Hypertension (HTN) is defined as blood pressure ≥ 130/80 (ACC) or ≥ 140/90 (ESC) mmHg on two or more occasions (each one on a different clinic visit),1,2 or on one occasion when BP is severely elevated with signs of end-organ damage (LVH, retinopathy, chronic kidney disease).2 Both the systolic blood pressure (SBP) and diastolic blood pressure (DBP) are associated with increased coronary, HF, and stroke risk. The risk is likely greater with increments in SBP than equivalent increments in DBP particularly in patients >50 years; also, SBP is an independent predictor of cardiovascular events more consistently than DBP.
Importantly, in patients older than 65 years or patients with CAD, a J curve is seen for DBP and SBP: a high DBP (>90 mmHg) increases cardiovascular risk, but a low DBP (<70 mmHg) is also harmful and increases the risk of coronary events.3–7 A J curve also exists for SBP (<120 mmHg). Younger patients have a hockeystick curve, wherein the risk remains flat, unchanged, at low DBP <70 mmHg.
The systemic arteries stiffen with increasing age, which leads to a sharp increase in pressure during systole and a sharp decline in pres- sure during diastole and upon standing, along with extreme salt sensitivity. Thus, with age, SBP and pulse pressure increase while DBP decreases and significant lability occurs; in some of these patients, achieving SBP goal <130 mmHg is unlikely to be tolerated. Chronic severe HTN begets more stiffening, more severe HTN peaks, and more HTN lability.
Target BP <130/80 mmHg in patients <65 years, with or without CAD or diabetes.
Target BP 130-139/70-79 mmHg in patients ≥65 years, regardless of CAD, diabetes, HFpEF, HFrEF, CKD or prior stroke
Avoid medication-induced SBP<120 mmHg or DBP<70 mmHg in all patients. While SBP<120 mmHg is ideal, actively reducing BP to this level with drug therapy has increased cardiovascular events and death in most studies. Though not mentioned in the guidelines, the only group where SBP <120 mmHg does not preclude medications is the heavily afterload-dependent systolic HF (up to SBP of 90 mmHg).
*Regarding heart rate: A tight rate control <70 bpm has proven beneficial in chronic HFrEF, but not in stable CAD, angina, HTN, HFpEF, or AF (even AF with HFrEF).
ESC targets are more focused on age than cardiovascular risk profile, as younger patients are more likely to tolerate lower BP (less J curve) and have more longevity to benefit from this lower BP.
B. Rationale for the guidelines (SPRINT trial is the driver of ACC guidelines)
In the HOT trial, which randomized patients to multiple DBP goals (<90 vs. < 85 vs. < 80), a DBP of 82 mmHg was associated with the lowest risk of cardiovascular events, with a J curve beyond that point. Diabetic patients derived further benefit from DBP <80 mmHg, with no evidence of a J curve. A similar lack of J curve in diabetes was seen in the UKPDS study. This led to the recommendation of a lower BP goal in diabetic patients.7,12 However, later on, the ACCORD trial of diabetic patients compared aggressive HTN control, i.e., SBP <120 mmHg (mean 119 mHg), with a more conservative HTN control of 130–140 mmHg (mean 133 mmHg).13 The aggressive HTN control did not improve mortality or the overall cardiovascular outcomes. It reduced the already low stroke risk in these appropriately treated patients (from 0.5% per year to 0.3% per year), but increased the risk of side effects (dizziness, creatinine rise). Moreover, post-hoc analyses from INVEST trial suggest that SBP <130 mmHg in diabetic patients, or <140 mmHg in patients older than 80 does not improve cardiovascular outcomes.14,15
Concerning CKD, three trials and several meta-analyses addressed BP goals lower than 140/90 mmHg in CKD and did not find any statistically significant benefit on renal outcomes (AASK, MDRD, REIN-2 trials). In the AASK trial of African-American patients, BP reduction to a mean of 128/78 mmHg did not improve renal outcomes in comparison with BP of 141/85 mmHg; conversely, the specific use of ACE-I improved renal outcomes compared to amlodipine.
