High Blood Pressure (Arterial Hypertension): Drug Therapy

Therapeutic Targets

  • The German Hypertension League e.V. (DHL) recommends a blood pressure goal of <140/90 mmHg; for all cardiovascular risk patients, a blood pressure goal of <135/85 mmHg (target corridor: systolic blood pressure: 125-134 mmHg). Cardiovascular risk patients include:
    • Patients with existing cardiovascular disease (excluding apoplexy patients).
    • Patients with chronic kidney disease stage 3 or greater (= GFR < 60 ml/min/1.73 m2).
    • Patients > 75 years

    Blood pressure in relation to diseases:

    • Diabetes mellitus: diastolic pressure: < 85 mmHg (80-85 mmHg).
    • Stage 3 renal failure (GFR: 30-59 ml/min; without dementia, diabetes mellitus, or history of falls):
      • Systolic blood pressure (target corridor): 125-134 mmHg; this is inconsistent with: in chronic kidney disease, the optimal blood pressure appears to be 130-159/70-89 mmHg.
      • Diastolic blood pressure: < 85 mmHg.
  • Current ESH/ESC guideline (European Society of Hypertension (ESH)/European Society of Cardiology (ESC); Barcelona, 2018):
    • Blood pressure of ≤ 140/90 mmHg; systolic blood pressure in relation to age:
      • Age 18-65: 130-120 mmHg
      • Age > 65-79: 140-120 mmHg
      • Age ≥ 80: 140-130 mmHg
    • Diastolic blood pressure: primary therapeutic goal of < 90 mmHg; regardless of age and concomitant morbidity, aim for a blood pressure target range of 80-70 mmHg.
    • Chronic renal insufficiency: < 140-130 mmHg.
    • Blood pressure limit: 120/70 mmHg
  • Hypertensive patients with high cardiovascular risk (see below Further notes/Sprint study).
  • Kidney Disease: Improving Global Outcomes (KDIGO): lower systolic blood pressure to < 120 mmHg in all, regardless of age or diabetes status (if patient tolerates).
  • Notice: In addition to drug therapy, lifestyle modification plays a significant role (see also under “Further therapy” under nutritional medicine).

Further notes

  • Seniors (≥ 80 years) and “frail” individuals: Adjustment level depending on individual tolerance; systolic blood pressure values between 140 and 150 mmHg are considered sufficient; a working group of representatives of the European Society of Hypertension (ESH) and the European Union Geriatric Medicine Society (EUGMS) recommends: 150-130 mmHg.
  • According to new evidence, blood pressure levels <140/70 mmHg should not be targeted even in high-risk groups; the ACCOR trial also demonstrated that in diabetic patients, blood pressure reduction below a systolic level of 120 rather than 140 mmHg was not associated with a lower rate of fatal or nonfatal cardiovascular events. This is reaffirmed by a meta-analysis that demonstrated that blood pressure targets in diabetics should be less aggressive than in nondiabetics: aim for a blood pressure < 140/85 mmHg.A study of data from the Korean National Health Insurance Service with 2,262. 725 type 2 diabetics with regular health checks between 2009 and 2012, excluding.patients with pre-existing cardiovascular disease (mean observation period: 6.5 years) was able to show that in patients, the optimal threshold for systolic blood pressure was 130 mmHg and for diastolic blood pressure was 80 mmHg.
  • The results of the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive blood pressure reduction to below 120 mmHg achieved better results than the previous target of 140 mmHg, Intensive blood pressure reduction to an average of 121.4 mmHg resulted in as early as 3 years, that the primary endpoint (composite of myocardial infarction (heart attack) or other acute coronary syndrome, apoplexy (stroke), heart failure, or death from cardiovascular causes) in incidence was 1.65% per year vs. 2.19% per year under standard treatment (here, average blood pressure: 136.2 mmHg); rate of significant GFR drops (GFR = glomerular filtration rate/most important functional parameter of the kidney), however, was significantly increased in the renal healthy group (standard: 0.35%/year; intensive: 1.2%/year).
  • Arterial hypertension (high blood pressure) and coronary artery disease: after therapeutic intervention, the lowest mortality was present in:
    • Systolic blood pressure between 120 and 130 mmHg
    • Diastolic blood pressure at least 85 mmHg
  • Lowering diastolic pressure too much can potentially damage the myocardium (heart muscle): In the observational study ARIC (Atherosclerosis Risk In Communities), low diastolic blood pressure (< 60 mmHg) was shown to be associated with subclinical myocardial damage (2.24 (95% confidence interval between 1.22 and 4.10; p = 0.01)). Furthermore, diastolic values below 60 mmHg were found to be associated with incidence of coronary heart disease/coronary artery disease (1.49 (95% confidence interval ranging from 1.20 to 1.85; p ˂ 0.001)) and all-cause mortality/all-cause mortality rate (1.32 (95% confidence interval ranging from 1.13 to 1.55; p ˂ 0.001).
  • Because nighttime elevated blood pressure is associated with a higher risk of cardiovascular events (cardiovascular-related death, myocardial infarction (heart attack), apoplexy (stroke), heart failure (heart failure)) than daytime-only hypertension, hypertensive patients with nighttime elevated blood pressure should take an antihypertensive drug primarily at bedtime.

