A. Definition of global and regional viability; viability tests

Viability implies that a dysfunctional myocardium is still metabolically active but is hibernating from persistent severe ischemia; or stunned after a transient episode of severe ischemia, even if perfusion is re-established. Those processes are called hibernation and stunning, respectively. A dysfunctional myocardial area is considered viable if:^58–62

• The regional dysfunction significantly improves after revascularization by at least one point (from akinesis to hypokinesis, or from hypoki- nesis to normal). This is called regional viability.
  

  or

  
  
• The overall EF significantly improves (>5%). This is called global viability .

Thus, viability can only be confirmed in retrospect, after revascularization is performed. In general, 70% of patients with chronic ischemic LV dysfunction have significant improvement in LV function after revascularization (81% in STICH trial). Four imaging modalities have been used to assess viability:

• Thallium myocardial uptake at rest and at 4 hours and 24 hours post-rest injection (rest-redistribution imaging). Also, technetium uptake at rest (or after nitrates administration) may be used to assess viability. An uptake ≥ 50% at rest or after thallium redistribution implies that the regional myocardium is viable.⁶³ Also, an absolute change of 12% during redistribution implies regional viability even if the uptake remains < 50%.^55,64
  
• Low-dose dobutamine echocardiography evaluates for an improvement of myocardial contraction in response to low doses of dobu- tamine (<10 mcg/kg/min): from dyskinesis or akinesis to hypokinesis, or hypokinesis to normal contraction (a change from dyskinesis to akinesis is not considered improvement). This is called myocardial contractile reserve. A decline in myocardial contraction at subsequent higher doses reflects ischemia; this biphasic response is highly predictive of myocardial recovery and viability. Conversely, a uniphasic response (progressive increment of contractility at higher doses of dobutamine) suggests that the coronary flow is not compromised and thus, revascularization cannot provide any benefit; myocardial dysfunction is non-ischemic, or ischemic with subendocardial scarring that persisted after blood flow was re-established. The absence of any response may imply non-viability; yet, 25–30% of viable segments do not augment with dobutamine. Nuclear studies are more sensitive for viability, albeit less specific.
  
• PET scan assesses metabolic uptake of a glucose analog tracer (metabolic viability). It can also assess perfusion with N¹³ or Rb⁸² tracer. A mismatch between a low perfusion and a high metabolic uptake implies viability. A reduction in both perfusion and metabolic uptake implies irreversible injury. PET has the highest sensitivity (~90%) but the lowest specificity (~58%) for viability assessment.
  
• Cardiac MRI: late myocardial hyperenhancement 10 minutes after gadolinium injection is a sign of scarring and highly predicts non-viability when it involves > 50% of the transmural myocardial thickness. Transmural involvement <25% highly predicts viability, while 25-50% involvement is less specific but usually viable.
  

  Also, several ECG, echocardiographic, and angiographic features are helpful, to a limited extent, in assessing viability:

1. The lack of Q waves implies less scar and necrosis and strongly predicts recovery.^65,66 However, the presence of Q waves does not rule out viability, as Q waves may be seen with a hibernating myocardium.⁶⁵
   
2. As compared to akinesis, hypokinesis does not necessarily imply a higher likelihood of recovery with revascularization. After revascu- larization, akinesis and dyskinesis frequently improve, while occasionally hypokinesis does not improve. The hypokinetic wall may be tethered by adjacent akinetic walls or extensive subendocardial necrosis and scarring.⁶⁷ Yet, hypokinesis implies the presence of viable tissue, and thus revascularization of a hypokinetic wall may prevent further deterioration of LV function and is more readily performed.
   
3. A thin and bright myocardium ≤ 5.5 mm on echo may imply a scarred, non-viable myocardium. Yet, if it is not extensive, it does not preclude a revascularization benefit to the surrounding walls. Also, one study showed that 18% of thin myocardial regions have a limited scar burden by MRI and recover myocardial thickness and contractility with revascularization, with Q-wave disappearance; thus, a thin myocardium does not preclude revascularization.⁶⁸
   
4. Severe LV dilatation (end-diastolic volume ≥ twice normal, which often corresponds to a diastolic diameter ≥ 70 mm) usually implies extensive scarring and negative remodeling that would not be reversed with revascularization and predicts a poor prognosis after revascularization.⁶⁹
   
5. When a dysfunctional segment is supplied by an occluded artery, good collateral flow predicts myocardial recovery.⁷⁰ In one study, the presence of grade 2 or 3 collaterals on coronary angiography, i.e., good collaterals that reconstitute partially or fully the epicardial vessel, predicted regional and global myocardial recovery in 81% of the cases.⁷¹

B. Variations in the definition of global viability

In the STICH trial, global LV viability has been defined as viability of ≥ 65% of all myocardial segments (11 out of 17 segments), counting both dysfunctional segments and segments with normal contractility.^55,72,73 Conversely, most studies have defined global viability with a focus on the dysfunctional segments. When the viable dysfunctional segments constitute ≥ 25% of the LV, global viability is considered present and a global improvement of EF is expected (e.g., ≥ 4 dysfunctional myocardial segments are viable).