Concerning diastolic HF, the I-PRESERVE and PARAGON-HF trials have shown that ARB and sacubitril-ARB do not provide any benefit in patients with controlled HTN (BP 136/76 mmHg), indirectly suggesting that a SBP goal much lower than 140 mmHg may not be warranted in diastolic HF.20,21
In CAD patients with normal EF and SBP of 130–140 mmHg who receive aggressive statin and revascularization therapy, the addition of ACE-I did not improve outcomes (55% had prior MI) (PEACE trial).22
The SPRINT trial randomized non-diabetic patients with HTN and one additional cardiovascular risk factor to SBP goal <120 mmHg vs. <140 mmHg (28% of patients had CKD, 20% had coronary or vascular disease, and 28% were older than 75).23In contrast to the above data, intensive SBP control led to a reduction of total mortality, HF, and cardiac mortality. Note, however, that the mean SBP achieved in the intensive group was 121.4 mmHg, not <120 mmHg, and that office BP was measured in an unusual way (automatic unattended measurement) which resulted in lower office BP values. Also note that the absolute mortality reduction was small, 0.37% per year; side effects such as syncope and acute kidney injury were increased, and renal outcomes were not improved. Baseline HF, including symptomatic diastolic HF, was excluded. Patients with prior stroke were excluded and stroke risk was not reduced.
Concerning the very elderly ≥80 years of age, only one randomized trial addressed HTN in this age group and aimed for a target SBP of 150 mmHg (HYVET trial).24 Thus, for patients ≥80 years, ESC recommends initiation of therapy only when SBP≥160 mmHg. SBP of 150-160 mmHg may be accepted in elderly frail patients who develop orthostatic symptoms with drug therapy, even if <80 years of age.
Optimal BP may differ for various vital organs. Several post-hoc analyses have shown that the risk of stroke continues to decrement with SBP below 120 mmHg, but MI and acute renal events may become more frequent.13,25 The J curve between BP (SBP, and even more so DBP) and coronary events is particularly evident in patients with underlying CAD or LVH that impairs coronary flow autoregulation. Hence the importance of keeping DBP≥70 mmHg (ESC).2,25
III. Treatment of hypertension: timing, first-line drugs, compelling indications for specific drugs
A. BP 130-159/80-99
For BP in this range, lifestyle modifications are initiated: sodium < 2 g/d (ESC), exercise, and weight loss (10 mmHg SBP drop for every 20 pounds). Also, home BP is monitored, and office BP is rechecked in 1 month.1,2 If BP is still elevated, drug therapy is initiated. Elderly
patients with non-compliant arteries, CKD patients, and black patients are particularly susceptible to high sodium intake.
B. BP ≥ 160/100 mmHg on two readings
For BP in this range, drug therapy is initiated immediately.1
C. How and what to start
If BP ≥ 20/10 above goal (≥150/90), a combination therapy is initiated. Otherwise, or in frail patients, one medication may be initiated with a slow stepwise titration.
D. First-line drugs
In the absence of any compelling condition, any of the following three classes of agents can be used as a first-line therapy:
(a)Thiazide diuretic, (b)ACE-I or ARB, (c)CCB
In the ALLHAT trial, all three classes achieved similar reduction in mortality and MI. Thiazide diuretic was superior to ACE-I for stroke prevention and slightly superior to ACE-I and CCB for HF prevention.26
β-Blockers, especially atenolol given once daily, are less effective for HTN control, patient survival, and stroke/MI risk reduction and should not be used as a first-line therapy unless there is a compelling indication (HF, arrhythmias, angina).27–31
E. Follow-up
One or two drugs are started, then BP is rechecked 1 month later (oral agents work slowly and take ≥1 week to achieve the optimal effect).
If BP remains uncontrolled, the dosage of the drug(s) is optimized (the target being at least one-half of the maximal dose, which is usu- ally an optimal dose). Subsequently, another first-line drug is added, then a third first-line drug is added if needed. If HTN persists in spite of drug A, doubling the dose of A achieves 5× less BP reduction than adding another drug.32 In addition, maximizing the dose of one drug increases side effects more than it improves BP control; therefore, in general, once a moderate dose of drug A is achieved, adding a new drug is preferred to maximizing the dose of drug A.