Refractory arterial hypertension exists when blood pressure is as follows with guideline-based therapy:

  • > 140/90 mmHg in general
  • > 130-139/80-85 mmHg in patients with diabetes mellitus.
  • > 130/80 mmHg in patients with chronic kidney disease (see above contradiction to).

Therapy recommendations

  • Therapy for hypertension is based on the severity of hypertension, the number of risk factors (the patient’s risk profile), and secondary or concomitant diseases (see the table below).
  • Current ESH/ESC guideline (European Society of Hypertension (ESH)/European Society of Cardiology (ESC); Barcelona, 2018):
    • Initial treatment with a two-drug combination; for the rest, see “Combination therapy in stages” below.
      • For other concomitant diseases, see below “Selection of antihypertensives according to concomitant diseases” (source ESH/ESC guideline)”
    • Therapy initiation:
      • Age 18-79: ≥ 140/90 mmHg
      • Age ≥ 80: ≥ 160 mmHg
    • Notes on therapy:
      • High-normal blood pressure values (130-139/85-89 mmHg): in patients with very high cardiovascular risk (especially coronary artery disease, CAD) start with antihypertensive drug therapy.
      • Grade 1 (mild) hypertension (syst. blood pressure 140-159 and /or diastolic blood pressure 90-99): before drug therapy should be a trial of several months of therapy with lifestyle measures
      • Grade 2 and 3 (moderate and severe) hypertension: immediate start with drug therapy.
      • Age > 80 years: Restart of antihypertensive therapy only at systolic blood pressure values of ≥ 160 mmHg.
  • The full effect of antihypertensives (blood pressure-lowering drugs) is usually achieved only within 2-6 weeks.
  • To increase patient compliance, antihypertensives with an assured effect over 24 hours should preferably be prescribed, requiring one dose per day hours. Treatment regimens should be as simple as possible. In addition, concomitant diseases, additional criteria, expected side effects and disturbances of well-being, and costs must be taken into account when choosing which substance to use.
  • Therapy of hypertension depending on concomitant diseases:
    • Albuminuria (≥ 300 mg/day or ≥ 300 mg/g creatinine): ACE-H (ACE inhibitors; angiotensin converting enzyme inhibitors, ACEi); if intolerant to ACE-H: ARB (angiotensin II receptor antagonists (angiotensin receptor blockers).
    • Heart failure: ACE inhibitors and angiotensin II receptor antagonists (AT1 receptor antagonists) – improve survival and have a beneficial effect on diabetic nephropathy; furthermore, they can reduce the risk of type 2 diabetes mellitus.
    • Pregnancy: dihydralazine and alpha-methyldopa; beta-blockers (eg, bisoprolol) and sustained-release nifedipineNote: ACE inhibitors and angiotensin II receptor antagonists (AT1-receptor antagonists) are contraindicated.
    • For other concomitant diseases, see below “Selection of antihypertensives according to concomitant diseases” (source ESH/ESC guideline).
  • Consider beta-blockers if there is specific evidence for their use, eg.B. Angina pectoris (“chest tightness”; sudden pain in the heart area), heart failure (heart failure), post-myocardial infarction (post-heart attack), atrial fibrillation (VHF), or younger women who are pregnant or planning a pregnancy
  • Hypertensive crisis (hypertensive emergency): align therapy primarily with potential complications or contraindications.
  • See also under “Further therapy”.

