new heart failure guidelines

this is blog from 5/7/2017:

These guidelines update the 2013 guideline for the management of heart failure, focusing on biomarkers, new therapies for both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved injection fraction (HFpEF), as well as new information on managing comorbidities including anemia, hypertension, and sleep apnea; and some new insights into the prevention of heart failure (see DOI: 10.1161/CIR.0000000000000509). This guideline is a 2^nd part to the 2016 guideline on new therapies (see http://blogs.bmj.com/ebm/2016/06/10/primary-care-corner-with-geoffrey-modest-md-heart-failure-guidelines-the-new-meds/ ), which included recommendations for the angiotensin receptor-neprilysin inhibitor valsartan/sacubitril (an ARNI) and the sinoatrial node modulator ivabradine . Seven of 17 on the AHA memberscommittee had ties to drug companies, though neither the chair nor vice chair did. My comments are embedded in the text

Biomarkers:
-- B-type natriuretic peptide (BNP) and N-terminal pro-B type natriuretic peptide (NT-proBNP) track similarly for both the presence and severity of heart failure, and either can be used, though not interchangeably
-- it is important to note that BNP, but not NT-proBNP, is a substrate for neprilysin, and therefore the ARNI  increases BNP levels. So, in studies using the ARNI, the NT-proBNP levels were reduced, associated with improved clinical outcomes [ie, it makes sense to use the NT-proBNP if starting the ARNI]
-- several studies have found that these biomarkers assist in the diagnosis or exclusion of heart failure as a cause of symptoms such as dyspnea or weight gain in the setting of chronic ambulatory heart failure, or in the setting of acute heart failure decompensation.
-- This still are no clear, consistent data showing that these biomarkers improve mortality or cardiovascular outcomes, so there is no specific recommendation regarding biomarker-guided therapy or the utility of serial measurements of these biomarkers in reducing hospitalization or deaths
-- other biomarkers include troponins I and T, which may be elevated in chronic or acute decompensated heart failure, and do have prognostic significance in the setting acute heart failure
-- and there are a slew of newer biomarkers (e.g., some reflecting inflammation, oxidative stress, vascular dysfunction, myocardial and matrix remodeling, myocardial fibrosis), which have in some studies predictive value for hospitalizations and deaths, and may have incremental prognostic value over the currently accepted biomarkers, but there need to be more studies on them
-- the STOP-HF study, an unblinded single center study evaluating patients who are at risk for heart failure because of hypertension, diabetes, or nonvascular disease but without systolic dysfunction or symptomatic heart failure at baseline, patients were randomized to screening BNP testing versus usual care, finding that those with BNP levels > 50, who then had echocardiograms and team-based therapy including a cardiovascular specialist, had reduced composite endpoint of asymptomatic left ventricular dysfunction with or without newly diagnosed heart failure. 
Biomarkerrecommendations:
-- for patients at risk for developing heart failure, natriuretic peptide screening followed by team-based care can be useful in preventing heart failure. strength of recommendation IIa, moderate quality evidence
-- for patients hospitalized with heart failure, a predischarge natriuretic peptide can be useful to establish a postdischarge prognosis, based on observational studies showing that those who did not have a significant decrease in these levels during hospitalization had worse outcomes. [This could key clinicians to more aggressive post-discharge management, though no specific biomarker thresholds for changes have been tested prospectively ,and they do not mention studies documenting the effectiveness of this approach]. Grade IIa recommendation, moderate quality evidence
-- measurement of other biomarkers (e.g. soluble ST2 receptor, galectin-3, high-sensitivity troponin) may be considered for additional risk stratification. Grade IIb, moderate strength of evidence