If not the first drug used, a thiazide diuretic is typically added as a second agent whenever a combination is needed. This is because hypervolemia is a common mechanism of HTN, sometimes exacerbated by vasodilator-induced volume retention. In fact, thiazide diuretics are synergistic with other antihypertensive drugs.
Conversely, the ACCOMPLISH trial suggests that when combination therapy is needed, the combination of ACE-I and amlodipine is superior to the combination of ACE-I and hydrochlorothiazide, with 20% more reduction of death, MI, and stroke.33 This trial mainly recruited white patients without CKD, with a high prevalence of diabetes and CAD. The results may not apply to other thiazide diuretics (chlorthalidone), or to black patients or patients with obvious hypervolemia or CKD. Diuretic therapy remains an appropriate second agent or, at least, third agent.
Assess for signs of orthostatic hypotension or fatigue, which may occur with fast BP reduction and dictate a slower titration as well as general measures to prevent orthostatic hypotension.
F. Compelling indications for specific antihypertensive drugs
CAD: β-blocker, ACE-I/ARB; aldosterone antagonist for LV dysfunction post-MI.
HF: β-blocker (carvedilol, metoprolol XL, bisoprolol), ACE-I/ARB, aldosterone antagonist, diuretic. The combination hydralazine–nitrates is a second-line therapy for persistent HF or refractory HTN despite the preceding regimen (especially for black patients).
CKD, proteinuria, or microalbuminuria: ACE-I/ARB. Volume overload, sometimes occult, is common in CKD and explains the antihypertensive efficacy of diuretics.
Diabetes or metabolic syndrome without nephropathy: the ALLHAT and VALUE trials suggest the lack of difference between ACE-I/ARB, CCB, and thiazide diuretic in terms of cardiovascular outcomes in the diabetic subgroup. Thus, any of the three first-line therapies may be initiated in diabetic patients. Yet ACE-I/ARB and CCB may be preferred, as they do not worsen diabetes control (ESC); in fact, ACE-I/ ARB therapy potentially improves insulin sensitivity and reduces the risk of diabetes in patients with metabolic syndrome. β-Blockers and thiazide diuretics increase the risk of diabetes and may worsen the lipid profile.2 ACE-I or ARB therapy is preferred in microalbuminuria.
Black patients do not respond well to ACE-I/ARB monotherapy when used for HTN control. Black patients are salt-sensitive, as they have a highly active distal tubular sodium channel (high renal sodium retention) and, consequently, low renin and angiotensin levels. Thiazides and CCBs are the most effective drugs for HTN in this population; aldosterone antagonists are also effective, as they reduce the amount of tubular sodium channels. However, ACE-I therapy is very effective in black patients with CKD or HF and remains first-line therapy in this context. ACE-I therapy is also an effective antihypertensive therapy in black patients already receiving CCB or diuretic therapy, both of which activate the renin–angiotensin system.25 The AASK trial addressed ACE-Is in black patients with CKD and showed that ACE-Is are as effec- tive as amlodipine in controlling HTN, and more effective in long-term GFR preservation.17
Non-compliance with low salt diet or drug therapy. Salt non-compliance may be assessed by measuring the 24-hour urinary sodium, which correlates with dietary sodium intake (a high urinary sodium implies a high sodium intake).
Obesity increases renin–angiotensin activity, aldosterone synthesis, and thus extracellular volume. It also increases sympathetic activity. Every 10 kg of weight loss reduces BP by ~10 mmHg, and thus obesity itself is the most common cause of resistant HTN in morbidly obese patients, and weight loss is of critical importance in these patients.
NSAID, steroid therapy, cocaine, excessive alcohol use (>2 drinks/day for men or >1 drink/day for women).
Occult hypervolemia: patients with resistant hypertension often have subclinical hypervolemia, which may be due to excessive salt intake, inadequate diuretic therapy, or a compensatory response to vasodilator therapy.