Further notes

  • Taking antihypertensives in the evening.
    • In nondippers (nocturnal blood pressure drop >0 and <10% of the daily mean on ambulatory blood pressure monitoring) or patients with severe hypertension reduces cardiovascular risk.
    • Achieved blood pressure values better on average when taken in the evening before bedtime?Note: The content and conduct of the HYGIA study are currently under review – the results should therefore be interpreted with great caution for the time being (as of 2020).
  • Taking antihypertensives in the evening reduced the risk of diabetes: when antihypertensives were taken in the evening, the incidence was 4.8% over six years, compared with 12.1% when they were taken in the morning. Risk reduction was most detectable with ACE inhibitors, AT-1 blockers, and beta blockers.
  • Note: Diastolic blood pressure increases in younger patients are a serious risk factor and indicate increased mortality.
  • First-line therapy for hypertension: the RAS inhibitors (= ACE inhibitors and AT1 antagonists) performed worse than thiazide diuretics but better than calcium antagonists and beta blockers with respect to cardiovascular morbidity. There were no differences in mortality.

Practice target pressures [ESC/ESH 2018: see Guidelines: 5]

Age group Practice SBP treatment ranges (mmHg)
Hypertension + diabetes + CKD + CHD + apoplexy/TIA
18-65 years Aim at ≤ 130, if tolerated target at ≤ 130, if tolerated target < 140-130, if tolerated target ≤ 130, if tolerated target at ≤ 130, if tolerated
Not < 120 Not < 120 Not < 120 Not < 120
65-79 yearsb Aim for 130 to 139, if tolerated target 130 to 139, if tolerated target 130 to 139, if tolerated target 130 to 139, if tolerated target 130 to 139, if tolerate
≥ 80 yearsb Aim for 130 to 139, if tolerated target 130 to 139, if tolerated target 130 to 139, if tolerated target 130 to 139, if tolerated target 130 to 139, if tolerated
Practice DBP treatment target range (mmHg). 70-79 70-79 70-79 70-79 70-79

Legend

  • SBP: systolic blood pressure
  • DBP: diastolic blood pressure
  • CKD (Chronic Kidney Disease): chronic kidney disease (includes diabetic and non-diabetic CKD).
  • ARelates to patients with prior stroke but not to BP target values immediately after acute stroke.
  • bTreatment decisions and BP target values may need to be modified in elderly patients who are frail and in need of assistance.

Current ESH/ESC guideline (European Society of Hypertension (ESH)/European Society of Cardiology (ESC); Barcelona, 2018)

  • Drug treatment of hypertension:
    • Start with a fixed 2-drug combination in the majority of patients.
    • Monotherapy (see below)should be considered only in patients with grade 1 hypertension and low cardiovascular risk* and in patients ≥ 80 years of age or even in frail patients in general.

* Wg cardiovascular risk see addendum below; “According to the ESH/ESC guideline, with knowledge of individual risk factors (RF; see below), the overall cardiovascular risk can be described”. Combination therapy in stages

Tablet(number) Level Medication
1 Initial therapy2-fold combination ACE-H or ARB + CA or diuretic.
1 2nd stage3-fold combination ACE-H or ARB + Ca + diuretic.
2 3rd stage3-fold combination+ spironolactone or other drug. Resistant hypertension Additional: spironolactone or other diuretic (e.g., chlortalidone: see below), α-blocker, or beta-blocker

Legend

  • ACE-H: ACE inhibitor
  • ARB: angiotensin II receptor antagonists (angiotensin receptor blockers).
  • CA: calcium antagonists (synonym: calcium channel blockers).

