heart failure: outpatient Initiation of sacubitril-valsartan

 

A recent article reviewed outpatient initiation of sacubitril/valsartan in those with heart failure (see heart failure outpt entresto JCadriovascPharm2021 in dropbox, or DOI: 10.1097/FJC.0000000000000966 ). The heart failure guidelines just released elevated sacubitril/valsartan to the highest tier (see http://gmodestmedblogs.blogspot.com/2022/05/ahaacc-guidelines-on-heart-failure.html . In order for sacubitril/valsartan to be a practical solution for the huge number of patients with HF, it is important to have a safe and efficient ability to initiate this med. 

 

Details:

-- 250 adults were prescribed sacubitril/valsartan in cardiology clinics in an academic institution from 2016-2018 in this retrospective cohort study with follow-up data collected until 3 months after medication initiation

-- average age 63, 74% males, 89% white

-- NYHA symptom class II in 64/ III in 31%; ejection fraction reduced in 94% (EF not quantified in the text)

-- hypertension 74%/diabetes 41%/atrial fibrillation 35%/MI 22%/stroke 8%

-- taking target dose of ACE/ARB at baseline: 20%

-- primary outcome: percentage of heart failure patients who were initiated on sacubitril/valsartan appropriately, as based on guidelines and package insert recommendations

-- secondary outcomes: rates of adverse events and need for adjustment of concomitant heart failure medications

 

Results:

-- 125 patients were appropriately initiated on sacubitril/valsartan

-- 125 were inappropriately initiated on medication:

    -- the most common reason for inappropriate start was an inappropriate dose conversion in 58%, inappropriate indication in 34%, and a combination of both in 8%

-- blood pressure on average decreased from 122.4/76.1 mmHg at baseline to 115.8/72.5 mmHg 30d after initiation of sacubitril/valsartan (minimally more decrease in the inappropriate start group)

-- adverse events: 100 patients (40%), more so in the inappropriate start group at 43% versus the appropriate group at 37% (not statistically significant)

    --hypotension: 

        -- inappropriate start group: 24% had BP <90/60 and 28% symptoms of hypotension

        -- appropriate start group: 16% had BP <90/60 and 16% symptoms of hypotension

            -- difference statistically significant, p=0.022

        --hypotensive patients also required more decreases in sacubitril/valsartan: 13% if inappropriately started versus 6% if appropriate, p=0.049

 

Commentary:

 

-- "appropriate" sacubitril-valsartan prescribing:

    -- sacubitril-valsartan comes in three doses: 24 mg sacubitril /26 mg valsartan, 49 mg sacubitril /51 mg valsartan, or 97 mg sacubitril /103 mg valsartan

    -- patients having heart failure with reduced ejection fraction (HFrEF): only prescribe sacubitril/valsartan in those with hemodynamically stable heart failure, with systolic blood pressure at least 100 mmHg, no increase in IV diuretic dose in the previous six hours, no use of IV vasodilator in the previous six hours, no use of IV inotrope in the previous 24 hours, and serum potassium <5 mEq/L

        -- best If patients have tolerated the equivalent of enalapril 10 mg b.i.d. (lisinopril and enalapril have equivalent daily dosages). Though all should stop the ACE inhibitor at least 36 hours before starting sacubitril-valsartan (No need to stop ARBs, but taking ACE inhibitors with sacubitril/valsartan is associated with increased risk of angioedema)

            -- if patient on at least 10 mg of enalapril equivalent or ARB >160mg of valsartan or equivalent, start with sacubitril-valsartan 49/51mg twice a day, then double dose as tolerated after two weeks, with the goal of reaching the maximum dose of 97/103 mg twice a day

            -- if patient on a lower dose of enalapril or ARB, or is not on an ACE inhibitor or ARB, start with sacubitril-valsartan 24/26 mg twice a day and double the dose as tolerated at two-week intervals, with attempt to reach the highest dose of 97/103 mg twice a day

    --In patients having heart failure with preserved ejection fraction (HFpEF):

        -- consider optimizing mineralocorticoid antagonist as well as SGLT-2 antagonist therapies first, particularly in those with ejection fraction <55%, those who are still hypertensive, or those who have been recently hospitalized for heart failure

        -- begin sacubitril-valsartan at 24/26 mg twice daily or 49/51 mg twice daily depending on the baseline blood pressure (not specified). Double the dose every two weeks to the target maintenance dose of 97/103 mg twice daily

    -- renal dosing: no adjustment if eGFR >30; if eGFR <30, start sacubitril-valsartan 24/26 mg twice-daily and double the dose as tolerated to achieve 97/103 mg twice daily, though no real safety data on those with eGFR <20