C. Limitations of viability testing

Viability testing has the following limitations:

• Viability tests have positive and negative predictive values of ~75–80%, for both regional and global viability. This is particularly the case with thallium or technetium nuclear viability testing (sensitivity ~80%, specificity ~60%) and dobutamine echocardiography (sensitivity 65%, specificity 85%), which were used in the STICH trial.^58,75 The assessment of the extent of transmural scarring by MRI is more valid (sensitivity and negative predictive value 90%, positive predictive value 60-80%, depending on the transmural cutoff used).
  
• The definition is not uniform. In a patient with anteroapical infarction, regional viability addresses the viability of the anteroapical segments to decide whether LAD revascularization is beneficial; conversely, global viability addresses whether there are ≥4 dysfunctional segments that are viable.
  
• Even without any viability and any contractile and EF improvement, revascularization improves symptom status, HF, and mortality.⁷⁶ Revascularization may improve LV remodeling, prevent further deterioration of LV function and further MI, preserve infarct border zone integrity, and reduce arrhythmogenesis.
  
• A STICH analysis has shown that patients with the most severe ischemic cardiomyopathy derive the most benefit from CABG (up to 29% mortality reduction); this was defined as a combination of 2 of the following 3 factors: 3-vessel CAD, EF<27%, dilated LV with end-systolic volume index >79 ml/m². ^56,57 This extends to many patients with limited viability, as their cardiomyopathy is more severe than the viable group.

D. Role of ischemic testing; difference between ischemia and viability

The concepts of ischemia and viability are different, and ischemia is a stronger marker of prognosis and functional myocardial recovery than the mere presence of viability.^77–80 On nuclear imaging, viability implies that at rest, the dysfunctional territory uptakes significant nuclear agent. Ischemia implies that at stress, the nuclear defect of the dysfunctional territory is significantly more intense or more extensive than at rest; or significant ST-segment deviations occur. An ischemic territory is viable; conversely, a viable territory may not be ischemic. The lack of ischemia means that the myocardial territory is already receiving enough blood supply, and should be able to recover its function without revascularization if truly viable, which questions the value of revascularization (Figure 4.4).⁸¹

Nonetheless, the assessment of ischemia in LV dysfunction with significant baseline defects is cumbersome, as fixed wall motion abnormality on echo or fixed defects on nuclear imaging may very well represent severe ischemia with hibernation, particularly if the nuclear uptake is ≥ 50%, or no Q wave is present, or the patient has angina or ST deviation; up to 75% of these defects reverse with revascularization.^82,83 This lessens the predictive value of ischemic testing in LV dysfunction; in STICH stress substudy, ischemia did not predict prognosis or response to CABG.⁸⁴

E. Indications for revascularization in ischemic LV dysfunction

Based on the STICH trial, global revascularization is mildly useful in chronic ischemic cardiomyopathy regardless of viability and of eventual EF improvement. Viability may be used to guide the specifics of regional revascularization, particularly with PCI, but not to exclude the overall revascularization (e.g., may not revascularize one non-viable territory, such as RCA CTO). On the other hand, regardless of viability, revascularization may not be beneficial in patients with a recent STEMI or Q-wave infarct that is 1–28 days old and responsible for the low EF (those patients were excluded from the STICH trial). As shown in the OAT trial, patients with acute MI who do not receive culprit artery reperfusion in the first 24 hours of presentation, and have an akinetic wall, a totally occluded culprit artery, and no residual angina, do not benefit from revascularization.⁸⁵

A. ACE-I or ARB^*

1. ACE-Is and ARBs increase cardiac output, reduce LV remodeling, and improve EF. They reduce mortality by ~20% and reduce HF hospi- talizations by ~30%.^86–89
   
2. ARB is an alternative to ACE-I when cough or angioedema occurs with ACE-I. There is a small cross-risk of angioedema with ARB (<5%), and thus extreme caution is advised when substituting ARB for ACE-I in a patient who had angioedema with ACE-I; this is not a contrain- dication to ARB (CHARM-Alternative). The main ARBs studied in HF are candesartan and valsartan.^90–93 When used as an alternative to ACE-I therapy, ARB therapy reduces mortality in systolic HF (CHARM alternative trial and ValHeFT substudy).
   