Five substance groups are available for 1st-line monotherapy:

  1. ACE inhibitors
  2. Angiotensin II receptor antagonists (angiotensin receptor blockers, ARBs)* .
  3. Sympatholytics – centrally acting substances, alpha receptor blockers, beta receptor blockers (beta blockers).
  4. Diuretics (diuretic drugs) – thiazides, loop diuretics, potassium-sparing diuretics.
  5. Calcium channel blockers (synonym: calcium antagonists).
  6. Vasodilators – hydralazine, minoxidil, etc. (not first-line therapy)

Selection of antihypertensives according to concomitant diseases (source ESH/ESC guideline 2013)

Concomitant diseases ACE inhibitors Angiotensin II receptor antagonists (ARBs)(synonym: sartans). Beta-blockers Diuretics Calcium channel blockers (synonym: calcium antagonists) Mineralocorticoid receptor antagonist (MRA).
Asymptomatic organ damage
Atherosclerosis + – – – +
Chronic kidney disease (renal insufficiency) + + – – –
Left ventricular hypertrophy + + – – +
Cardiovascular complication
Angina pectoris – – + – +
Aortic aneurysm – – + – –
Heart failure + + + + – +
Myocardial infarction, c. n. + + + – –
Peripheral arterial occlusive disease (pAVK) + – – – +
Terminal renal failure/proteinuria + +
Atrial fibrillation

  • Prevention (Th. consider)
  • ventricular HF control
 +- +- ++ — –
+(no dihydropyridines) 		or +
Other
African descent – – – + +
Albuminuria (microalbuminuria) + + – – –
Diabetes mellitus + + – – –
High cardiovascular risk + – + + –
Insult, c. n. + + + + +
Insult prevention + – – + –
Isolated syst. Hypertension(in the elderly) – – – + +
Coronary artery disease (CAD) + + + – +
Metabolic syndrome + + – – +
Pregnancy(or methyldopa) – – + – +

More hints

  • Beta-blockers are probably not the ideal class of agents for initial monotherapy of hypertensive patients, yet they continue to be among the first-line drugs in European guidelines in contrast to the UK NICE/BHS guidelines. Patients are less likely to suffer cardiovascular complications under calcium antagonists and renin-angiotensin system (RAS) inhibitors.
  • RAAS blockers are indicated in patients with heart failure, mild renal insufficiency, and for diabetics
  • RAAS blockers (ACE inhibitors and angiotensin II receptor antagonists (ARBs), synonym: sartans) are considered first-line therapy for diabetic patients with hypertension according to the American Diabetes Association, American Society of Hypertension, and International Society of Hypertension guidelines. An analysis of 19 controlled trials showed that RAAS blockers are no better than other antihypertensives at preventing cardiovascular-related deaths, strokes, and end-stage renal failure in diabetic patients.
  • A meta-analysis suggests that initial therapy using a calcium channel blocker produces better results than angiotensin II receptor antagonists (angiotensin receptor blockers, ARBs) in preventing myocardial infarction and apoplexy
  • ACE inhibitors, angiotensin II receptor antagonists, and the direct renin inhibitor aliskiren (dual RAS blockade) should not be combined because of increased renal dysfunction (especially in diabetics with pre-damaged kidneys)!
  • ACE inhibitors and calcium antagonists behave neutrally with regard to erectile function.
  • Potassium-sparing diuretics (dehydrating drugs): well suited for hypertension therapy in combination with a thiazide diuretic; the amiloride/HCT combination (at half dose each: 5-10 mg and 12.5-25 mg) showed neither worsening nor improvement of glucose tolerance in oGTT analysis.
  • Thiazide diuretics:
    • With thiazide diuretics as first-line therapy, hypertensive patients experience cardiovascular complications less frequently than with ACE inhibitors (15% fewer myocardial infarctions (heart attacks), apoplectic strokes (strokes), and hospitalizations for heart failure (heart failure) occurred than in patients on ACE inhibitors).
    • In a double-blind, randomized trial of patients with grade 1 hypertension, chlortalidone performed better than hydrochlorothiazide (HCT). The primary end point of the study was the difference in 24-hour ambulatory blood pressure (ABPM) measurements:
      • Reduction in mean systolic or diastolic blood pressure in ABPM after 12 weeks with chlorthalidone (-11.1/7.8 mmHg) but not with HCT (-6.0/4.2 mmHg).
      • Nocturnal systolic ABP significantly lower with chlorthalidone than with HCT (-10.2 versus -4.9 mmHg).