    -- hepatic dosing: do not use with severe impairment (Child-Puch class C), start with sacubitril-valsartan dose of 24/26 twice-daily if class B, and no adjustment necessary if class A

-- make sure to check for drug-drug interactions

-- contraindications to sacubitril-valsartan include pregnancy, history of angioedema of any cause, as well as severe hepatic impairment

 

-- The FDA approved sacubitril-valsartan in 2015 for patients with chronic HFrEF, with NYHA class II or III symptoms, who tolerate an ACE inhibitor or ARB; the FDA expanded approval of sacubitril-valsartan to patients with HFpEF in 2021 (see https://www.fda.gov/media/144379/download )

    -- HFrEF study: the basis for the initial FDA approval for patients with HFrEF in 2015 was the PARADIGM-HF trial, assessing sacubitril/valsartan versus enalapril in 8442 patients having class II, III, and IV heart failure and an ejection fraction < 40%; they found a 20% decrease in the primary outcome (composite of death from cardiovascular causes or hospitalization for heart failure) with sacubitril/valsartan, as well as 16% decrease in death from any cause, 20% decrease from cardiovascular deaths, and 21% decrease in hospitalizations for heart failure (see https://www.nejm.org/doi/full/10.1056/nejmoa1409077 )

        --This trial did find a higher proportion of patients with hypotension (14% on sacubitril/valsartan and 9.2% on enalapril; and for a documented BP <90/60 it was 2.7% vs 1.4%) and nonserious angioedema (0.2% versus 0.1%), but there were lower proportions on sacubitril/valsartan who developed renal impairment, hyperkalemia, and cough than with enalapril

            -- by contrast, this current trial did find that even in those appropriately started on sacubitril/valsartan, 20% had documented BP <90/60. the likely reason for the difference: those patients in the PARADIGM-HF study were first trialed at enalapril 10mg and a beta-blocker to ensure tolerability prior to randomization

            --  secondary analysis of the PARADIGM-HF in patients with HFrEF found significantly decreased renal dysfunction with sacubitril/valsartan versus enalapril (see http://gmodestmedblogs.blogspot.com/2018/05/heart-failure-less-renal-toxicity-with.html )

    -- HFpEF studies: the FDA expanded approval of sacubitril-valsartan to HFpEF patients, citing the PARAMOUNT and PARAGON-HF trials (see https://www.fda.gov/media/144379/download 

        -- PARAMOUNT trial (phase 2) compared 301 patient with HFpEF of >45% in a double-blind trial comparing sacubitril/valsartan versus valsartan alone, assessing changes in NT-proBNP, cardiac structure and function, and HF symptoms and signs; they found at 12 weeks that the NT-proBNP level was reduced by 23% from 783 pg/mL to 605 mg/dL, and this was found in all prespecified subgroups assessed; at 36 weeks there was a greater reduction in left atrial size, more patients experienced an improvement in NYHA heart failure functional class (22.8% versus 13.6% at 36 weeks) and there was less deterioration in renal function. See https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61227-6/fulltext

        -- PARAGON-HF trial (phase 3) in 2019, assessed 4822 patients with HFpEF (>45%), randomized to sacubitril-valsartan (97 mg/103 mg twice a day) versus valsartan alone (160 mg twice a day). The primary outcome was a composite of total hospitalization for heart failure and death from cardiovascular causes: almost statistically significantly different, with rate ratio of 0.87 (0.75-1.01), p=0.06.  However, the rate of hospitalizations for heart failure was a statistically significant 15% decrease with rate ratio 0.85 (0.72-1.00); the NYHA HF class improved in 15% of the patients on the sacubitril-valsartan versus 12.6% on valsartan alone, OR 1.45 (1.13-1.86); renal function decline was less prevalent on sacubitril-valsartan versus valsartan: 1.4% versus 2.7%, HR 0.50 (0.33-0.77); and the mean change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) was 1.0 points higher at 8 months on sacubitril-valsartan (the higher, the better on scale 0-100, ie not much change since 5 points is considered clinically meaningful).  Subgroup analysis found sacubitril-valsartan benefit was more significant in females, those with left ventricular ejection fraction <57%, those in atrial fibrillation, those on a mineralocorticoid receptor antagonist, and those with baseline eGFR<60; there was a similar 25% drug discontinuation rate in both groups (see https://www.nejm.org/doi/full/10.1056/NEJMoa1908655 )

-- the concern addressed in the above study is that in clinical practice titrating sacubitril-valsartan to the appropriate doses is difficult (largely limited by hypotension)