3. Avoid or be cautious in cases of:
   
   
   
   • Hypotension with SBP < 90 mmHg or with symptoms of low output (dizzy, obtunded, oliguric). A low SBP of 90 mmHg may be well tolerated in HF because it helps unload the LV; dizziness upon ACE-I initiation often improves with time.
     
   • Elevation of creatinine of over 50% within 1–2 weeks of ACE-I/ARB initiation. In advanced HF, the worsening of renal function may be related to the low BP/low kidney perfusion state aggravated by ACE-I initiation, which impairs renal autoregulation (Figure 23.1). Yet, a rise in creatinine of over 25% and/or over 0.3 mg/dl early after initiation of ACE-I is not associated with a loss of benefit with continued ACE-I therapy, and renal function largely recovers on follow-up; in fact, in 2 studies, patients with early worsening of renal function appeared to derive the largest benefit from continued ACE-I therapy, partly because renal deterioration is a reflection of severe HF and baseline renal hypoperfusion.^94,95 If creatinine rises ≥ 50% or ≥ 0.5 mg/dl, reduce other BP-lowering drugs, ensure the patient is not using NSAIDs, assess for excessive diuresis and consider reducing the diuretic dose. Along with that, hold the ACE-I for a few days to allow renal recovery then restart half the initial dose. In fact, one study suggests that even ACE-I-induced creatinine elevations ≥ 50% are not associated with increased mortality.⁹⁴ Only if creatinine rises ≥ 100% ACE-I is stopped.⁸
     

     ACE-I/ARB is avoided in acute kidney injury, as it may acutely worsen renal perfusion. Short of that, it may be initiated or uptitrated acutely in decompensated HF, wherein it improves diuretic response and possibly even renal perfusion.^96,97

     
     
   • K >5 mEq/l at baseline or >5.5 mEq/l with therapy. If K rises to 5.5-5.9 upon ACE-I initiation without a severe rise in creatinine, discontinue potassium supplements, then, if needed, reduce the dose of the aldosterone antagonist and the ACE-I.

4. Attempt titration every 5 days to the optimal dose used in randomized trials, which is approximately one-half of the maximal dose. In comparison with the low dose, the intermediate or high dose further reduces HF hospitalizations by 24% but does not significantly improve mortality (ATLAS trial, where lisinopril 2.5–5 mg was compared with 30–40 mg). Thus, even if a high dose is not reached, it is expected that the low dose will lead to similar benefit on mortality.⁹⁹
   

   Examples of doses:

   
   
   
   
   • Lisinopril (ACE-I): start 5 mg Qday and try to reach 20–40 mg Qday. It is renally eliminated and the effect is doubled in patients with renal failure, wherein the starting dose may be 2.5 mg Qday.
     
   • Enalapril (ACE-I): start 2.5 mg BID and reach 10 mg BID (also renally eliminated).
     
   • Candesartan (ARB): 4 mg Qday; goal, 32 mg Qday (biliary elimination).
     
   • Valsartan (ARB): 40 mg BID; goal, 160 mg BID (biliary elimination).
   
   
5. Significant, sometimes drastic, improvement of exercise duration (20–50%) and functional class is seen with ACE-I.⁹⁰ Symptomatic improvement may occur within 48 hours of ACE-I initiation but is generally delayed weeks to months. Abrupt withdrawal of ACE-I can lead to clinical deterioration and should be avoided, except in decompensated HF with low output and hypotension, or severe deterioration of renal function.
   
6. In CHARM-Added trial, the addition of ARB to ACE-I in class II–III HF already receiving a β-blocker reduced both HF hospitalizations and cardiovascular death in comparison to ACE-I alone, without an effect on total mortality.⁹¹ Yet in patients receiving ACE-I, preference should be given to adding an aldosterone antagonist rather than ARB, as an aldosterone antagonist is associated with a larger reduction of HF hospitalizations and cardiovascular death, and a striking reduction of total mortality. Because the triple combination ACE-I/ARB/aldosterone antagonist is contraindicated (risk of hyperkalemia), the role of the ARB/ACE-I combination is limited in HF.

B. β -Blockers

1. β-Blockers used to be contraindicated in HF, and in fact they may worsen HF initially, especially in the first 2–3 weeks after therapy initiation and/or up-titration. This is due to their initial negative inotropic effect. But when used over the long term, β-blockers:
   
   
   
   • Improve contractility, EF (by 5–15%), and HF symptoms, and reduce mortality by 35–60% and HF hospitalizations by 40%.^100–102
     
   • Reverse the deleterious and apoptotic effects of catecholamines on the heart. The reduction in energy demands reduces apoptosis.
     