      However, an analysis of cohort studies finds more disadvantages with the thiazide analogue: there was a higher risk inb. of hypokalemia/potassium deficiency (+172%), but also of hyponatremia/sodium deficiency (+31%), acute renal failure (+37%), chronic kidney disease (+24%), and type 2 diabetes (+21%). In contrast, the risk of “abnormal weight gain” was lower with the thiazide analog compared with therapy with HCT (-27 percent); probably because of more effective diuresis.

  • Resistant hypertension: in addition to amiloride, the aldosterone antagonist spironolactone also achieved a good effect.
  • See at the end of this chapter: active substances in hypertension in children.

* Abandonment of the stepwise regimen!According to the current recommendations, antihypertensive treatment can be designed more flexibly than before, with the different groups of agents judged to be equivalent for initial therapy. Initially, combination therapy is recommended if it is foreseeable that normal values cannot be achieved with one antihypertensive agent alone. Other therapeutic agents (outside the above five groups of agents that are 1st-line monotherapy):

Alpha-1 blockers
  • Doxazosin
  • Terazosin
  • Urapidil
Antisympathotonics
  • Clonidine*
  • Methyldopa
Direct vasodilators
  • Dihydralazine
  • Minoxidil
Direct renin inhibitors
  • Aliskiren

* Not recommended as a monotherapeutic agent due to high rate of side effects.

Agents in hypertension in children

  • Primary hypertension – ACE inhibitors, beta blockers.
  • Renal (kidney-related) disease – ACE inhibitors.
  • Advanced renal failure (renal impairment) – calcium antagonists.
  • Z.n. Isthmusstenose (narrowing of the aorta) – ACE inhibitors, beta blockers.
  • Cortisone-induced hypertension – diuretics.

Further notes

  • In nearly 60% of previously refractory hypertensives, spironolactone brought elevated blood pressure under control.

Addendum

According to the ESH/ESC guideline, with knowledge of the individual risk factors (RF; see below), the overall cardiovascular risk can be described

Risk factors Blood pressure (mmHg)
Blood pressure high normalSBP 130-139DBP 85-89 Hypertension grade 1SBP 140-159SBP 90-99 Hypertension grade 2SBP 160-179DBP 100-109 Hypertension grade 3SBP ≥ 180 orDBP ≥ 110
No RF – Low risk Moderate risk High risk
1-2 RF Low risk Moderate risk Moderate to high risk High risk
> 2 RF Low to moderate risk Moderate to high risk High risk High risk
Organ damage (OD),chronic. Kidney disease (CKD),diabetes Moderate to high risk High risk High risk High to very high risk
Symptomatic cardiovascular disease (CVD),chronic kidney disease,diabetes with organ damage (OD) Very high risk Very high risk Very high risk Very high risk

Risk factors (RF) listed in the table include:

  • Men > 55 years
  • Women > 65 years
  • Smoking
  • Cardiovascular disease/cardiovascular disease (CVD) in the family.
  • Obesity (BMI ≥ 30 kg/m²).
  • Abdominal circumference ≥ 102 cm in men, ≥ 88 cm in women.
  • Dyslipidemia/dyslipidemia (total cholesterol > 190 mg/dl, LDL > 115 mg/dl).
  • Glucose intolerance (pathological glucose tolerance).
  • Chronic kidney disease (CKD)

End organ damage (ED) includes:

  • Left ventricular hypertrophy (LVH; enlargement of the left ventricle).
  • Atherosclerosis (arteriosclerosis, hardening of the arteries)
  • Incipient renal insufficiency (kidney weakness)

Cardiovascular disease includes:

  • Apoplexy (stroke)
  • Myocardial infarction (heart attack)
  • Heart failure (cardiac insufficiency)
  • Diabetic nephropathy (kidney disease)
  • Chronic renal insufficiency (kidney disease).
  • Peripheral vascular disease
  • Retinopathy (retinal disease)

Supplements (dietary supplements; vital substances)

Suitable dietary supplements should contain the following vital substances:

Note: The listed vital substances are not a substitute for drug therapy. Food supplements are intended to supplement the general diet in the particular life situation.