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ORIGINAL ARTICLE
Ahead of print publication  

Prescription practices, experiences, and perspectives on the usage of hydroxychloroquine among rheumatologists and other specialists


1 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Emergency Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 MBBS Student, Medical College, The Aga Khan University, Karachi, Sindh, Pakistan
4 Department of Clinical Immunology and Rheumatology, JIPMER, Puducherry, India
5 Department of Medicine, PGIMER, Chandigarh, India
6 Department of Surgical Gastroenetrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
7 Department of Medicine, University College of Medical Sciences, Delhi, India

Date of Submission25-Nov-2020
Date of Acceptance19-Jan-2021
Date of Web Publication08-May-2021

Correspondence Address:
Latika Gupta,
Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_319_20

  Abstract 


Background/Objectives: The use of hydroxychloroquine (HCQ) for COVID-19 has raised concerns for adverse effects. We aimed to understand the practice, perceptions, and experience of adverse drug reactions (ADRs) with HCQ use for COVID-19 and other indications.
Methods: A validated e-survey with 30 questions was circulated among rheumatologists and other specialists using SurveyMonkey. Responses from rheumatologists were compared with other doctors (odds ratio [OR], median, interquartile range), and ADRs encountered based on their indications.
Results: Among 410 respondents (71.2% rheumatologists, 27% academicians) with a lifetime experience of 17886 (4884–52074) patients over 12 (7–20) years, and 148 (48–349) prescription of HCQ per month, one-third (135) were managing COVID-19 with 10 (0–60) prescriptions per physician. Electrocardiograms were seldom ordered preprescription (5%), but visual scans were requested by one-thirds, especially by rheumatologists (OR-1.9). Agreement on the safety of HCQ for non-COVID indications was nearly unanimous (99%), but only two-third (64%) perceived it to be safe for COVID-19, with most (72%) being uncomfortable using HCQ with macrolides. ADRs were most often encountered after middle-age with skin pigmentation (554 [123–2063]) being the most frequent, followed by gastrointestinal intolerance (222 [42–980] per million prescriptions). Cardiac toxicity was rarely reported. ADRs other than cutaneous and visual were noted more frequently by nonrheumatologists. Rheumatologists were less likely to consider HCQ unsafe (OR-0.04) and reportedly faced a greater challenge in drug procurance (OR-2.6) during the pandemic.
Conclusions: Most ADRs are rare with HCQ use in our respondent population with a large user experience. HCQ use was considered unsafe by one-thirds in the setting of COVID-19 but not outside it, lesser so by rheumatologists.

Keywords: COVID-19, drug-related side effects and adverse reactions, hydroxychloroquine, practices, surveys and questionnaires



How to cite this URL:
Naveen R, Verma A, Raza HA, Chengappa K G, R Naidu G S, Sharma S, Goel A, Misra DP, Sharma A, Gupta L, Agarwal V. Prescription practices, experiences, and perspectives on the usage of hydroxychloroquine among rheumatologists and other specialists. Indian J Rheumatol [Epub ahead of print] [cited 2021 Jun 18]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=315684




  Introduction Top


Since the beginning of the pandemic, researchers and clinicians have engaged in an unrewarding quest for the magic elixir against the coronavirus 2 disease (COVID-19).[1],[2] While immunosuppressants are by convention associated with an accentuated infection risk, immunomodulators hold the potential to fight both an immune-suppressed state, and an accentuated, dysfunctional, and potentially harmful immune response to a pathogen.[3] The unique immunomodulatory action of hydroxychloroquine (HCQ) makes it a particularly attractive drug for use in COVID-19-induced inflammation.[4] The ability of HCQ to bind the angiotensin-converting enzyme 2 (ACE) receptors and its weak anti-thrombotic effects add to the predicted potential. Despite the initial investments of hope, recent conflicting and varied reports of inefficacy have cast doubt on its utility.[5] Moreover, reports of cardiac toxicity in the setting of COVID-19 have further compounded the issue.[6] The widespread nature of the pandemic and rising social media use among physicians as well as the lay public for research material on the subject, has led to greater awareness of recent research as well as misinformation from unverified sources.[7] As a result, widespread concerns of safety have given rise to reluctance among patients with rheumatic disease (RD) to continue the drugs for their primary illness.[8],[9],[10]

