, ARB
Peripheral artery disease	ACE inhibitor, calcium antagonist
Other
ISH (elderly)	Diuretic, calcium antagonist
Metabolic syndrome	ACE inhibitor, ARB, calcium antagonist
Diabetes mellitus	ACE inhibitor, ARB
Pregnancy	Methyldopa, BB, calcium antagonist
Blacks	Diuretic, calcium antagonist

Management of Hypertension in Special Populations

Ethnic groups

• African Americans: Enforcement of DASH diet due to its association with greater reduction of BP than other ethnicities (Ref: 11136953). According to the ALLHAT trial that included 15,000 Blacks, diuretics were more effective for African Americans than other classes of anti-hypertensive agents.

• Mexican Americans, other Hispanic Americans, Native Americans, and Asian/Pacific Islanders have been recruited in insufficient numbers in research trials to adequately identify special considerations.

Diabetic Patients

• According to the American Diabetes Association, BP goal for diabetic patients must be < 140/80 mmHg to reduce the progression of target organ damage but that lower systolic blood pressure targets <130 mmHg can be targeted in younger patients. The recent shift in the approach to hypertension in diabetics proposed by the 2013 ADA guidelines as well as the 2013 ESH/ESC guidelines is supported by the fact that no major trials have consistently achieved a blood pressure level below 130/80 mmHg in diabetics nor have the smaller trials shown any major benefit from intensive treatment to reach that threshold. In parallel to the ADA, the 2013 ESH/ESC guidelines only support a lower DBP goal set at 80-85 mmHg.

• According to the American Diabetes Association, ACEI and ARBs are considered superior agents in diabetic patients for their renal protective effects (delay in both GFR decrease and albuminuria worsening). Although RAAS blockers such as ACEI and ARBs are beneficial their combination can sometimes have significant effects on renal function especially in high risk patients.

• Thiazide-type diuretics were shown to be beneficial in reducing heart disease in diabetic patients. Despite their side effects of worsening hyperglycemia, thiazide-type diuretics were associated with stable target organ damage compared to other anti-hypertensive agents.

• According to the LIFE study, beta-blockers are especially beneficial in diabetic patients with ischemic heart disease despite their controversial role as monotherapy. Even though decreased insulin sensitivity is a side effect, beta-blockers are not absolutely contraindicated in diabetes.

• In the management of hypertension, CCBs are unquestionably useful in the reduction of BP values. However, their role in preventing target organ damage in diabetic patients is inferior to other agents. The ALLHAT study demonstrated that amlodipine, a DHP CCB, was less effective than thiazides in reducing heart failure. Similarly, the ABCD Trial also showed that nisoldipine, a dihydropyridine CCB was less effective than enalapril, an ACEI, in reducing ischemic heart disease.

Patients with Metabolic Syndrome

• Metabolic syndrome as a clinical concept is largely debatable, mostly since studies have shown little added benefit of the definition on the predictive power of each of the constitutive individual factors, making recommendations about hypertension treatment in this subpopulation limited.

• Lifestyle modification plays the most important role in anti-hypertensive therapy in patients with metabolic syndrome.

• Persistence of high BP > 140/90 mmHg still warrants pharmacologic therapy.

• Management of dyslipidemia, glucose intolerance, and other concomitant comorbidities is essential for reduction of BP in patients with metabolic syndrome.

Elderly Patients

• There is particular advantage in weight loss and reduced sodium intake in elderly subjects. Trial of Non-pharmacologic Interventions in the Elderly (TONE) showed that sodium intake of less than 80 mmol per day (2 g of sodium per day or 5 grams of sodium chloride salt) could allow the discontinuation of anti-hypertensive agents in 40% of elderly.

• The 2013 ESH/ESC guidelines modified the approach adopted in 2007 to treat hypertension regardless of age. The new guidelines advocate holding medical therapy for elderly patients with stage 1 hypertension and initiating treatment only in those with stage 2 hypertension or greater. It is also recommended to target a SBP below 150 mmHg rather than 140mmHg. This rationale follows several studies involving elderly patients not achieving blood pressure measurements below 140mmHg. In patients below 80 years of age, treatment can be targeted below 140 mmHg if goal can be tolerated.

• The HYpertension in the Very Elderly Trial (HYVET) showed that in patients older than 80 years-old with SBP >160mmHg, a significant reduction in major CV events and all-cause mortality can be seen by aiming at SBP values <150mmHg.

• The JNC7 guidelines concluded in 2004 that antihypertensive therapy should not be withheld in patients with stage 1 hypertension based on age, even though no RCTs had shown benefits from treatment in this population at the time.

Pregnant Women

• Distinguishing gestational from pre-gestational hypertension in pregnant women is essential. Hypertension is not considered to be caused by pregnancy when it develops before 20 weeks of gestation.

• Hypertensive women who plan to become pregnant should be instructed to use safe anti-hypertensive medications, such as methyldopa preferentially because long-term follow up studies are available. Labetolol and nifedipine are also other treatment options that can be considered in pregnancy.

• Pregnant women with stage 1 hypertension present with low cardiovascular risk and anticipated physiological lowering of blood pressure during pregnancy. Thus healthcare providers might advise mere lifestyle modification as therapy during pregnancy and breast feeding, with caution on excessive weight reduction and with possible restriction of aerobic physical activity.

• The 2013 ESH/ESC guidelines recommend drug treatment of severe hypertension in pregnancy defined as SBP >160 mmHg or DBP >110 mmHg. They also advocate considering treatment in pregnant women with persistant hypertension ≥150/95 mmHg and in symptomatic patients or patients with target organ damage with BP ≥140/90 mmHg.

Patients with Hypertensive Emergency or Urgency

• Hypertensive emergency is defined as high blood pressure causing acute target organ damage. Usually BP exceed 180/20 mmHg, but can sometimes occur at even lower values in patients who do not usually have high blood pressure.

• Hypertensive urgency is defined as a BP > 180/120 mmHg without target organ damage. Hypertensive urgency may or may not be symptomatic.

• Triage to differentiate between hypertensive emergency and urgency is crucial for appropriate management. While hypertensive emergencies require intensive care unit (ICU) admission for close monitoring and aggressive parenteral agents, hypertensive urgencies can be managed in the emergency department with outpatient follow-up for optimization of therapy.

• Treatment is based on titrated intravenous medications that act rapidly but safely especially in avoiding severe hypotension and ischemic organ damage. Nicardipine, sodium nitroprusside, labetalol, furosemide and nitrates are some of the agents used. In certain cases of volume overload-associated hypertensive emergency where diuresis is insufficient, dialysis and ultrafiltration may be of benefit.
• Generally, JNC 7 outlines the acute management of hypertensive emergencies as reduction of a maximum of 25% of mean arterial BP within the first hour followed by decrease of BP to 160/100 within the next 2 to 6 hours. Normalization of blood pressure should occur at a span of 24-48 hours. Rapid decrease in BP might precipitate ischemia caused by target organ damage.

• The 2013 ESH/ESC guidelines do not dwell much into the treatment of hypertensive emergencies due to the lack of evidence considering the small number of cases but recommend that treatment be individualized by the physician.

• Specific clinical situations are considered exceptions to the abovementioned management plan:
  • Ischemic stroke will not require immediate BP lowering to maintain cerebral perfusion.
  • Aortic dissection requires SBP to be lowered immediately to < 100 mmHg if tolerated followed by rapid specific management.