   • Reverse remodeling and reduce cardiac chamber size by reducing LV wall stress.
     
   • Prevent arrhythmias; and reduce heart rate, which, by itself, is beneficial in HFrEF
   
   
2. The three agents that have been shown to improve survival and outcomes in HF are:
   
   
   
   1. Long-acting metoprolol (metoprolol succinate): metoprolol is a selective β₁-blocker, but loses selectivity with high doses > 100 mg. Long-acting metoprolol has a more sustained effect than metoprolol tartrate; this limits the daily fluctuations of the β-blocker effect and the β-blocker withdrawal effect that occurs between the doses of metoprolol tartrate.
      
      
      
      • Dose: Start 12.5 or 25 mg Qday and titrate to 200 mg Qday
      
      
   2. Carvedilol: carvedilol is a non-selective β₁-blocker, β₂-blocker, and α₁-blocker (vasodilatory effect), with additional antioxidant proper- ties. Despite its α-blocker effect, it is as well tolerated as metoprolol in patients with borderline BP. The non-selective blockade of adrenergic receptors is advantageous. While metoprolol upregulates β-receptor density towards normal levels, carvedilol maintains a low density of these receptors. Moreover, selective β₁-blockade with metoprolol may enhance the ino- and chronotropic response to β₂-adrenergic stimulation, an untoward effect.¹⁰³ Thus, carvedilol is a more potent antiadrenergic agent than metoprolol, as mani- fested by the more significant blunting of heart rate response.¹⁰⁴ With its more comprehensive blockade of all adrenergic receptors, carvedilol improves myocardial function, EF, and cardiac hemodynamics such as stroke volume, PA pressure, and PCWP, more than other β-blockers and reverses remodeling more effectively.^103,104 Because of the α-blocking effect, carvedilol acts as a moderate vasodilator acutely, but with long-term treatment the vasodilator activity is no longer prominent, as tolerance to the α-blocking effect occurs. This transient α-blocker effect is useful, as it allows an early improvement in stroke volume and LV remodeling before the long-term effect of β-blockade kicks in.¹⁰⁵
      
      
      
      • Dose: start 3.125 mg BID; titrate to the goal of 25 mg BID if patient’s weight < 85 kg, 50 mg BID if weight > 85 kg.
        
      • A long-acting formulation of carvedilol, Coreg CR, is available. It is given once daily. Coreg CR 10 mg is equivalent to carvedilol 3.125 mg BID. Start Coreg CR 10 mg Qday and titrate up to 80 mg Qday.
      
      
   3. Bisoprolol, a selective β₁-blocker. Start 1.25 mg Qday; goal, 10 mg Qday.
   
   
3. Keys to β-blocker therapy:
   
   
   
   1. Start “low and slow.” Patients must be euvolemic and stable. During hospitalization for HF, low-dose β-blockade is started before discharge, after the patient has stabilized.
      
   2. Contraindications: overt HF, SBP < 90 mmHg or symptomatic hypotension, bradyarrhythmia (bradycardia < 55 bpm, any second- or third-degree AV block, PR > 0.24 s), bronchospasm.
      
   3. Double the dose every 2 weeks and monitor for worsening of dyspnea, edema, weight gain, bradycardia, and hypotension. If the patient is off the β-blocker for over 1 week for any reason, or after an episode of cardiogenic shock, restart at the lowest dose and re-titrate.
      
   4. If edema increases or HF develops within a week of titration, increase the diuretic dose; if this is not effective, decrease the β-blocker dose and titrate more slowly.
      

      In case of severe fatigue, decrease the dose of β-blocker (and sometimes the diuretic) or titrate more slowly. Most often, fatigue resolves spontaneously in a few weeks.

      
      

      In case of bradycardia (symptomatic bradycardia < 55 bpm, asymptomatic bradycardia < 50 bpm, or AV block), try to decrease the dosage of digoxin and amiodarone first, then, if needed, reduce the β-blocker.

      
      
   5. It is not necessary to reach an optimal dose of an ACE-I before starting a β-blocker. In fact, it is preferred to start low doses of both and titrate up in an alternating fashion. The combination of a low β-blocker dose and a low ACE-I dose produces a greater symptomatic improvement and mortality reduction than an increase in the ACE-I dose.
      

