What to Know About Medical Therapy for Cardiomyopathy

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

The diverse range of cardiomyopathies demand a diverse set of treatments, but some overarching themes do apply across many clinical scenarios.

For patients who develop heart failure with reduced ejection fraction of 40% or less (HFrEF), the "four cornerstones," or "four pillars," of treatment are:

• Renin-angiotensin system inhibition

• Beta-blocker

• Mineralocorticoid receptor antagonist (MRA)

• Sodium-glucose cotransporter 2 (SGLT2) inhibition

For renin-angiotensin system inhibition, the 2022 American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend that HFrEF patients get angiotensin receptor-neprilysin inhibition with sacubitril/valsartan (Entresto) as the preferred agent, or an angiotensin-converting-enzyme (ACE) inhibitor when not feasible. The next in line for patients unable to tolerate an ACE inhibitor due to cough or angioedema is an angiotensin receptor blocker (ARB).

The guidelines also give a class 1a recommendation to the combination of hydralazine and isosorbide dinitrate for patients self-identified as African American who have New York Heart Association (NYHA) class III-IV disease atop other optimal medical therapy and a 2b recommendation to use for patients who can't tolerate other agents or who have renal insufficiency.

Omega-3 polyunsaturated fatty acid supplementation also got a recommendation as "reasonable," as did ivabradine (Corlanor) for class II-III HFrEF and elevated resting heart rate and digoxin for patients symptomatic despite optimal medical therapy. But anticoagulation was not recommended without a specific indication.

For patients with mildly reduced ejection fraction in the 41-49% range, SGLT2 inhibitors got a 2a recommendation while the other "pillars" got a 2b recommendation, particularly for consideration at the lower end of the spectrum.

For heart failure with preserved ejection fraction, the strongest recommendation was to control blood pressure, followed by a 2a recommendation for management of atrial fibrillation to ease symptoms and for use of SGLT2 inhibitors. Selected patients could also be considered for MRAs, ARBs, and sacubitril/valsartan, especially on the lower end of the ejection fraction range.

The AHA/ACC guidelines on heart failure suggested that efficacy and safety of omecamtiv in patients with stage D heart failure with reduced ejection fraction is an area that needs further research. FDA's decision on approval is expected in November.

Hypertrophic Cardiomyopathy

For medical management in hypertrophic cardiomyopathy (HCM), the 2020 AHA/ACC guidelines recommended direct oral anticoagulants for persistent or paroxysmal atrial fibrillation as the default, regardless of CHA₂DS₂VASc score.

For patients with symptomatic left ventricular outflow tract obstruction (LVOTO), the guidelines gave a class 1 recommendation to nonvasodilating beta-blockers (or nondihydropyridine calcium channel blockers if not tolerated or ineffective) and to the addition of disopyramide in cases of persistent severe symptoms from LVOTO despite those agents.

For patients with obstructive HCM, the guidelines gave a class 1 endorsement of vasoconstrictors without inotropic activity (alone or with beta-blockers) for acute hypotension unresponsive to fluid administration and a class 2b recommendation for cautious use of low-dose oral diuretics for persistent dyspnea with volume overload and high left-sided filling pressures.

Discontinuation of vasodilators and digoxin was deemed reasonable, whereas verapamil was noted as potentially harmful for patients with obstructive HCM patients with severe dyspnea at rest, hypotension, resting gradients over 100 mm Hg, or age less than 6 weeks.

While not yet incorporated into guidelines, mavacamten (Camzyos) received the FDA approval in April for the treatment of obstructive hypertrophic cardiomyopathy in people with NYHA class II-III symptoms. Access, though, is through a restricted program under a risk evaluation and mitigation strategy due to risk of reducing ejection fraction and pushing patients into heart failure due to systolic dysfunction. FDA cautioned against use in patients for people with left ventricular ejection fraction (LVEF) below 55%, nor as a continued therapy for users who experience LVEF dipping below 50% or heart failure symptoms while taking the medication.

Restrictive Cardiomyopathy

For patients with restrictive cardiomyopathy (RCM), aside from treating any identified underlying cause, heart failure management with the usual agents is complicated, noted a review in Circulation Research by Morie Gertz, MD, and colleagues.

Volume status can be challenging to manage with diuretics, "as patients with RCM rely on high filling pressures to maintain cardiac output and excessive diuresis may result in tissue hypoperfusion," the authors explained. "The use of beta-blockers or calcium channel blockers to increase filling time or to manage arrhythmias should be carefully introduced, as some patients may be intolerant."

ACE inhibitors and angiotensin II receptor blockers aren't well proven for these patients and may not be well tolerated.

On the other hand, most patients stand to benefit from anticoagulation, due to elevated risk of left atrial thrombus. That's especially the case for cardiac amyloidosis patients, for whom anticoagulation has a class 2a recommendation with atrial fibrillation regardless of CHA₂DS₂-VASC risk score and for those with an enlarged atrium even when in sinus rhythm, according to a review in Current Treatment Options in Oncology.

Dilated Cardiomyopathy

Specific considerations for types of dilated cardiomyopathy noted in a 2016 scientific statement from the AHA included taking into account both pregnancy and breastfeeding status when using guideline-directed medical therapy for peripartum cardiomyopathy. Classes of medications not safe in animal models in pregnancy include ACE inhibitors and ARBs, while warfarin carries known fetal risks. Medications deemed unsafe for use while nursing include ACE inhibitors, ARBs, carvedilol, spironolactone, enoxaparin, nitroprusside, and dobutamine.