Since drug metabolism, pharmacodynamics, and efficacy are influenced by various factors, we hypothesize that the efficacy and safety of HCQ may differ significantly in RDs from the setting of COVID-19. Moreover, physician experience with drug usage can influence confidence in safety and perceptions of its utility as well as safety. Understanding of the disease pathogenesis, including the molecular basis and mechanism of actions, can be another crucial determinant of a physician's choice of drugs. Treading the thin line between infection and inflammation, rheumatologists are more experienced with the unique situation of using immunosuppressants/modulators in infection as well as drug interactions and polypharmacy.[11]

We hypothesize that the physician's specialty may significantly influence their perception of the safety concerns in the usage of the drug. Moreover, we sought to determine the difference in experience with the usage of drugs by physicians and rheumatologists in the setting of COVID-19 as well as outside it. We undertook this survey among physicians who have prescribed the drug for any indication, to understand their practice, experience, and perceptions about the drug, followed by intergroup comparisons.


  Methods Top


Questionnaire design

Our questionnaire featured 30 questions, seven of which were open-ended. The survey was designed to arrive at the indications for usage, frequency of usage, dosing and monitoring practices, and adverse drug effects (adverse drug reactions [ADR]) experience. Besides, questions pertaining to experience with COVID-19, usage for self, and prescription practices for COVID-19 and adverse effect (ADR) profile in the COVID-19 setting were assessed. The penultimate section consisted of their perceptions regarding the safety of the drug, and their sources of information on the same. Finally, three questions aimed to characterize the respondent population's demographic profile, expertise, and location. The average survey time was 9 min and 5 min for those where logic function skipper certain sections. The respondents could change the answers before submission but not after it. Logic functions (checkpoints) were incorporated in the survey design to eliminate those who did not prescribe HCQ for prophylaxis and treatment. Those who had not done so were automatically directed to the next page of the survey after skipping the number of questions relevant to the two categories. All questions were mandatory. The survey was completely anonymized with the exception of Internet protocol (IP) addresses.

Survey validation

Five individuals (all consultants in rheumatology and one undergraduate medical student) from the team participated in the assessment face-validity. The survey was then uploaded on the SurveyMonkey platform. The logic function was used to bypass questions on experience while using HCQ for self and COVID-19 when the answer to the first question of the section was “no.” Following this, the final survey was preliminarily filled by five individual respondents to identify mistakes in wording, grammar, and syntax, and critically evaluate the modifications from the original survey. Further, various answers were chosen for each section to check the correct functioning of the logic function of the survey. Clutter and junk responses were omitted before analysis. Overall, the questionnaire underwent fifteen rounds of revision.

Population selection

The questionnaire was widely disseminated over social-media platforms (Twitter, Facebook, and WhatsApp) with the hashtags #HCQ and #COVID-19 to be voluntarily filled by rheumatologists and other specialists who have prescribed the drug. It was also circulated over E-mail to members of the Indian Rheumatology Association. Convenience sampling was the technique used, and all those who agreed to participate were included in the survey. The eligible participants were given 3 weeks to voluntarily complete the questionnaire from June 22 to July 14, 2020. Reminders were sent five times during the period to accrue a better response.

Ethics clearance

An exemption from the review was obtained from the institute ethics committee of Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India as per local guidelines (2020-110-IP-EXP-16).[12] We adhered to the Checklist for Reporting Results of Internet E-surveys to report the data.[13] A cover letter detailed the nature and intent of the survey, with the investigator details and data anonymization policy. Informed consent was taken at the beginning of the survey, and no incentives were offered for survey completion. IP addresses were checked to prevent duplication of responses.

Analysis

Descriptive analyses (median, interquartile range) were employed, and figures were downloaded from https://www.surveymonkey.com/or drawn using Microsoft Powerpoint. For the purpose of analyses, agree and strongly agree were considered as agreement and disagree and strongly disagree clubbed together as disagreement. Responses from rheumatologists were compared with other physicians (odd's ratio [OR]), and ADRs encountered in COVID-19 compared with use for other indications.


  Results Top


Respondent characteristics

Of the 2616 who were invited to participate, 1121 (43%) had opened the survey, and 410 of them (36.5%) had completed the survey (227 via survey monkey web link, 183 via E-mail invitation). Out of 410 respondents, (292, 71.2%) were rheumatologists and (107, 27.72%) were academicians, with most (319, 82.64%) being from India followed by the United State of America (15, 3.89%), Australia (8, 2.07%), 112 (29.27%) used HCQ for COVID-19 at the time of the survey. The median user experience amounted to 17886 (4884–52074) patients and 148 (48–349) prescriptions per month over 12 (7–20) years of user experience. 162 (40%) and 3 (1%) were excluded from subsequent questions when they had responded that they had not used HCQ for prophylaxis or for treatment [Table 1].
Table 1: Demographics and hydroxychloroquine response of total participants

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Prescription practices in rheumatology

SLE was the most common indication (344, 84%), followed by RA (340, 83%) and other inflammatory arthritides (195, 48%). Most (268, 65%) used HCQ at a dose of 5 mg/kg, with merely a minuscule fraction (4, 0.98%) using it at doses >6.5 mg/kg.

