Nifedipine, Amlodipine linked to lower mortality, intubation in COVID-19 patients: Study

COVID-19 pandemic continues to affect people worldwide with confirmed cases in more than 200 countries. As per recent reports, over 20+ million people have been infected with the novel coronavirus globally, with India alone accounting for over 2.5 million+ cases till now.

As the COVID-19 pandemic continues to break records, there have been concerns on medication intake by patients with cardiometabolic disorders as they are more vulnerable to the coronavirus infection. 

Patients with existing cardiovascular diseases are known to be at higher risk of complications due to COVID-19. It has been found that patients with diabetes, hypertension, and other comorbidities are at higher risk of death from the virus (1,2). Previous speculations proposed that treatment of hypertension with RAS inhibitors may influence SARS-CoV2 binding to ACE2, promoting the disease (8). These speculations were based on some experimental findings that RAS inhibitors cause a compensatory increase in tissue levels of ACE2 (9) and that ACE- inhibitors or ARBs may be detrimental in patients exposed to SARS-CoV-2 (10) 

With many consequent studies negating these findings, major CV Societies came forward and stated that patients on ACEIs or ARBs should not stop their treatment. (11,12) 

In contrast to ACEi/ARB, many studies have gone head to point out that calcium channel blockers (CCBs) do not appear to upregulate ACE2 (3).A recent study by Reynolds et al. (4) also favoured the safety and efficacy of CCB in COVID-19 patients.

In their study published in the journal Lancet, Lei Fang and colleagues (5) also suggested that clinicians should consider withholding angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) because of a potential increased risk of worse clinical outcomes in patients with coronavirus disease 2019 (COVID-19). They further suggested calcium channel blockers as an alternative.

Dihydropyridine calcium channel blockers (CCB) such as Nifedipine including long-acting Nifedipine as well as Amlodipine are typically used agents in the clinical management of hypertension. At the same time, both medications have been utilized to treat various pulmonary disorders with vasoconstriction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been described to use the angiotensin-converting enzyme 2 (ACE2) receptor for entry into target cells expressed by the epithelial cells of the lung, leading to vasoconstrictive, proinflammatory, and pro-oxidative effects (6). This vasoconstriction may play a role in the pathogenesis of the disease. Dysregulation or loss of hypoxic pulmonary vasoconstriction is suspected in Coronavirus Disease 2019 (COVID-19) as well (7-8).

In a recent study published in the Cureus Journal of Medical Science, Isaac Solaimanzadeh, Internal Medicine, Interfaith Medical Center, Brooklyn, USA, conducted a retrospective review on CCB use in hospitalized patients in search of any difference in outcomes related to specific endpoints: survival to discharge and progression of disease leading to intubation and mechanical ventilation.

The authors noted that Nifedipine and Amlodipine were found to be associated with significantly improved mortality and a decreased risk for intubation and mechanical ventilation in elderly patients hospitalized with COVID-19

Methodology

The authors performed a retrospective review of electronic medical records for all patients admitted to a community hospital who tested positive for SARS-CoV-2, who were at or above the age of 65, and who either expired or survived to discharge from hospital between the start of the public health crisis due to the viral disease (earliest admission date of a patient that tested positive at this hospital: February 27, 2020) and April 13, 2020.

Only patients with a final disposition on the day of study conclusion were included and that many more patients still hospitalized were not included in this review. The two groups were: (1) Treated with either nifedipine or Amlodipine as part of the CCB group or (2) not treated with either Amlodipine or nifedipine as part of the no-CCB group. Being "on" either of these medications required that they received more than one dose.

Patients in both groups were managed with antibiotics in addition to hydroxychloroquine depending on patient consent and/or QTc prolongation status.

The patient outcomes were assessed for survival to discharge or signed out independently against medical advice (AMA) and expiration. Besides, the authors looked at as a secondary outcome was the need for intubation and mechanical ventilation.

Findings

Based on the above criteria, a total of 77 patients were identified. Of the 77 patients that were identified, 18 survived until discharge, and 59 expired. Seven patients from the expired group were excluded since they died within one day of presentation to the hospital. Five patients were excluded from the expired group since their age was above that of the eldest patient in the survival group (89 years old).

On the remaining patients, the authors made the following findings.

• With 65 patients left, 24 were found to have been administered either Amlodipine or nifedipine (CCB group), and 41 were not (No-CCB group).
• Patients treated with a CCB were significantly more likely to survive than those not treated with a CCB: 50% survived, and the remaining 50% expired in the CCB group vs. 14.6% that survived and 85.4% that expired in the No-CCB treatment group.
• 67% of patients that survived and that were successfully discharged from the hospital were on a CCB, whereas 74% (35/47) of the patients that expired were not on a CCB
• CCB patients were also significantly less likely to undergo intubation and mechanical ventilation. Only one patient (4.2%) was intubated and mechanically ventilated in the CCB group whereas 16 (39.0%) were intubated in the No-CCB treatment group.
• Other sample medications administered, including antibiotics, fluids as well as steroids were not significantly different between groups.

These results revealed that dihydropyridine calcium channel blocker (nifedipine or Amlodipine) usage is associated with significantly improved mortality in elderly patients hospitalized for COVID-19. The results also implied that CCB usage is associated with a significantly decreased risk for intubation and mechanical ventilation.

While pointed out that larger clinical studies are warranted on this matter, the authors noted the possible benefits of nifedipine and Amlodipine in patients hospitalized with COVID-19.

"For those that already have hypertension and present to hospital with elevated blood pressure, assuming no contraindications exist, it may be fair to give preference to a CCB as first-line therapy for concomitant benefit," they wrote

"Moreover, CCB treatment, while monitoring blood pressure closely in patients that are suffering from COVID-19, and that do not have underlying Hypertension, may be envisaged," the added

The authors called for further studies of other potential therapies that function as vasodilators in the pulmonary arterial flow to be pursued as well adding that potential benefits may outweigh the risks of including nifedipine or Amlodipine in the treatment regimens of elderly patients with hypertension hospitalized with COVID-19.

This data provides an impetus to explore different approaches to the treatment of patients with COVID-19. Focusing on vasodilatory agents may allow for an alternative treatment strategy. Herein, improved flow via the alveolar-capillary unit may be achieved. With improved flow, impediments to oxygenation, including inflammation and vasoconstriction, maybe better negotiated. Furthermore, blood transit improvement as a result of vasodilation may potentially offset clot formation. Lastly, fluid accumulation or oedema that can inhibit oxygenation may be collectively reduced as well. Altogether, the improved flow may attenuate the precipitous progression of the disease.

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Nifedipine, click here

References:

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2. Zhou F et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.

3. Balasubramanyam M. COVID-19: Is it time to revisit the research on calcium channel drug targets? EMJ Diabet. 2020; DOI: 10.33590/emjdiab/200608 

4. Reynolds HR et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19. N Engl J Med. 2020;NEJMoa2008975

5. Fang L Karakiulakis G Roth M Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020; (published online March 11.) https://doi.org/10.1016/S2213-2600(20)30116-8

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