      Order of therapy: start low-dose ACE-I (lisinopril ~5 mg), then start low-dose β-blocker and titrate β-blocker every 2 weeks. Spironolactone then SGLT2 inhibitor may be sequentially initiated while the patient is still on small doses of ACE-I and β-blocker, before full uptitration of the latter. After reaching the maximally tolerated dose of β-blocker, and if it is possible from the blood pressure and renal standpoints, up-titrate the ACE-I at 1-week intervals.

      
      
   6. If the patient has been on a β-blocker for more than a few weeks and is hospitalized with HF decompensation, the β-blocker should not generally be withheld. In low-output HF decompensation with borderline BP, the β-blocker dosage may be reduced. In full-blown shock, or when inotropes are considered, the β-blocker is withheld. Discontinuation of β-blocker therapy is independently associated with increased short- and long- term mortality and should be avoided if possible.¹⁰⁹ If interrupted, β-blocker is restarted at the lowest dose after the patient stabilizes, before hospital discharge, then re-titrated.
      
   7. How about EF 40-50%? Major β-blockers trials mainly included patients with EF<35-40%. Yet, two small studies that included any EF and a meta-analysis of β-blockers in HF showed that EF 40-50% derives the same mortality benefit as lower EF.¹¹⁰
      

      How about AF? Although no specific benefit was seen in AF subgroups on post-hoc analyses, major trials included patients with AF at baseline (~15%) and thus, AF patients should receive β-blockers.¹¹¹

      
      
   8. Should β-blockers be titrated to achieve a specific target heart rate (HR)? The improvement in outcomes with β-blocker therapy is incremental with the following three factors, in order of importance: (1) dose achieved; (2) baseline severity of HF; (3) HR achieved and HR reduction.^{108,110,115,116} The 3 factors are interactive. The HR achieved with β-blocker therapy depends on the overall HF severity and catecholamine level, rather than just the β-blocker dose. A more severe or decompensated HF is associated with a higher HR yet derives a larger mortality benefit even from a small β-blocker dose. Thus, β-blockers are not titrated to achieve a specific target HR, although a low HR (~60–70 bpm) is desirable, is associated with a reduced mortality, and implies better HF control through both β-blockade and adjunctive HF therapy. Part of the reason metoprolol XL achieved similar relative benefit vs placebo at low and high doses is the similar HR achieved with both doses in the trial. Either a high β-blocker dose or a low HR (<70 bpm) should at least be achieved, and it is crucial to keep pushing the β-blocker dose even if the patient becomes asymptomatic. Even if HR remains > 70 bpm, the mortality is low when a high dose of β-blocker is reached.¹¹⁵ The relationship between lower heart rate and survival is only true in sinus rhythm, not AF.¹¹¹
      

      While a high HR is essentially secondary to HF, it may also, by itself, perpetuate systolic HF through perpetuating energetic and metabolic inefficiencies. A trial of a pure sinus node blocker (ivabradine) showed that pure HR reduction was associated with reduced HF hospitalizations, confirming a direct role of HR in the pathophysiology of systolic HF.¹¹⁷

C. Aldosterone receptor antagonists (spironolactone, eplerenone)

1. The high aldosterone levels seen in HF not only induce renal sodium retention but directly act on the myocardial and arterial aldoster- one receptors, leading to myocardial and arterial fibrosis and baroreceptor dysfunction (sympathetic augmentation). In fact, the small doses of aldosterone antagonists studied in HF only have a mild or no diuretic effect (RALES trial).¹¹⁸ The benefit in HF mainly results from: (i) blockade of myocardial and baroreceptor aldosterone receptors; (ii) increase in potassium (antiarrhythmic effect); (iii) reduction of the tubular resistance to loop diuretics.¹¹⁹ Aldosterone antagonists reduce HF mortality by 30%, HF hospitalization by 30–40%, and improve NYHA functional class (RALES trial).^118,120,121
   

   Aldosterone acts at the DNA level and induces the genomic synthesis of distal tubular Na channels and basal Na/K pumps that absorb Na and secrete K and H. The aldosterone receptor blockers inhibit this synthesis rather than directly block Na/K pumps, and therefore have a slow onset of action of 2–3 days and a slow offset (3–4 days), similar to aldosterone and other steroids.

