Baylor Heart and Vascular Institute

Packer, M. (2017). “Who should deliver medical therapy for patients with chronic heart failure? An immediate call for action to implement a community-based collaborative solution.” Circ Heart Fail 10(8): 1-4.

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When we communicate with our colleagues in primary care medicine, why do we convey only a broad philosophical directive rather than a detailed list of specific actionable recommendations? The management of chronic heart failure is not simple. Optimal treatment requires the skillful orchestration of as many as 7 different classes of drugs, together with the appropriate application of different types of devices.2 Heart failure is generally more disabling and lethal than cancer,3 and its comprehensive management is frequently far more challenging. When chemotherapy is given to patients with cancer, its administration is tightly controlled by medical oncologists, who prescribe antineoplastic drugs aggressively and under close supervision, generally at doses and durations that closely resemble those used in randomized clinical trials. Serious adverse effects are expected, but patient compliance and provider enthusiasm is enhanced by societally reinforced fears about the need for aggressive therapy to prevent the silent spread of malignantcells. In contrast, although heart failure with a reduced ejection fraction also progresses silently and requires complex multidrug regimens over long periods of time, specialists are generally not involved, and intensive pharmacological strategies and doses are rarely achieved in clinical practice.4 Continued pursuit of optimal regimens often ceases at the first hint of patient intolerance or reluctance. As in the management of cancer, the treatment of patients with heart failure requires knowledge, experience, and perseverance, which necessitates a multidisciplinary team of healthcare providers that can deal effectively with each patient’s individual circumstances. Those who care for patients with cancer are richly rewarded for creating these conditions; those who care for patients with heart failure are not.5

Bernstein, R. A., H. Kamel, C. B. Granger, R. C. Kowal, P. D. Ziegler and L. H. Schwamm (2017). “Stroke of known cause and underlying atrial fibrillation (stroke-af) randomized trial: Design and rationale.” Am Heart J 190: 19-24.

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BACKGROUND: Approximately 20% of ischemic strokes are associated with clinically apparent atrial fibrillation (AF). Regardless of stroke etiology, detection of AF in patients with ischemic strokes often changes antithrombotic treatment from anti-platelet to oral anticoagulation therapy. The role and the optimum duration of cardiac monitoring to detect AF in patients with strokes presumed due to large vessel atherosclerosis or small vessel disease is unknown. This manuscript describes the design and rationale of the STROKE-AF trial. STUDY DESIGN: STROKE-AF is a randomized, controlled, open-label, post-market clinical trial. Detection of AF will be evaluated using continuous arrhythmia monitoring with an insertable cardiac monitor (ICM) compared with standard of care follow-up in patients with stroke (within the prior 10 days) that is presumed due to large vessel cervical or intracranial atherosclerosis, or to small vessel disease. Approximately 500 patients will be enrolled at approximately 40 centers in the United States. Patients will be randomized 1:1 to arrhythmia monitoring with an ICM (continuous monitoring arm) or standard of care follow-up (control arm). Subjects will be followed for >/=12 months and up to 3 years. OUTCOMES: The primary objective is to compare the incidence rate of detected AF through 12 months of follow-up between the two arms. CONCLUSION: This trial will provide information on the value of ICMs to detect subclinical AF in patients with stroke presumed due to large vessel atherosclerosis or small vessel disease, which will have implications for guiding treatment with oral anticoagulation for secondary stroke prevention.

Packer, M. (2017). “Why has a run-in period been a design element in most landmark clinical trials? Analysis of the critical role of run-in periods in drug development.” J Card Fail: 2017 Jul [Epub ahead of print].

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Prior exposure to one of the randomized treatments has been a routine design element of large-scale trials in patients at high cardiovascular risk. A run-in feature has allowed our trials to be more realistic; it has strengthened their ability to estimate the true treatment effect, and it has never undermined the validity of a trial’s findings. Those who suggest that run-in periods distort the results of large-scale trials should become more familiar with our history of drug development and our standards of clinical practice. Physicians use run-in periods every day in real life, and trialists have used run-in periods for decades to reliably establish the role of new cardiovascular drugs. Those who reflexively criticize the trials because of their inclusion of a run-in period need to carefully re-examine how medicine is practiced and how it advances.

Solomon, S. D., A. R. Rizkala, J. Gong, W. Wang, I. S. Anand, J. Ge, C. S. P. Lam, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, M. M. Redfield, J. L. Rouleau, D. J. Van Veldhuisen, F. Zannad, M. R. Zile, A. S. Desai, V. C. Shi, M. P. Lefkowitz and J. J. V. McMurray (2017). “Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: Rationale and design of the paragon-hf trial.” JACC Heart Fail 5(7): 471-482.

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OBJECTIVES: The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial is designed to determine the efficacy and safety of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan compared with valsartan in patients with chronic heart failure and preserved ejection fraction (HFpEF). BACKGROUND: HFpEF is highly prevalent, associated with substantial morbidity and mortality, and in need of effective therapies that improve outcomes. The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan, which has been shown to benefit patients with heart failure (HF) and reduced ejection fraction, demonstrated favorable physiologic effects in a phase II HFpEF trial. METHODS: The PARAGON-HF trial is a randomized, double-blind, parallel group, active-controlled, event-driven trial comparing the long-term efficacy and safety of valsartan and sacubitril/valsartan in patients with chronic HFpEF (left ventricular ejection fraction >/=45%), New York Heart Association functional class II to IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Before randomization, all patients entered sequential single-blind run-in periods to ensure tolerability of both drugs at half the target doses (i.e., valsartan titrated to 80 mg bid followed by sacubitril/valsartan 49/51 mg [100 mg] bid). The primary outcome is the composite of cardiovascular death and total (first and recurrent) HF hospitalizations. CONCLUSIONS: PARAGON-HF will determine whether sacubitril/valsartan is superior to angiotensin receptor blockade alone in patients with chronic symptomatic HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF].

Packer, M. and J. J. V. McMurray (2017). “Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure.” Lancet 389(10081): 1831-1840.

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The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.