    -- given that 16% of those appropriately started on sacubitril/valsartan had documented BP <90/60 mmHg (vs 24% of those not appropriately started), this raises the issue that maybe even for those appropriately started per recommendations, that this might be too aggressive. perhaps we should start with a lower dose in many more patients:

    -- perhaps at a certain BP cutpoint, such as blood pressure <130mmHg systolic (to be determined)

    -- or automatically cutting back on loop diuretic dose (in this study with 250 people, 145 were on a loop diuretic, and 46 of them needed a diuretic dose adjustment with an average decrease of 73% over the 3 months assessed)

    -- or perhaps decreasing the mineralocorticoid antagonist or b-blocker dose

    -- and subsequently gingerly titrate up on the sacubitril/valsartan and gradually reinstate other meds as needed/tolerated??

    -- perhaps a lower dose of many guideline-directed medical therapy meds would be even better than just maximizing sacubitril/valsartan at the expense of the other meds??

        -- of interest, a post-hoc analysis of the SOLVD trial with enalapril found that below target enalapril dosing had similar clinical efficacy as full target dose (http://gmodestmedblogs.blogspot.com/2018/01/lower-enalapril-dose-effective-in-heart.html ); there is also evidence that starting with the lowest dose of sacubitril/valsartan in those with HFrEF, at 24/26 mg versus 49/51 mg twice daily, was associated with similar decreases in NT-proBNP, similar increases in left ventricular ejection fraction, and no differences in symptomatic hypotension, worsening renal failure, hyperkalemia, cardiovascular mortality, and rehospitalizations from heart failure, despite the fact that the maximal target dose of 97/103 mg was achieved in only 9.4% in the 24/26 mg group versus 27.0% started on the 49/41 mg twice daily dose  (eg see https://www.nature.com/articles/s41598-021-95787-w#Fig2 ). In fact, detailed analysis from this study found:

             -- those started at 24/26 mg: almost half never achieved a higher dose (but they were able to continue with b-blockers, mineralocorticoid antagonists, and loop diuretics) vs those started at the standard dose (who had to decrease or stop the other meds)

            -- which means that perhaps we really need to assess the complex interaction of all of the guideline-directed medical therapies to evaluate the optimal mix, along with guidance on minimally effective doses in the mixes

 

Limitations:

-- no information on the ejection fraction of those in the study, just that 94% had a reduced EF; no granular information on most sociodemographic variables

-- not much granular data: did hypotension occur more in those at a specific prior blood pressure prior to the sacubitril/valsartan? or if they were on specific meds (loop diuretics/b-blockers/MRAs) at specific doses associated with more hypotension on introducing sacubitril/valsartan?

-- it would also have been useful to know not just the blood pressures before and after the meds, but also the patients' orthostatic blood pressures (including both the initial and delayed orthostatic responses, eg see http://gmodestmedblogs.blogspot.com/2016/05/orthostatic-hypotension-revisited.html )

-- it also might be useful to compare sacubitril/valsartan to valsartan/spironolactone (and not just valsartan alone), since there is added effect to his latter combination, as noted in http://gmodestmedblogs.blogspot.com/2020/02/sacubitrilvalsartan-dec-hosp-and-cv_3.html .

--overall, it would be important to have more detailed information about what really is the appropriate target doses for different patients (ie studies actually randomizing different people to different doses and assessing both clinical and adverse event outcomes). perhaps with people stratified by their current drug regimen, comorbidities, age, etc, or at least as prespecified endpoints)

 

 So, this small, observational study, though lacking a lot of information as noted above, does raise a few issues:

-- It is clear that sacubitril/valsartan is an important drug for the treatment of heart failure. (but we really should have more information/studies, per comments above!!, though they may not be in the drug company’s interest to fund them)

-- It is also clear that it is important to follow recommendations on how to initiate this medication (and, the mis-prescribing done in this study actually happened in cardiology clinics in academic hospitals!!!)

-- hypotension seems to be the most common problem, and seems to be particularly common in those whose initial blood pressure is lower, and on loop diuretics.

-- my sense in reading these articles as well as the small number of patients that I have started on sacubitril/valsartan is that it does seem to make sense to start with 24/26 mg twice daily, especially in those with relatively low blood pressure initially (perhaps <120-130 mmHg??), those intolerant of higher doses of ACE/ARB before starting the sacubitril/valsartan, and those on loop diuretics (and consider decreasing the loop diuretics if clinically appropriate when starting the sacubitril/valsartan). It does seem that even lower sacubitril/valsartan doses seem to work similarly, allowed for continuation of the other HF meds, and with similar results to starting at a higher dose (per the Nature study noted above)...

geoff

 

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