   
   
2. An aldosterone receptor antagonist is indicated in chronic HF with EF ≤ 35% and NYHA classes III–IV.¹¹⁸ Aldosterone antagonist therapy has also reduced mortality in class II systolic HF (EF ≤ 35%) with elevated BNP or recent cardiovascular hospitalization in the last 6 months, and is recommended for these patients (class I recommendation).¹²⁰
   

   It is also indicated after a recent MI (within 30 days) when EF is < 40% and any degree of clinical HF or diabetes is present.¹²¹

   
   
3. Contraindications: creatinine > 2 mg/dl or GFR < 30 ml/min; K > 5 mEq/l. In the RALES trial, patients with mild renal failure (GFR 30–60 ml/ min) had a higher risk of worsening renal function and hyperkalemia with spironolactone in comparison to those with normal renal function, but derived the largest absolute mortality reduction. Thus, patients with mild renal failure are appropriate candidates for this therapy if well monitored.¹²²
   
4. Dosage of spironolactone: 12.5–25.0 mg daily; careful up-titration to 37.5–50.0 mg daily may be tried in patients with refractory HF or persistent hypokalemia. If gynecomastia develops, eplerenone may be used instead of spironolactone. Potassium and creatinine should be checked within 3 days and again at 1 week after therapy initiation, then Q2–4wk for the next 3 months. Typically, all potassium supple- ments need to be stopped at the initiation of the aldosterone antagonist; a minority of patients will continue to require a potassium sup- plement, but this is restarted only after blood testing. In real-world registries, hyperkalemia is common with aldosterone antagonists (up to 20%), therefore justifying careful K monitoring. In fact, these agents should be avoided if K monitoring is not possible (compliance issues), and the patient should be instructed about interruption of therapy should diarrhea or dehydration occur (renal failure). If K rises to 5-5.4 with spironolactone, maintain the same dose; if K rises to 5.5-5.9, hold it for a few days then resume half the dose; if K ≥6, discontinue it.
   
5. RAAS activation leads to a marked elevation of aldosterone levels in both HF and cirrhosis, exaggerated by the fact that aldosterone catabolism, a hepatic process, is impaired. In cirrhosis, a high dose of spironolactone (100–400 mg), higher than the one studied in HF, has been shown to induce more natriuresis than a loop diuretic. In fact, the avid distal sodium reabsorption induced by hyperaldosteronism makes loop diuretics ineffective in 50% of cirrhotic patients.¹²³ This high dose has not been largely studied in HF because of the combined therapy with ACE-I, but illustrates the potential value of spironolactone in patients with combined heart and liver failure and the possible role of higher spironolactone doses in patients resistant to loop diuretics.¹²³ In ATHENA-HF trial, a 4-day course of spironolactone 100 mg in acute HF, on top of furosemide, did not improve urine output, weight loss, and NT-pro-BNP but was safe (trial limitations: treatment was brief and patients were furosemide-responsive).¹²⁴
   
6. Patiromer is a K binder that removes K at the gastrointestinal level, hence lowering K by ~ 1 mEq/l. It allows the continuation of the same ACE-I and aldosterone antagonist doses when K is 5.5-5.9; and even when K is ≥6, after 1 week of interruption.¹²⁵

D. Angiotensin receptor-Neprilysin inhibitor (sacubitril–valsartan combination)

Neprilysin is a peptidase that degrades natriuretic peptides, bradykinin, and adromedullin. Neprilysin inhibition increases the level of these substance via a “double negative” effect, counteracting vasoconstriction, sodium retention, and LV remodeling. In fact, natriuretic peptides reduce maladaptive hypertrophy and fibroblast proliferation in the heart and kidneys. In a trial of patients with HF and EF<40%, NYHA II–IV, and BNP > 150 or a prior HF hospitalization in the last year, valsartan+ neprilysin inhibitor (combined in one molecule, not just one pill) reduced the 2-year mortality by ~3% in comparison with ACE-I (relative risk reduction 16%).¹²⁶ Hospitalization for HF was also reduced by ~3%. Angiotensin–neprilysin inhibitor was associated with more symptomatic hypotension yet less renal dysfunction and hyperkalemia than ACE-I, and slower renal decline over the long term: natriuretic peptides selectively vasodilate the afferent arteriole, thereby increasing renal flow and offsetting the hypotensive effect and the efferent dilatation.¹²⁷ This benefit was seen despite a background therapy that included β-blockers and aldosterone antagonists (PARADIGM-HF trial). Most patients had class II symptoms, and the benefit was seen in stable and relatively low-risk patients, which argues that even early-stage HF patients who are stable on ACE-I are better switched to this therapy; the indication is more compelling in patients with recent or current HF hospitalization. In-hospital initiation of angiotensin-neprilysin inhibitor dramatically reduces early HF rehospitalizations by 42%, compared to in-hospital ACE-I followed by a later switch to angiotensin-neprilysin inhibitor at 8 weeks (PIONEER-HF trial).¹²⁸ Yet, its selective use in advanced class IV HF with mean SBP ~110 did not improve outcomes or NT-pro-BNP vs. ARB (LIFE trial); and its initiation in acute MI with low EF was not superior to ACE-I (PARADISE-MI).