White-coat HTN (ambulatory or home BP measurements are typically indicated in resistant HTN).
Inappropriately small cuff size leads to BP overestimation in obese patients.
Secondary HTN, particularly hyperaldosteronism (20% of resistant HTN), sleep apnea, and renal artery stenosis.
Pseudohypertension of the elderly. In this case, the peripheral arteries are stiff and calcified and can hardly be compressed by the BP cuff, even if the intra-arterial pressure is normal. This results in a falsely elevated BP measurement. Hints to pseudohypertension:
“Severe HTN” is present without any end-organ damage, and small doses of antihypertensive drugs induce dizziness.
Radial or brachial arteries remain palpable, albeit pulseless, upon cuff inflation beyond the audible systolic BP.
The definitive diagnosis is established by performing intra-arterial measurements.
B. If HTN is truly resistant, second-line drugs may be added
Spironolactone 25–50 mg daily or amiloride (a potassium-sparing diuretic) if GFR is ≥ 45 ml/min:2 the addition of a small dose of spironolactone has been found to be very effective in treating drug-resistant HTN and decreases BP by ~20/10 mmHg in black or white patients (PATHWAY-2 trial and ASCOT substudy).34,37,38 This may be particularly true in obese patients and in the frequently underdiagnosed primary hyperaldosteronism. The efficacy, however, appears independent of renin level or renin/aldosterone ratio.
Consider increasing the dose of hydrochlorothiazide (HCTZ) or switching to chlorthalidone or a loop diuretic for better control of hypervolemia, including subclinical hypervolemia. The efficacy of HCTZ, but not chlorthalidone or loop diuretics, is reduced in patients with GFR <30 ml/min. According to the ESC and ACC guidelines, increasing the diuretic dose and/or adding spironolactone is the immediate next step in resistant HTN management.1,2,27
β-Blockers, especially nebivolol or the α/β-blocker carvedilol.
α-Blockers. In the PATHWAY-2 trial of resistant HTN, bisoprolol and extended-release doxazosin (4-8 mg) were significantly effective in resistant HTN compared with placebo, but 50% less effective than spironolactone. Doxazosin was also effective in an ASCOT substudy.39
Central sympathomimetics (clonidine: α2-agonist).
Direct vasodilators (hydralazine).
The combination of ACE-I and ARB or renin inhibitor is neither useful nor recommended for patients with refractory HTN.
C. Consider the mechanism of the resistant HTN, and try to treat it accordingly35 (volume, vascular tone, catecholamine tone)
If the patient has CKD or volume overload on exam, consider increasing the diuretic therapy, or adding spironolactone if GFR ≥ 45 ml/min.
If the patient’s heart rate is >84 bpm, consider catecholamine excess as a cause of HTN or a result of diuretic and vasodilator therapy, and add or increase β-blocker therapy.
In the absence of the above, try to increase vasodilator therapy. Alternatively, or later on, increase diuretic therapy for occult hypervolemia.
In obese patients, hypervolemia (sometimes occult) is a key component of HTN and thus, weight loss, increasing diuretic therapy and adding spironolactone are critical measures. CPAP has not clearly improved HTN control and its effect is marginal at best (<7 mmHg reduction of SBP).40 In the large SAVE trial of patients with cardiovascular disease and moderate-to-severe obstructive sleep apnea, CPAP improved sleepiness and quality of life but did not reduce cardiovascular events.41 CPAP is more beneficial in HFrEF, where it improves LV function.
V. Secondary hypertension
Hypertension is primary (essential) in 90% and secondary in 10% of patients. Tables 23.1–23.4 list the features that suggest secondary HTN, the causes of secondary hypertension, and the workup of hypertension.
