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| EDITORIAL |
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| Year : 2021 | Volume
: 3
| Issue : 2 | Page : 49-50 |
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Drug treatment of cardiac failure
Govindan Vijayaraghavan
Department of Cardiology, Kerala Institute of Medical Sciences, Trivandrum, Kerala, India
| Date of Submission | 16-Dec-2021 |
| Date of Decision | 27-Dec-2021 |
| Date of Acceptance | 04-Jan-2021 |
| Date of Web Publication | 21-Jan-2022 |
Correspondence Address:
Prof. Govindan Vijayaraghavan
Department of Cardiology, KIMSHEALTH, Trivandrum - 695 029, Kerala
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ACCJ.ACCJ_23_21
How to cite this article:
Vijayaraghavan G. Drug treatment of cardiac failure. Ann Clin Cardiol 2021;3:49-50 |
For centuries, drugs that allegedly increase the power of contraction of the failing heart have been used for the treatment of dropsy. Squill or sea onion, Urginea (Scilla) maritima, a seashore plant, was known by the ancient Romans and Syrians and possibly also by the ancient Egyptians. Squills were used erratically, but some prescriptions indicate that they may have also been used for the treatment of edematous states. The toxic effect of Strophanthus species was known from poisoned arrows used by the natives of Africa. Digitalis derived from the foxglove plant, Digitalis purpurea, is mentioned in writings as early as 1250. A Welsh family, known as the Physicians of Myddvai, collected different herbs and Digitalis was included in their prescriptions. Dr. William Withering, an English physician and botanist, published a monograph in 1785, describing the clinical effects of an extract of the foxglove plant. The indication and the toxicity of digitalis were reported in his book, “An Account of the Foxglove and Some of Its Medical Uses” with practical remarks on dropsy and other diseases. The narrow dosage scheduling of digoxin and its overlap of therapeutic and toxic dosing guidelines became a major handicap in the use of this drug in cardiac failure. We had to understand the exact role of this drug and we zeroed down on only two indications; one, where it reduces the readmission rates of patients with heart failure (HF); and two, in controlling heart rate in atrial fibrillation.
Over the last two centuries, the diagnosis and treatment of cardiac failure underwent radical changes and we learned a lot about how to improve the mortality and morbidity of this disease. The attention changed from improving contractility of the heart muscle to improving the entire hemodynamics of cardiac failure. The next development came from Dr. Carl Wenckebach's clinic in Vienna with the discovery of mercurial diuretics. Later, the thiazide diuretics were discovered followed by the loop diuretics. However, it became clear that these drugs did not alter the mortality of cardiac failure.
Beta-blockers were introduced in the 1960s with a strict warning that it should not be used in cardiac failure. It took many years to discover that sympathetic over-activity was responsible for worsening cardiac failure and careful use of beta-blockers resulted in alleviation of symptoms of cardiac failure with reduced mortality and morbidity. Experimental work showed that mineralocorticoid hormones increase myocardial fibrosis and spironolactones reduce myocardial fibrosis in cardiac failure. Introduction of angiotensin-converting inhibitors and later angiotensin receptor blockers with its vasodilatory property gave remarkable relief to patients with cardiac failure, which again reduced mortality and morbidity. There was one more step forward with the understanding of neprilysin inhibition in cardiac failure and the use of angiotensin receptor blocker valsartan and neprilysin inhibition together in cardiac failure.
Over the years, we realized that about 60% of patients with HF do have diabetes mellitus. Patients with this condition do die mostly from cardiovascular (CV) disease, and the antidiabetic drugs that control blood sugars do not reduce mortality of this disease. We needed drugs that can control the blood sugar and at the same time reduce the diabetic vascular disease. Newer sodium glucose co-transporter 2 (SGLT2) inhibitor drugs could achieve both, and these drugs proved to be reducing cardiac failure probably by the osmotic diuresis induced by the SGLT2 inhibition. This is a distinctly different diuretic mechanism than that of other diuretic classes and results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid space than from the circulation. Many gliflozins appears to lessen and reverse adverse remodeling. While reducing dilation and hypertrophy of the left ventricle, it increases the ejection fraction. Dapagliflozin is an SGLT2 inhibitor that demonstrated a significant and clinically meaningful reduction in both the CV death and worsening HF components of the primary composite endpoint in patients with HF with reduced ejection fraction (HFrEF), both with and without type 2 diabetes. SGLT2 inhibitors empagliflozin and dapagliflozin are recommended for the treatment of chronic HFrEF, according to the latest 5-year update of the European Society of Cardiology Guidelines in acute and chronic HF. This was a major step forward in patients with diabetes and HF.
Research workers never lost their interest in improving the contractility of the ventricular muscle in cardiac failure. It is well known that any drug that increases the contractility may increase the heart rate and such drugs are useful only to tide over emergencies in cardiac failure. Among patients with HF and a reduced ejection fraction, those who received omecamtiv mecarbil, a drug that increases the contractility of the myocardium, had a lower risk of a composite of HF events and CV death than those who received placebo. Omecamtiv mecarbil, which is the first of this class, augments cardiac contractility by selectively binding to cardiac myosin, thus increasing the number of force generators (myosin heads) that can bind to the actin filament and initiate a power stroke at the start of systole. Short-term intravenous administration of omecamtiv mecarbil improved cardiac performance in early clinical studies. In patients with chronic HFrEF, the administration of omecamtiv mecarbil for 20 weeks increased the left ventricular systolic ejection time and stroke volume, decreased the left ventricular systolic and diastolic volumes (which suggested beneficial reverse cardiac remodeling), and reduced the plasma natriuretic peptide levels and heart rate. In the GALECTIC-HF trial among patients with HF and reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a HF event or death from CV causes than those who received placebo. This trial proved that improving cardiac function by selectively targeting the cardiac sarcomere with omecamtiv mecarbil can improve clinical outcomes.
Vericiguat is an oral, once-daily soluble guanylate cyclase (sGC) stimulator, an essential enzyme in the nitric oxide (NO) signaling pathway. HF results in impaired synthesis of NO and decreased activity of sGC. NO binds to sGC and stimulates the synthesis of intracellular cyclic guanosine monophosphate (cGMP), a second messenger involved in the maintenance of vascular tone, as well as cardiac contractility and remodeling. Defects in this pathway are thought to contribute to the myocardial and vascular dysfunction associated with HF and are therefore a desirable target in its treatment. Vericiguat bypasses the need for NO-mediated activation and in doing so causes an increase in the production of intracellular cGMP that results in vascular smooth muscle relaxation and vasodilation. In the VICTORIA clinical trial, 4.2% reduction was observed in the annualized absolute risk with vericiguat compared to placebo during the study. The treatment result represented a decline in both cardiovascular death and HF. The most common adverse reactions observed in the patients during the clinical trial were anemia and hypotension. The difference favoring vericiguat appeared after approximately 3 months of treatment and persisted throughout the trial. The 10% relative difference between the groups in the primary composite outcome in this high-risk population at a median follow-up of 10.8 months translated into an absolute event rate reduction of 4.2 events per 100 patient-years. The prespecified events were accrued earlier than expected and thereby leaving a relatively short exposure time and potentially limiting the assessment of a later effect. The drug was FDA approved by January 2021.
The drug treatment of HF seems to have taken a turn toward increasing the contractility and ejection fraction of the heart. We are back in the digoxin era. What the digoxin lacked, we hope to achieve with the newer drugs.
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