In order to prevent angioedema, the recommended washout period between an ACE inhibitor and sacubitril–valsartan is 36 hours. A prior history of angioedema with ACE-I contraindicates the use of sacubitril–valsartan, but a prior history of cough is not a contraindication.

Of note, neprilysin inhibitor is the only HF therapy that increases BNP, a consequence of its direct effect. This affects the diagnostic value of BNP, at least during therapy initiation, but BNP remains useful for monitoring in respect to the new baseline. Conversely, NT-pro- BNP is not directly affected, as it is not a derivative of BNP, but a byproduct of the same precursor (pro-BNP).

E. Hydralazine–nitrate combination

In the V-HeFT-I trial, the hydralazine–nitrate combination reduced mortality by 34% in comparison to placebo or α-blocker therapy; this was the first trial ever to show a mortality reduction with vasodilator therapy in HF.¹²⁹ The mortality reduction was mainly driven by the benefit in black patients. In the V-HeFT-II trial of hydralazine–nitrate vs. ACE-I, the hydralazine–nitrate combination reduced mortality as much as ACE-I in black patients, and was superior to enalapril in terms of exercise tolerance and EF improvement.^130–132 The hydralazine– nitrate combination was also beneficial in white patients, in whom it was superior to enalapril in terms of exercise tolerance and EF improvement, although the mortality was lower with enalapril. The reduction in hospitalization with hydralazine–nitrate was similar to enalapril and similar between white and black patients.¹³² In the A-HeFT trial of class III–IV black patients already receiving ACE-I and β-blocker therapy, the hydralazine–nitrate combination therapy strikingly reduced mortality by an additional 43% and reduced HF hos- pitalizations by 40%.¹³³

Therefore, the combination is indicated as an additional therapy to ACE-I/ARB and β-blocker in black patients with a functional class III–IV (class I recommendation). It may be considered in non-black patients with persistent symptoms or persistent HTN (>140/90 mmHg); nitrates, per se, may be used for decongestion and symptom relief in all races (CHAMPION trial algorithm). The combination may also be used instead of ACE-I or ARB in case of intolerance to ACE-I/ARB, i.e., renal failure occurs with ACE-I/ARB and does not improve by reducing the dose of furosemide, or hyperkalemia occurs with ACE-I/ARB and does not improve with potassium restriction (class IIa recommendation regardless of race).

The benefit is partly related to the afterload and preload reduction. More importantly, nitrates are metabolized into nitric oxide (NO), while hydralazine prevents the oxidation of NO through its antioxidant properties, allowing to maintain the NO effect. ACE-I also prevents NO oxidation and may be beneficial in combination with nitrates. NO promotes endothelial and vascular homeostasis and appropriate myocardial remodeling and contractility, which improves EF by up to 5%. Hydralazine–nitrate combination may also directly reduce pulmonary vascular resistance in patients with left HF-associated pulmonary hypertension. Black patients frequently have a defective genetic variant of NO synthase that may explain the particular benefit; many white patients also have this variant, and thus pharmacogenomics rather than race may guide hydralazine–nitrate therapy in the future.

Dosing: start hydralazine 12.5 mg TID, increase it to 25 mg TID in 2–4 days, then increase by 25 mg/dose Qweek. Target is ~50–75 mg TID (may reduce to BID in renal failure). Start isosorbide dinitrate 20 mg TID and titrate up to 40 mg TID.

BiDil is a pill that combines 37.5 mg of hydralazine and 20 mg of isosorbide dinitrate (ISDN); BiDil may be started at one-half pill TID and titrated up to two pills TID. Beware, hydralazine causes a lupus syndrome of rash and arthralgia in 5-10% of patients.

A. Diuretics

• Overview and effect of disease states. Thiazide diuretics are weak diuretics that block the distal tubule’s Na-Cl transporter, which reabsorbs ~3–5% of sodium, and are mainly used in chronic HTN rather than HF. Loop diuretics (furosemide, bumetanide, torsemide) block the ascending loop of Henle (Na-K-2Cl transporter), which reabsorbs ~25% of sodium, and are often the mainstay diuretics in HF. Both loop and thiazide diuretics are secreted by the proximal tubule into the lumen and work from the luminal side of the nephron.
  

