Optimal GDMT leads to reversal of cardiac remodeling, reduction of LV volumes (7), and a concomitant reduction in functional MR (39); thus, although percutaneous mitral valve repair is of bene t in patients with optimized GDMT and persistent symptoms with severe MR, it is essential that GDMT is optimized before referral for the procedure to ensure the greatest likelihood that patients will receive the combined bene ts of optimal GDMT together with edge-to-edge repair. 5.1.8. Patients in Whom New Therapies May Not Be Indicated Contraindications may preclude the initiation of some agents among some patients. Additionally, after being presented with all evidence for and against these thera- pies, a well-informed patient may make a personal judg- ment, in terms of bene ts and risks, and decide against initiation. In a patient whose life expectancy is short (<1 year) due to other comorbidities, some therapies (such as implant- able devices) may not be appropriate. Similarly, in pa- tients with NYHA class IV and Stage D HF being considered for advanced therapies (i.e., transplant or LV assist device), home inotropes, hospice, or initiation of new drug therapies may not be appropriate, especially given the absence of evidence addressing their ef cacy in such patients. 5.2. How to Achieve Optimal Therapy Given Multiple Drugs for HF, Including Augmented Clinical Assessment That May Trigger Additional Changes in GDMT (e.g., Imaging Data, Biomarkers, and Filling Pressures) 5.2.1. Target Doses To achieve the maximal bene ts of GDMT in patients with chronic HFrEF, therapies must be initiated and titrated to maximally tolerated doses (16,40 42). Doses of GDMT J Maddox et al. higher than those studied in randomized clinical trials, even if tolerated, are not known to provide incremental bene ts, and are generally not recommended. 