VI. Peripheral vs. central aortic pressure: therapeutic implications
The systolic pressure increases in the peripheral arteries as a result of the pressure waves that are reflected from arterial bifurcation points and small peripheral vessels and that add to the systolic wave. After the age of 60, the reflected waves not only amplify the peripheral arterial pressure but also return to the central aorta quickly as a result of heightened arterial stiffness; this is called increased pulse wave velocity. Thus, these waves reach the aortic root in late systole, which leads to augmentation of the central aortic pressure as well as the peripheral pressure.45–48 In fact, in the elderly, the systolic and pulse aortic pressures are increased because of: (1) ejection of the stroke volume into a stiff aorta; (2) increased pulse wave velocity that allows the reflected waves to return to the aorta in systole. In contrast, in the young patient, the reflected waves return to the central aorta in early diastole, which increases diastolic pressure and potentially coro- nary filling. The aortic systolic pressure is closer to the peripheral systolic pressure in the elderly than in the young.
Table 23.1Situations that warrant workup for secondary HTN.
Age <30 with systolic or diastolic HTN; age >60 with diastolic HTN
Resistant HTN (= resistant to three drugs at optimal doses, including a diuretic)
Acute HTN with DBP >110 mmHg, or malignant HTN
Laboratory findings (creatinine, K, urinalysis)
↓ K or metabolic alkalosis in the absence of diuretic therapy (→ RAS or hyperaldosteronism)
↑ Creatinine at baseline or with ACE-I (→ RAS or chronic renal failure)- Abnormal urinalysis (glomerular hematuria, proteinuria)
Unilateral small kidney (kidney size difference ≥1.5 cm suggests RAS)
Primary hyperaldosteronism (adrenal hyperplasia, or adrenal adenoma [Conn’s syndrome, 30% of cases]). This is a common cause of resistant HTN, including severe HTN >180/110 mmHg, and is seen in up to 5-10% of HTN and 20% of resistant HTN.34,42,43 K is often normal, as hypokalemia is only seen late in the disease process. Obesity and sleep apnea trigger a disproportionate increase in aldosterone (>renin), via both renin-dependent and independent pathways, sometimes mimicking primary hyperaldosteronism.
Renal artery stenosis (RAS): ~2% of HTN (uni- or bilateral RAS)
Chronic kidney disease (CKD): CKD is the cause of HTN in ~2% of patients (diabetic nephropathy, glomerulonephritis, or polycystic kidney disease), but is more commonly a complication of essential HTN
Sleep apnea is present in 25-50% of hypertensives and is an aggravating factor, not usually the cause of HTN. CPAP therapy has not clearly improved HTN control or cardiovascular events40,41
Cushing’s syndrome, including its most common cause, steroid therapy
Pheochromocytoma: permanent HTN with paroxysmal spikes: ~50%; permanent HTN with no paroxysms: ~45%; purely paroxysmal HTN: ~5%
Hypercalcemia
Hyper- and hypothyroidism. Hypothyroidism causes hypervolemia and a predominantly diastolic hypertension, while hyperthyroidism usually causes isolated systolic hypertension
Coarctation of the aorta
These causes, especially RAS, generally lead to elevations of both systolic and diastolic BP, as both hypervolemia and vasoconstriction occur. Isolated systolic HTN is unlikely to be secondary to RAS.
Creatinine, potassium, calcium; urinalysis (signs of glomerulopathy [proteinuria, hematuria])
Look for end-organ damage
ECG (± echo when ECG is abnormal or HF is present): LVH voltage on ECG correlates with the left ventricular mass and with the risk of developing HF. LBBB or strain ST–T changes correlate with worse LVH and a higher risk of LV dysfunction.
LVH voltage may regress with therapy. This correlates with a reduction of HF risk44
Echo may show diastolic dysfunction, which precedes LVH and is more prevalent than LVH
Urinalysis
Proteinuria hints at glomerular damage causing HTN or secondary to HTN
Microalbuminuria (ratio of urinary albumin/creatinine on a spot urine): hints at early glomerular damage from diabetes or HTN
Decreasing albuminuria is a treatment goal and is associated with renoprotection and improved cardiovascular outcomes
Table 23.4Specific workup when secondary HTN is suspected.
