Goldilocks Dilemma of Dose Titration in Heart Failure With Reduced Ejection Fraction
2017; Lippincott Williams & Wilkins; Volume: 10; Issue: 8 Linguagem: Inglês
10.1161/circheartfailure.117.004406
ISSN1941-3297
AutoresLarry A. Allen, James C. Fang,
Tópico(s)Electrolyte and hormonal disorders
ResumoHomeCirculation: Heart FailureVol. 10, No. 8Goldilocks Dilemma of Dose Titration in Heart Failure With Reduced Ejection Fraction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBGoldilocks Dilemma of Dose Titration in Heart Failure With Reduced Ejection FractionToo Little, Too Much, or Just Right? Larry A. Allen, MD, MHS and James C. Fang, MD Larry A. AllenLarry A. Allen From the Division of Cardiology, University of Colorado School of Medicine, Aurora (L.A.A.); and Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City (J.C.F.). and James C. FangJames C. Fang From the Division of Cardiology, University of Colorado School of Medicine, Aurora (L.A.A.); and Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City (J.C.F.). Originally published8 Aug 2017https://doi.org/10.1161/CIRCHEARTFAILURE.117.004406Circulation: Heart Failure. 2017;10:e004406See Article by Khan et alMedication optimization for heart failure with reduced ejection fraction (HFrEF) is hard work. For a patient recently diagnosed with HFrEF, the number of available therapies has become dizzying. Medications include β-blockers (BB), angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) with added neprilysin inhibitor, mineralocorticoid receptor blockers, hydralazine/isosorbide dinitrate, and ivabradine; this in addition to decongestion with loop diuretics, implantation of devices, referral to cardiac rehabilitation, management of comorbidities, and education of both patients and care providers.1 Recognizing the possible deleterious acute effects of many of these medications, clinical practice guidelines suggest staggered initiation of HFrEF medications, beginning at a low dose for each drug and then slowly increasing to maximum doses targeted in randomized controlled trials. Even with vigilant serial adjustments at 2-week intervals, medication intensification usually takes 3 to 6 months. Meanwhile, frequent monitoring for symptoms, hypotension, and renal dysfunction is needed. Within this context, it is not surprising that up to 80% of patients with HFrEF receive less than recommended doses.2Table. Principles of HFrEF Medication Dose Titration1. Know target doses of HFrEF medications used in clinical trials.2. Relatively low blood pressure alone is not a contraindication to use HFrEF medications; follow symptoms and end-organ dysfunction.3. β-Blockers should be titrated to target doses; ACEi/ARB/ARNi dosing should be adjusted to facilitate BB titration.4. Titrate all meds to target dosing if BP allows, every 2–4 weeks..5. Regular monitoring of symptoms, blood pressure, heart rate, and laboratory testing of electrolytes and renal function should guide dose titration.6. Tolerating only low-dose HFrEF medications or worsening intolerance of such medications should prompt consideration of referral to a HF center capable of advanced therapies (eg, transplantation, mechanical circulatory support).ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, added neprilysin inhibitor; BB, β-blocker; BP, blood pressure; HF, heart failure; and HFrEF, heart failure with reduced ejection fraction.Although dose maximization is ingrained in chronic ambulatory HFrEF care, the data behind it is surprisingly limited. Do BB improve outcomes in patients with HFrEF? Unequivocally yes. Do higher doses of BB improve outcomes more than lower doses of BB in patients with HFrEF? Despite stepwise improvements with increasing BB dose in surrogate end points, such as ejection fraction,3 few high-quality data exist for clinical end points, such as mortality and hospitalizations. Observational data are commonly confounded because progressive disease leads to hypotension and renal dysfunction, which in turn promote intolerance of high doses of various HFrEF medications.4 Yet, the benefits of these drugs in randomized trials accrue at the doses titrated to in clinical trials. Moreover, dose response is a commonly accepted pharmacological and biological principle.Within this context, Dr Khan et al5 set out to summarize existing randomized data on ACEi/ARB dose optimization and outcomes. Their systematic review produced 6 randomized trials totaling 9171 patients, dominated by the HEAAL6 (Heart Failure Endpoint Evaluation of AII-Antagonist Losartan Study), ATLAS7 (Assessment of Treatment With Lisinopril and Survival), and NETWORK8 (Network of General Practitioners and Hospital Physicians Involved in the Study of Low Versus High Doses of Enalapril in Patients With Heart Failure) trials. Together the data showed that targeting a high dose compared with a low dose led to a modest reduction in all-cause mortality (relative risk=0.94; 95% confidence interval=0.89–1.00). These data were not able to show a significant difference between high versus low target doses on heart failure hospitalizations (relative risk=0.94; 95% confidence interval=0.70–1.26) or all-cause hospitalizations (relative risk=0.97; 95% confidence interval=0.85–1.11). Importantly, targeting higher doses of ACEi/ARB did not lead to significant increases in adverse events as measured by discontinuation rates (odds ratio=1.13; 95% confidence interval=0.92–1.39). The meta-analysis was limited by lack of uniform background BB use, significant heterogeneity in the heart failure hospitalization analysis (I2=52.8%), and inability to address specific patient subgroups, such as patients with ischemic heart disease, hypertension, and diabetes mellitus.The positive effect on survival seen in these pooled trials is consistent with early phase dose-finding studies and underlying physiology, providing important support for clinical practice guideline recommendations on dose intensification. Inhibition of the renin–angiotensin–aldosterone system has been clearly shown to improve ventricular remodeling in a dose responsive fashion. Adequate inhibition, achieved by adequate concentrations of active drug, is a central tenant of pharmacotherapy. Analogous to the question posed here, cardiologists are also well-versed in the use of high-dose high-potency statins for patients with coronary heart disease.9While providing some clarity, interpretation and integration of these dose findings into the totality of HFrEF care require a nuanced approach. The effect size of high-intensity ACEi/ARB is modest: 6% relative risk reduction, translating to much smaller absolute benefits dependent on the baseline event rate. In addition, there was no statistically significant benefit on hospitalization. Even if the lack of hospitalization differences represents a type 2 error, the pooled data argue that a statistically hidden reduction in hospitalization would be small.Although the individual trial data in this meta-analysis are relatively well-known, the authors should be applauded for bringing our attention back to the topic of target dosing. With the proliferation of multiple treatments for HFrEF, being able to prioritize the value of various treatment options is important. As clinicians, should we prioritize dose increases in ACEi (or ARB)? Or should we redirect that time and effort to switching to added neprilysin inhibitor early on? Or should we prioritize dose maximization of BB over dose maximization or ACEi/ARB or even added neprilysin inhibitor? In the landmark BB trials, investigators were encouraged to decrease ACEi doses to accommodate target BB doses when blood pressure was limiting; relative risk reductions in those BB trials were on the order of 35%. And all the while, how do we minimize patient confusion, out-of-pocket cost, and general treatment burden?In the current era of further expansion of HFrEF therapies, this ACEi/ARB dose intensity meta-analysis provides important perspective. ACEi/ARB dose intensification likely should remain a goal. But ACEi/ARB dose titration may be superseded by other goals, such as conversion to added neprilysin inhibitor, maximizing BB dosing, addition mineralocorticoid receptor blockers, or perhaps even prioritization of comorbidity treatment (eg, sodium glucose co-transporter 2 inhibitor use in patients with diabetes mellitus). Given the number of options available, we should use basic principles to tailor drug titration, prioritizing treatment options with the greatest absolute anticipated benefit in the context of tolerability (Table). Quality measures should likely remain focused on prescription of HFrEF agents rather than on doses achieved, at least until higher quality data are produced. Such new research would ideally clarify the absolute value of dose intensification for various classes of medications and patient subgroups; perhaps one day, we will use patient-specific targets. In the end, we should continue to encourage providers to push dosing of all HFrEF neurohormonal antagonist agents when we are not focused on other goals. We should be reassured by the data that patients are unlikely to experience major adverse events from dose maximization in the setting of appropriate monitoring. In the end, we should not push too hard, nor push too little, but push dosing just enough.DisclosuresDr Allen receives consulting fees from Novartis and Janssen and grant support from Patient Centered Outcomes Research Institute, American Heart Association, and the National Institutes of Health. Dr Fang reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circ Heart Fail is available at http://circheartfailure.ahajournals.org.Correspondence to: Larry A. 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Sharma Y, Horwood C, Hakendorf P and Thompson C (2021) Trends in Frailty and Use of Evidence-Based Pharmacotherapy for Heart Failure in Australian Hospitalised Patients: An Observational Study, Journal of Clinical Medicine, 10.3390/jcm10245780, 10:24, (5780) August 2017Vol 10, Issue 8 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.117.004406PMID: 28790054 Originally publishedAugust 8, 2017 Keywordsdose responseangiotensin-converting enzyme inhibitorsheart failurecomorbidityEditorialsPDF download Advertisement SubjectsHeart Failure
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