  In HF and renal failure with reduced renal blood flow, less diuretic reaches the kidneys and gets secreted into the lumen, implying the need for higher doses. Moreover, the reduced amount of renally filtered sodium reduces the total amount of sodium that can be elimi- nated with every single diuretic dose, implying the need for more frequent administration.¹³⁴

  
  

  All diuretics are highly bound to albumin, which traps them and delivers them to the secretory site of the nephron. In very low albumin states (<2 g/dl), some of the diuretic is lost in the extravascular space, and in nephrotic syndrome, even the diuretic that gets to the nephron’s lumen is bound to the urinary albumin, preventing it from acting on the sodium pump.

  
  
• Renal failure and diuretics (especially thiazide). In patients with GFR < 30 ml/min, less sodium is filtered overall. Thus, less sodium can be eliminated by any diuretic (especially a thiazide diuretic), particularly because each of the remaining nephrons is already maximizing its sodium elimination. Hence, thiazide diuretics are less effective in patients with advanced renal failure, but, contrary to common belief, remain effective after cumulative dosing or in combination with a loop diuretic that increases the salt delivery to the distal tubule.^105,106 Metolazone, a thiazide-like diuretic that also works on the proximal tubule, maintains its efficacy in advanced renal failure; it also has a prolonged duration of action (~1 week). All thiazide diuretics are renally eliminated and have a long half-life, and thus cumulate in renal failure (not just metolazone), which further potentiates their effect after multiple dosing. Some data suggest that thiazide monotherapy is effective in hypertensive patients with advanced CKD after multiple dosing.¹³⁵
  
• Diuretic threshold. A diuretic dose is only effective if it exceeds the required threshold at the tubular level. This threshold varies between individuals and diseases. Once the threshold is exceeded, there is a point at which maximal natriuresis is achieved, and beyond which no further natriuresis is gained with higher doses.¹³⁴
  
• Pharmacokinetics of loop diuretics.¹³⁴ Approximately 50% of oral furosemide is absorbed, with a high intra- and inter-individual variation (10–90%). Thus, in general, the effective oral dose of furosemide is numerically twice the intravenous dose. Bumetanide and torsemide are more consistently and thoroughly absorbed (80–100%). With all these agents, the absorption is slowed by intestinal edema and poor intestinal flow; this flattened absorption curve prevents peaking of the diuretic concentration above the diuretic threshold and requires higher doses or an intravenous course of therapy before oral dosing is effective again.
  

  The duration of action is short (~4–6 h) and the nephron may avidly retain sodium between doses, which shows the importance of splitting the dose when a high total daily dose is required. Torsemide is twice longer acting (~12 hours) than the other two agents, has better oral bioavailability than furosemide, has a hepatic metabolism, and is given once daily; 2 small randomized trials showed that outpatient torsemide is superior to furosemide (less HF hospitalizations, reversal of myocardial fibrosis).^136,137 It may be considered in patients with erratic diuretic effect or those with refractory fluid retention. While torsemide and bumetanide are metabolized by the liver, furosemide is renally excreted; thus, in renal failure, the elimination of furosemide is delayed, which prolongs its action and narrows its dose equivalence to the other two agents.

  
  

  Bumetanide dose equivalent: 1 mg = 40 mg of furosemide (or 20 mg in advanced renal failure); torsemide dose equivalent: 20 mg = 40 mg furosemide.

  

  
  
• Practical use of oral loop diuretics:
  
  
  
  • Use the lowest chronic oral dose to maintain euvolemia: furosemide 20 mg once daily, up to 40–80 mg 2–3 times daily. If the patient has a diuretic response to 40 mg of furosemide and is requiring a total of 80 mg per day, it is better to give 40 mg BID than 80 mg Qday to provide a more sustained diuretic effect and less metabolic perturbations.
    
  • The patient needs to take extra dose(s) if weight increases > 3 lb in < 5 days. He needs to continue taking an extra dose of diuretic daily until the weight returns to baseline. If in 1–2 days, the weight continues to rise, a clinic visit is immediately warranted and metolazone may be added for 1-2 days.
    
  • Euvolemic outpatients who are minimally symptomatic on a small daily dose of furosemide ≤ 40 mg may consider furosemide withdrawal (ReBIC trial).¹³⁸ On the other hand, patients with severe HF requiring high chronic doses of furosemide (>200 mg/d) may be supplemented with a biweekly or triweekly dose of chlorthalidone or metolazone.
    
  • Oral potassium (~20–40 mEq per day) may be added, particularly if the patient is not receiving an aldosterone antagonist. K goal is ≥ 4 mEq/l. Patients requiring high doses of potassium are often magnesium-deficient and should receive magnesium supplementation.

VII. Devices