Doppler ultrasound of the renal arteries (or MRA or renal perfusion nuclear scan)
Aldosterone serum level and plasma renin activity (PRA). If aldosterone/PRA ratio >20, with aldosterone >6-10 ng/dl, primary hyperaldosteronism is suggested.a ACE inhibitors and β-blockers affect this testing, but not enough to warrant drug interruption (the former ↑ PRA, the latter ↓PRA).7 Aldosterone antagonists should, however, be stopped for 4 weeks before testing
Serum-free metanephrines and normetanephrines, and 24-hour urinary metanephrines and normetanephrines (these two tests have the best yield for the diagnosis of pheochromocytoma)
TSH
Consider sleep study in the appropriate context
a A primary elevation in aldosterone level leads to a feedback decrease in PRA. Aldosterone is expressed in ng/dl while PRA is expressed in ng/ml/h.
β-Blockers, when used for hypertension, reduce the peripheral arterial pressure but less so the central arterial pressure (pseudo-anti- hypertensive effect).46–48 This is because β-blockers exert less effect on arterial remodeling and stiffness than calcium channel blockers, ACE inhibitors, or diuretics. Furthermore, a reduction in heart rate prolongs the cardiac ejection phase and may allow the backward wave reflec- tion to reach the central systolic pressure at its peak rather than late. Also, a reduction in heart rate may lead to the ejection of a higher stroke volume into a poorly compliant aorta. Consequently, the central aortic pressure may increase with heart rate reduction.45–47 Vasodilators (ACE-Is, CCBs), diuretics, and aldosterone antagonists improve arterial compliance and delay reflected waves. Thus, these agents reduce peripheral pressure, but even more the central aortic pressure, and supplement diastolic coronary filling.
VII. First-line antihypertensive drugs
A. ACE-Is and ARBs
1. Mechanism of benefit in CKD
ACE-Is/ARBs are the preferred agents in CKD, including advanced CKD. ACE-I/ARBs vasodilate the efferent renal arterioles more than the afferent arterioles, which may reduce GFR and increase creatinine acutely. However, over the long term, the kidneys are protected from the high glomerular pressure that leads to scarring (Figure 23.1). ACE-Is/ARBs reduce the rate of decline of renal function and the incidence of end-stage renal disease by ~20–50% as compared to other antihypertensive agents, particularly CCBs, despite comparable BP reduction (AASK and IDNT trials).16,17,49 This benefit is achieved with optimal to high doses and is accentuated in patients with proteinuria >1 g/d; in fact, ACE-Is/ARBs more effectively reduce proteinuria than any other agent.17,49 The worse the proteinuria, the more striking the benefit. The benefit continues to be seen in advanced renal failure (up to a creatinine of 5 mg/dl).46 It is also seen in black patients with CKD.17 ACE-Is may not be more nephroprotective than CCBs or thiazide diuretics in patients with early nephropathy and no proteinuria (ALLHAT study).26,51
2. Contraindications and monitoring
ACE-I/ARB initiation is contraindicated in acute kidney injury and in bilateral RAS, in which cases kidney perfusion is dependent on angiotensin II.
Figure 23.1Effect of ACE-I/ARB on the renal flow and renal function. Angiotensin II constricts the afferent and more so, the efferent arteriole, which is smaller. The net result of ACE-I/ARB is efferent arteriolar vasodilatation.
In HTN and diabetes, there is glomerular hyperfiltration through the afferent arteriole with elevated glomerular pressure (Pr), which is damaging to the nephron over the long term. ACE-I reduces Pr without a dramatic effect on GFR and protects the nephron.
In severe HF, the mechanism of renal benefit is indirect as Pr is already low (≠HTN).Background- In severe HF, renal blood flow in the afferent arteriole (RBF) may be severely reduced, up to 5 times, yet GFR is minimally reduced. This is related to significant efferent vasoconstriction, which diverts a bigger proportion of the afferent flow into the glomerulus (=high filtered fraction>50%, the normal being ~20%). Thus, efferent artery vasodilation by ACE-I/ARB may particularly harm the renal function. Yet, studies show that HF patients whose GFR declines with ACE-I/ARB derive the largest benefit from it, as those patients have the lowest cardiac output.
