Nifedipine revisited: Extended-release formulations superior in patients with coronary artery disease, shows study

Nifedipine acts via vasodilatation, thus reducing peripheral resistance. This further lowers the arterial blood pressure and the myocardial oxygen demand. It also acts via sympathetic activation to lower the heart rate (4,5). Such multifaceted action of this potent drug has been its strength in sustaining its importance in heart diseases for such a long time. Addressing the varied potential applications of this drug, some studies have highlighted the sympathetic stimulation by nifedipine, leading to its use in cases of acute angina and hypertensive patients (6), yet some others have focused on the severe adverse effects (7,8,9) related to calcium channel antagonists on clinical outcomes of patients with coronary artery diseases.

As this drug was widely used previously in the form of short-acting formulations, there have been mounting concerns in the last decade on the safety of the same and this has shifted the focus on long-acting and extended-release nifedipine.

Previous trials on the effect of nifedipine have given mixed results. Studies as early as 1995 had pointed out that that short-acting nifedipine increased mortality by up to 16 percent in patients with coronary heart disease. The research team further noted that the trend of prescribing short-acting nifedipine for indicated medical conditions has declined substantially over the past 5 years. (9) More recently, a notable study by Snider et al (5) summarizing the available data on long-acting nifedipine and its role in the management of hypertension, had highlighted that due to the high incidence of tachycardia and vasodilatory symptoms associated with short-acting nifedipine, emphasis is now being put on determining the benefits of extended-release nifedipine.

Under such a scenario, thorough research on this drug, taking into account the two formulations available, specifically on known patients with coronary artery disease, has been till now lacking.

To bridge such inconsistencies in previous literature, in 2019, a team of researchers under John D. Parker, from the Department of Pharmacology and Toxicology, University of Toronto, Ontario, Canada, sought to carry out a comprehensive assessment of the effects of nifedipine,in both short-acting and extended-release formulations, in patients with stable coronary artery disease. The interesting findings have been put forth in Scientific Reports.(10)

The current study was a single-centre study designed to compare the pharmacokinetic, pharmacodynamic and sympathetic nervous system responses to two different formulations of the dihydropyridine calcium antagonist- nifedipine.

The study population included 40 patients with known coronary artery disease. and a history of stable angina. None had experienced an acute coronary syndrome or revascularization procedure within 3 months of their participation in the study. All patients had preserved lef ventricular systolic dysfunction with an ejection fraction ≥45 percent by two-dimensional echocardiography and none had a history of congestive heart failure. All participants were taking either atenolol (25–50 mg daily) or metoprolol (25–75mg twice daily). Randomization was done to receive the drug in a blinded manner using a double-dummy technique for allocation to placebo (n=9), short-acting nifedipine 10 mg, TID (n=16) or extended-release nifedipine Gastrointestinal Terapeutic System (GITS) 60mg, OD (n=15). These medications were continued for 7–10 days.

On the final day, systemic blood pressure, cardiac filling pressures, cardiac output, plasma norepinephrine (NE) and total body NE spillover were measured at baseline (time 0) and repeated at intervals for 6hours.

Fick method was used to estimate cardiac output. Total body sympathetic activity was estimated using the NE spillover technique. Plasma concentrations of NE were quantified using HPLC and tritium-labeled NE concentrations were determined using scintillation spectroscopy. Active plasma renin, atrial natriuretic peptide and endothelin-1 concentrations were determined using radioimmunoassay. Plasma nifedipine concentrations were measured using gas chromatography.

Blood sampling for catecholamines and plasma nifedipine concentrations were carried out at control (time 0) and at 30, 60, 90, 120,270, 300, 330 and 360 minutes post study medication.

As for the data analysis, researchers followed a two-way analysis of variance (ANOVA) with treatment (placebo, short-acting nifedipine or nifedipine GITS) as a factor for continuous variables while Fisher's exact test was used to compare categorical variables.

Key highlights from the results have been summarised as follows-

• There were no differences in baseline measures between groups. Following the morning dose of study medication, there were no changes in hemodynamics or sympathetic activity in the placebo group.

• However, there was a significant fall in blood pressure and a significant increase in total body NE spillover in both nifedipine groups.

• Importantly, the increase in sympathetic activity in response to short-acting nifedipine began earlier (30minutes), remained elevated for 120 minutes, and was much greater than that observed in the extended-release group, which occurred later (270minutes).

• The ANOVA revealed significant changes in heart rate and mean arterial blood pressure over time and significant interaction with treatment allocation. There was no significant change in heart rate following the administration of the placebo .

• There was a rapid increase in heart rate following administration of short-acting nifedipine at 30minutes (P<0.001). This increase in heart rate rapidly returned to control values by the 60-minute time point. There was no significant change in heart rate following administration of nifedipine GITS.

Observing such results, the research team made some important suggestions.

• A major observation made in this study was that the peak time, duration, as well as the magnitude of variability, noted for the fall in blood pressure, rise in NE spillover and heart rate, among the short release and extended-release nifedifine depended very much on the pharmacokinetics and pharmacodynamics of the individual drug formulations.

• This study,once again, reinforced the fact that extended-release nifedepine has a much wider safety and tolerability profile when compared with the short-acting one, especially in cardiac patients.

• Unlike previous study designs which mostly took into account plasma NE, involving patients with hypertension; this was the first of its kind study where radiotracer methodology was used to examine the impact of nifedipine on the activity of the sympathetic nervous system; thus providing a more accurate measurement which accounts for both changes in production and clearance of NE. This further implies that no place of controversy on the fact that extended releases /long-acting formulations are better than the short-acting ones.

"Given the potential adverse effects of sustained increases in sympathetic activity in patients with cardiovascular disease, the current study suggests that when patients with coronary artery disease are treated with nifedipine, concurrent therapy with a beta-adrenergic blocking agent should be used whenever possible. Finally, our study confirms that the use of short-acting nifedipine is associated with abrupt decreases in systemic arterial blood pressure and greater reflex increases in activity of the sympathetic nervous system which serve to emphasize that short-acting formulations of dihydropyridine antagonists should be avoided in patients with cardiovascular disease." the team concluded.

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