For acute dilated cardiomyopathy from giant cell myocarditis, immunosuppressive therapy that includes calcineurin inhibitors and corticosteroids was recommended with a level of evidence B.

For cardiac sarcoidosis, specific considerations are risk of high-grade atrioventricular block in patients without pacemakers when using beta-blockers and risk of heart block and arrhythmias with digoxin in the acute stage. Corticosteroids are a mainstay of therapy and immunosuppression has been used as well, although without randomized trial evidence and only "sometimes" associated with positive outcomes, according to a 2021 review in the Journal of the American Heart Association.

Supportive care for stress-induced (Takotsubo) cardiomyopathy centers on managing heart failure symptoms and treating hypotension and cardiogenic shock, the AHA scientific statement noted. Observational data have suggested lower risk of recurrence with ACE inhibitors, ARBs, and beta-blockers. However, the scientific statement cautioned, "Although the mechanism of stress cardiomyopathy is neurohormonally mediated, the role of neurohormonal agents is as yet unknown."

Cardiac Amyloidosis

For cardiac amyloidosis, most supportive medications for heart failure management are not well tolerated, the review by Gertz and co-authors noted. "Angiotensin-converting enzyme inhibitors and angiotensin receptor II blockers often lead to profound hypotension, even in modest doses. Beta-blockers and calcium channel blockers may aggravate hypotension because of the fixed stroke volume and need for a higher heart rate to maintain cardiac output."

Loop diuretics and aldosterone antagonists are mainstays in cardiac amyloidosis to address heart failure symptoms, albeit requiring monitoring for changes in creatinine and electrolytes, the team added. "Care should be taken to avoid excessive diuresis as this may invoke a fall in filling pressures and result in systemic hypoperfusion."

For cardiac amyloidosis patients with arrhythmia, rate control with digoxin risks toxicity because it can bind to amyloid fibrils, and amiodarone "has not been proven to be beneficial and can cause significant thyroid dysfunction," but beta-blockers "may be used cautiously for this purpose," the authors noted.

Thanks to growing disease awareness and progress in diagnosis, specific therapies developed in recent years for these patients represent "real progress," said the authors of a review in Current Treatment Options in Oncology.

For systemic light chain immunoglobulin (AL) amyloidosis, the most common form of this type of restrictive cardiomyopathy, advances in chemotherapy and immunotherapy have boosted survival to the point where "therapies such as implanted cardiac defibrillators and heart transplantation that were usually not indicated for patients with advanced light chain amyloid cardiomyopathy to now be applied in selected patients," the reviewers noted.

The goal for AL amyloidosis is complete (or near-complete) reduction in the amyloid precursor, Gertz and co-authors noted. "If this cannot be achieved within 2 to 3 months of initial treatment, an alternative regimen is warranted."

Autologous stem cell transplantation for candidates can be challenging, but the depth and durability of responses to this method of suppressing amyloidogenic light chain synthesis are better than those of conventional chemotherapy.

Melphalan and dexamethasone combination chemotherapy doesn't work well in advanced cardiac disease but does yield responses in up to two-thirds of patients otherwise. A three-drug combination with bortezomib can increase the response rate further but also increase cardiac symptoms, the authors noted. The combination of those three agents with the monoclonal antibody daratumumab plus hyaluronidase-fihj (Darzalex Faspro) was approved for newly diagnosed AL amyloidosis in 2021 based on improved hematologic complete response rates.

Starting induction chemotherapy can potentially improve organ function sufficiently to allow patients who weren't candidates for stem cell therapy to become eligible, Gertz and colleagues noted.

Immunomodulatory drugs like thalidomide or preferably lenalidomide and pomalidomide combined with corticosteroid treatment have antiplasma cell activity in AL amyloidosis as well.

For transthyretin (ATTR) amyloidosis -- the second most common form of amyloidosis with cardiac involvement -- tafamidis (Vyndaqel, Vyndamax) is approved to stabilize transthyretin based on findings of reduced mortality and cardiovascular hospitalization, albeit with a high price tag. The agent received a class I recommendation in the AHA/ACC guidelines for select patients with wild-type or variant ATTR amyloidosis and NYHA class I-III symptoms, albeit judged of low economic value.

The non-steroidal anti-inflammatory drug diflunisal (Dolobid) is often used off-label for the same purpose in ATTR amyloidosis, with some results supporting better cardiac structure and function. Drugs that slow production of TTR through gene silencing, such as patisiran (Onpattro) and inotersen (Tegsedi), are approved for treating polyneuropathy associated with hereditary ATTR amyloidosis.

Read previous installments in this series:

Part 1: Cardiomyopathy: What are the Signs, What are the Symptoms?

Part 2: Diagnosing Cardiomyopathy: History, Examination, and Testing

Part 3: Cardiomyopathy: Epidemiology, Etiology, and Pathophysiology

Part 4: Case Study: Cardiomyopathy From Epinephrine in Anesthesia

Part 5: Cardiomyopathy: Cascade Screening for Families

Part 6: Cardiomyopathy: Outside the Office

Part 7: Deciding on Implantable Cardiac Devices for Cardiomyopathy

Part 8: Case Study: The Dangerous Habit That Led to Non-Ischemic Cardiomyopathy in a Healthy Man

Up next: Inpatient Management