ACE-I/ARB has indirect renal benefits: (i) increased cardiac output increases RBF, by up to 60% in one study,52 (ii) at high concentrations, angiotensin II constricts the afferent artery, thus paradoxically reducing GFR; vasodilatation of the clamped afferent artery by ACE-I/ARB overcomes the harm from efferent vasodilatation, (iii) sacubitril-valsartan increases natriuretic peptides which have direct afferent dilatation (>efferent dilatation), further increasing RBF compared with ACE-I/ARB.
Creatinine is checked 7–14 days after starting ACE-I/ARB. An increase in creatinine of up to 30% is tolerated, as these agents are beneficial over the long term.53 An acute increase ≥30% is associated with worse long-term renal outcomes compared to no acute increase (in most studies).54,55 Yet even in the latter patients, the worsening of renal function may rather be a marker of adverse renal hemodynamics than harm from ACE-I, and continued ACE-I therapy seems to reduce long-term renal and cardiac events compared to no ACE-I therapy.55,56 This has also been shown in HFrEF.57 That said, it is prudent to withhold ACE-I when creatinine rises ≥30% (or ≥50% in HFrEF). The following three conditions most commonly explain a creatinine rise ≥30%: hypovolemia (overdiuresis), severe HF, nephropathy with GFR dependence on the angiotensin system. While less common, bilateral RAS is also considered. Thus, if creatinine rises ≥30%:
The patient is assessed for hypovolemia (orthostatic hypotension). A diuretic that was recently initiated may be withheld.
In the absence of obvious hypovolemia or recent diuretic initiation, ACE-I is discontinued at least temporarily, with an attempt to resume it later, at a lower dose, after ruling out RAS.
3. Differences between ACE-I and ARB
Renin is released by the juxtaglomerular apparatus in response to low BP or low distal tubular Na. Renin converts angiotensinogen to angiotensin I, which is then converted to the active angiotensin II by the angiotensin converting enzyme, secreted by the vascular endothelium, especially in the lungs. Angiotensin II stimulates the adrenal secretion of aldosterone and acts as a vasoconstrictor. ACE-Is prevent the conversion of angiotensin I to the active angiotensin II and prevent the degradation of a vasodilator, bradykinin.
ARBs block angiotensin-II type 1 receptor, which is the receptor involved in salt retention, vasoconstriction, tissue growth, and deleterious vascular and cardiac remodeling.
The main advantage of ARB over ACE-I is the lower frequency of angioedema and the absence of cough (cough being a side effect of ACE-I-triggered bradykinin release, occurring in 10% of patients). A cross-reactive angioedema rarely occurs with ARB, in <5% of ACE-I reactive patients; ACE-I- related angioedema does not preclude the use of ARB in patients with a strong compelling indication, such as HF or CKD (close monitoring is warranted).
4. The combination of ACE-I and ARB should be avoided1,2,16
The combination ACE-I/ARB has not been shown to improve cardiovascular outcomes or HTN control, with a worsening of major renal outcomes (ONTARGET trial).53 In HF, the combination ACE-I–aldosterone antagonist is preferred to ACE-I–ARB, as the former improves survival, whereas the latter improves HF hospitalization without any effect on mortality.
B. CCBs
1. Types of CCBs and mechanisms of action
Dihydropyridines (DHPs; e.g., nifedipine, amlodipine, felodipine) are vasodilators that have minimal to no negative chronotropic and ino- tropic effect. Felodipine has the least negative inotropic effect, and both amlodipine and felodipine have been studied in systolic HF and shown to be safe. Amlodipine is a very long-acting DHP, with sustained 24-hour BP reduction, which explains its clinical efficacy.
Non-DHPs (diltiazem and verapamil) have negative inotropic and chronotropic effects, particularly prominent with verapamil. They also have a vasodilatory effect, slightly less prominent than that of DHPs.
A slight diuretic effect may be seen early on, via renal vasodilatation. Both DHPs and non-DHPs are similarly effective in HTN. The combination of a DHP and a non-DHP is not generally used. This combination, however, may be used in patients with refractory HTN who cannot receive β-blockers because of asthma. If a patient can receive a β-blocker, DHP is better combined with a β-blocker than with a non-DHP.