HFrEF (for Stage C, symptomatic failure):
-- overall clinical strategy is to use an ACE inhibitor or ARB or ARNI, along with beta blocker and aldosterone antagonist in selected patients, to reduce morbidity and mortality. Grade I recommendation, high quality evidence
-- both ACE inhibitors and ARBs are recommended in patients with prior or current symptoms of chronic heart failure to reduce morbidity and mortality, with ARBs being recommended in patients who are ACE inhibitor intolerant because of cough or angioedema. Grade I recommendation, high quality evidence [I remain concerned about using ARBs in patients with angioedema, since I have seen 2 patients admitted to the ICU with angioedema in this situation, and there are many more in the literature, though I realize that small studies have found this not to be a problem, and there is no clear mechanistic reason why it should happen, other than those with ACE inhibitor-induced angioedema may be more generally allergic to other medications]
-- ARNI is recommended in patients with chronic symptomatic HFrEF who tolerate ACE inhibitors or ARB, to further reduce morbidity and mortality, based on a study comparing ARNI versus enalapril showing improved clinical outcomes with the ARNI. Grade I recommendation, high quality evidence
-- but, ARNI should not be used in conjunction with either ACE inhibitors or ARBs, and is associated with higher incidence of angioedema (and studies have shown that the combination of it with an ACE inhibitor is associated with unacceptable levels of angioedema and significant morbidity). As a result of this high incidence of angioedema with this combination, subsequent studies have excluded patients with a history of angioedema, so the recommendation is not to use the ARNI in patients with any history of angioedema, just to be safe. Black patients and smokers seem to be particularly at risk. The recommendation is that initiating ANRI should be at least 36 hours after terminating ACE inhibitors. [ARNI  seems to be a good drug clinically, but I am concerned about the fact that inhibition of the neprilysin enzyme, which has multiple biological targets, creates the potential for more downstream adverse effects detected over time]
-- although not in a formal recommendation, in the flowchart they do promote the hydralazine-nitrate combination in black patients, and they do support ICD usage in patients with NYHA class II to IV heart failure and LVEF <35%; and cardiac resynchronization therapy in these same patients as with ICD but have a QRS interval greater than 150 ms and left bundle branch pattern
--Ivabradine, a selective inhibitor of the I_f current in the sinoatrial node, is useful for heart rate reduction, and has been found to be beneficial in reducing heart failure hospitalizations for patients with symptomatic stable chronic HFrEF on otherwise maximal management including a beta blocker at maximum tolerated dose, are in sinus rhythm, and have a heart rate>70 at rest. This is based on an RCT of patients with NYHA class II to IV HFrEF (though class IV HFrEF was not well represented), LVEF <35% and in sinus rhythm (though some had paroxysmal atrial fibrillation). However, as they note, only 25% of patients in the study were on optimal doses of beta blocker therapy, so they recommend starting ivabradine only in patients on maximal doses of beta blockers). grade IIa recommendation, with only moderate quality evidence
-- there is a useful table of the maximal doses of drugs as well as the mean doses achieved in the clinical trials, with the following sampling:
                -- enalapril, maximum dose 10 to 20 mg BID, mean dose in trials 16.6 mg a day
                -- lisinopril, maximum dose 20 to 40 mg daily, mean dose and trials 35 mg per day
                -- losartan, maximum dose 50 to 150 mg a day, mean dose and trials 129 mg a day
                -- valsartan maximum dose 160 BID, mean dose and trials 254 mg a day
                -- carvedilol, maximum dose 50 mg b.i.d., mean dose in trials 37 mg a day
                -- metoprolol extended release, maximum dose 200 mg a day, mean dose in trials 159 mg day
                -- isosorbide/hydralazine, maximum dose 40 mg isosorbide dinitrate with 100 mg hydralazine TID, mean dose achieved not available
                -- spironolactone, maximum dose 25 mg daily or BID, mean dose in trials 26 mg a day
                -- eplerenone, maximum dose 50 mg a day, mean dose in trials 42.6 mg a day

HFpEF
-- systolic and diastolic blood pressures should be controlled in accordance with current clinical guidelines, to prevent morbidity. Grade I recommendation, strength of evidence moderate
-- diuretics should be used to relieve symptoms due to volume overload in patients with symptomatic HFpEF. Grade I, a low level of evidence
-- coronary revascularization is reasonable in patients with symptomatic CAD that is felt likely to have an adverse effect on their HFpEF. Grade IIa, low level of evidence
-- management of atrial fibrillation according to guidelines is reasonable to improve symptomatic heart failure. Grade IIa, low level of evidence
-- use of beta blockers, ACE inhibitors, and and ARBs in patients with hypertension is reasonable to control blood pressure. Grade IIa, low level of evidence [a study found that ARBs might decrease hospitalizations for HFpEF patients, Grade IIb, moderate level of evidence
-- it is reasonable in patients with symptomatic HFpEF to use aldosterone receptor antagonists to decrease hospitalizations in patients who have ejection fraction >45%, elevated elevated BNP levels or heart failure admission within one year, estimated GFR >30, creatinine 2.5 mg/dL, and potassium <5 mEq/l (see http://blogs.bmj.com/ebm/2014/05/14/primary-care-corner-with-geoffrey-modest-md-spironolactone-in-diastolic-heart-failure/ ). Grade IIb, moderate level of evidence
-- use of nitrates, phosphodiesterase-5 inhibitors, and nutritional supplements are not recommended, felt to have no benefit

Anemia
--in those with NYHA class II or III heart failure and iron deficiency (ferritin <100ng/ml, or 100-200 if transferrin saturation <20%), intravenous iron therapy may improve functional status, based on 3 studies. In general patients did not have severe anemia (eg FAIR-HF trial, NEJM 2009; 361: 2436) had mean hemoglobin of 11.9 g/dL, MVC 92, ferritin 52, transferrin sat 18%), finding improved symptoms, functional capacity and quality of life (and, on further analysis, this was independent of having anemia).  Grade IIb, moderate level of evidence. No data on oral iron supplementation. And no benefit from erythropoietin- stimulating agents. so only intravenous iron recommended at this point.

Hypertension
--optimal blood pressure in those at increased risk of heart failure is <130/70, from the SPRINT trial of patients >75yo, established vascular disease or CKD, or Framingham Risk Score >15%, showing decrease in new onset heart failure, though they note that this goal is an approximation because office BP is typically about 5-10 mmHg higher than in this trial (see http://blogs.bmj.com/ebm/2017/02/27/primary-care-corner-with-geoffrey-modest-md-blood-pressure-guidelines-for-older-adults/ , for issues about the unusual methodology of the SPRINT trial which limit its direct generalizability, and http://blogs.bmj.com/ebm/2016/06/02/primary-care-corner-with-geoffrey-modest-md-sprint-trial-elderly-subgroup-study-of-lower-blood-pressure-goal/ for review/critique of the SPRINT trial subset in elderly). Grade I, moderate level of evidence.
-- goal of systolic <130 in those with HFrEF, Grade I, expert opinion. Not tested in RCTs
-- goal of systolic <130 in those with HFpEF. Avoid nitrates. Preferred choice ACE inhibitors, ARBs, and possibly ARNI, Grade I, expert opinion. Limited data to support

Sleep-disordered breathing
--perform sleep assessment in those with NYHA class II-IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, Grade IIa, not much data, but a study of patients with chronic heart failure found 61% had either central or obstructive sleep apnea, but treatments are different and one needs to know which one the patient has.
--in patients with cardiovascular disease and OSA, CPAP may be reasonable to improve sleep quality and daytime sleepiness, Grade IIb, moderate quality evidence. 
-- in patients with central sleep apnea and class II-IV HFrEF, using servo-ventilation treatment causes harm!! (higher mortality)
--[this recommendation befuddles me a bit: it is true that people with symptomatic OSA who use CPAP have better sleep quality and function better. But that is true if they have heart disease or not. And the study they quote (ORBIT-AF) just showed that those with atrial fib plus OSA and put on CPAP had less progression to more permanent atrial fib. Not sure that means much clinically, and this was not a study in heart failure patients. I assume that this section was added to highlight that sleep studies are indicated when people are not sleeping well (though this happens with heart failure a lot), and that we NOT go the servo-ventilation route if it is central sleep apnea, but that CPAP is okay for OSA. Which I guess is a reasonable point, but bringing in the atrial fib study in those not in heart failure seems a bit off-track.]

Commentary:
-- although HFpEF seems to have pretty much the same prevalence as well as morbidity/mortality as HFrEF, it is quite striking how poorly equipped we are to provide great therapy. Personally I have had pretty good success with adding on spironolactone in patients with severe, resistant disease to help with symptoms and decrease multiple admissions.
-- As noted in prior blogs, treating patients effectively with HPrEF has been one of the major advances in therapeutics over the last several decades. In my experience these patients do exceptionally well overall, can be treated effectively in the primary care setting, and do very well over the long-term and into very old age. I recently had a patient to had a severe MI at age 72, was resuscitated, maintained a left ventricular ejection fraction which never exceeded 10%, was basically asymptomatic with optimal heart failure therapy, and ultimately died over 20 years later..
-- these guidelines do add some important new recommendations, especially: further promoting the use of natriuretic peptide​ biomarkers and integrating them more into care, considering using them to identify and manage patients at high risk of heart failure, and there seems to be value in checking iron levels in those with HFrEF​ even without anemia [I will integrate that into my approach to care, though will deviate to using oral supplementation if iron deficient]. And, as mentioned, I think these guidelines help us manage heart failure patients in a primary care setting, which I have found to be incredibly successful and satisfying for me (and I think for my patients)....