2. Contraindications
Non-DHPs are contraindicated in systolic HF, significant sinus bradyarrhythmia (rate <55–60 bpm) or second- or third-degree AV block. Non- DHPs are avoided in combination with β-blockers, except for the rate control of AF, where the combination β-blocker–diltiazem may be used.
Long-acting DHPs are not contraindicated in compensated HF or in bradyarrhythmias. In general, the short-acting nifedipine is avoided in CAD as it leads to reflex tachycardia and subsequent myocardial ischemia, even though its direct effect is slightly rate slowing.
3. Other side effects
Headache, edema (mainly with DHPs), constipation (mainly with verapamil). Peripheral edema is related to CCB’s preferential precapillary dilatation, with less postcapillary venous dilatation, which increases the capillary hydrostatic pressure. It is dose dependent (5% with amlodipine 5 mg, 25% with 10 mg) and not responsive to diuretics unless a component of hypervolemia is present. It may be reduced with ACE-I/ARB, which has superior venodilating capacity. It is worse in obese or immobilized patients.
C. Diuretics (thiazide diuretics, loop diuretics, aldosterone antagonists)
Thiazide diuretics are weak diuretics that block sodium reabsorption in the distal tubule (Na-Cl transporter), where ~3–5% of sodium is reabsorbed. Loop diuretics block sodium reabsorption in the ascending loop of Henle, where ~25% of sodium is reabsorbed. Thiazide diuretics are the typical diuretics used in HTN. They are longer acting than loop diuretics, and induce less hypovolemia and hypokalemia than loop diuretics, but more hyponatremia. Chronic diuretic administration also produces mild vasodilation and improves arterial compliance by inhibiting sodium entry into smooth muscle cells.
Chlorthalidone is longer acting than hydrocholorothiazide (HCTZ), provides greater 24-hour BP reduction, and is possibly associated with better outcomes.59 At the recommended dose of 12.5–25 mg, HCTZ reduces 24-hour ambulatory BP less than chlorthalidone 12.5–25 mg and other antihypertensives (ACE-I, CCBs), even though office BP may be similarly reduced.60 HCTZ 50 mg achieves optimal 24-hour BP reduction and may be reserved for patients with refractory HTN. While more efficacious, chlorthalidone may be associated with a higher early risk of acute kidney injury and hypokalemia warranting close monitoring. Indapamide is a thiazide-like diuretic with a more pro- nounced vasodilatory effect.
Side effects of thiazides:
Hypovolemia, hypokalemia, hypomagnesemia: mainly with HCTZ doses >25 mg/day or chlorthalidone. K drops by ~0.4 mEq/L with 25 mg of HCTZ, and ~0.7 mEq/L with 50 mg of HCTZ. Hypokalemia explains why thiazide diuretics were associated with an increased risk of sudden death in old studies. Potassium level should be closely monitored after thiazide initiation. The combination of thiazide and a potassium-sparing diuretic counteracts the increased risk of sudden death.61 Creatinine and potassium are checked 7 days after diuretic initiation.
Hyponatremia may be due to hypovolemia, but may also be due to the fact that the target of thiazide action, the distal tubule, is the diluting segment of the nephron (while the loop of Henle is the concentrating segment); thus, urine is more concentrated when thiazides are used, which gives a “SIADH-like” picture, especially in the elderly.
Hypercalcemia (whereas loop diuretics have a direct calcium-reducing effect).
Other dose-dependent metabolic side effects: hyperuricemia, hyperglycemia (mostly related to hypokalemia and attenuated with K sparing diuretics), increased LDL.
Dose of chlorthalidone: 12.5–25.0 mg/day. Dose of HCTZ: 25 mg/day (~2:1 equivalence to chlorthalidone). HCTZ may be increased to 50 mg/day in resistant HTN. The 12.5 mg HCTZ dose has limited efficacy, except when combined with a potassium-sparing diuretic.
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