ADRs were most often encountered in middle-aged (216, 53%) individuals, followed by the elderly (180, 44%), young adults (107, 26%), children (24, 6%). An electrocardiogram (ECG) was always prescribed before HCQ by 19 (5%), with 368, either requesting it seldom (98, 24%) or not at all (270, 66%) [Figure 1]. Among the investigations ordered, hemogram was the most common (220, 54%), followed by liver function tests (209, 51%). Renal function tests (195, 48%), fundus (250, 61%), urine microscopy (76, 19%), electroretinogram (31, 8%), optical coherence tomography (110, 27%), and visual field testing (165, 40%) were advised sometimes. 44 (11%) doctors did not investigate at all before initiating HCQ.
Figure 1: (a and b) Response to questions pertaining to investigations prior to hydroxychloroquine prescription (c and d) response to questions pertaining to hydroxychloroquine prescription for COVID-19 (e) sources of information for the respondents

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Use for the management of COVID-19

Among 410, 135 (33%) were managing COVID-19 patients at their hospital. 208 (51%) took HCQ for prophylaxis themselves, with 200 mg twice a week being the most common dose (101, 46%). 398 (97%) prescribed HCQ to colleagues, family, and patients for prophylaxis against COVID-19. This amounted to 38439 prescriptions with a median of 10 (0–60) prescriptions per physician.

Perspectives on the efficacy and safety of antimalarials in patients with COVID-19

Most respondents 222 (57%) were not sure of HCQ's effectiveness as postexposure prophylaxis, though a few 153 (39%) felt treatment with HCQ reduces the severity of COVID-19 illness, while 142 (37%) were not sure anymore. Most (274, 72%) respondents were either uncomfortable using the combination of macrolides and HCQ or held neutral opinion about it.

All respondents (381, 99%) agreed on the safety of HCQ, though 213 (55%) thought HCQ is safe but chloroquine is not. However, in patients diagnosed with COVID-19, the opinion was largely divided, with 130 (34%) considering antimalarials safe, 126 (32%) supporting the safety of HCQ alone, and 112 (29%) being unsure.

These perspectives were shaped largely by information gathered from narrative reviews for most respondents (244 [63%]), followed by original articles (214 [55%]) or through observations (174 [45%]) while treating patients [Table 2].
Table 2: Source of most recent information on hydroxychloroquine

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Adverse drug reactions while using hydroxychloroquine in patients with and without COVID-19

While prescribing for non-COVID-19 indications (SLE, RA, inflammatory arthritis, etc.,) for every 1,00,000 prescriptions, skin pigmentation (554 [123–2063]) was the most common ADR, followed by gastrointestinal (GI) intolerance (222 [42–980]). A very few encountered rashes (93 [8–370]), pruritis (66 [0–330]), and bull's eye maculopathy (26 [0–165]) while prescribing HCQ in those without COVID-19. Other ADRs such as tinnitus, vertigo, arrhythmias, myopathy, corneal deposits, hemolysis, bone marrow toxicity, hypoglycemia, SJS/TEN, and insomnia were seldom reported [Table 3].
Table 3: Adverse drug reactions with use of hydroxychloroquine for COVID-19 and nonCOVID-19 indications

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While prescribing in patients with COVID-19, most ADRs were rare [0 per million prescriptions, [Table 3]] but reported by 46 (11%). GI intolerance (total 209) and skin pigmentation (total 117) being the most common. Interestingly, the most speculated complication of HCQ (cardiac arrhythmias) was seldom reported in patients with COVID-19 as well as those without it [Table 3].

Comparison in adverse drug reactions while using hydroxychloroquine in patients with and without COVID-19

All ADRs were more frequent with prescriptions for non-COVID indications [Figure 2] and [Table 3]. While using HCQ outside the COVID-19 setting, skin pigmentation (654 vs. 287 per million prescriptions) and Bull's eye maculopathy (35 vs. 0 per million prescriptions) were more frequently reported by rheumatologists. On the other hand, vertigo (151 vs. 0 per million patients, P 0.03), GI intolerance (6084 vs. 2470 per million patients, P 0.024), hemolysis (0 [0–394] vs. 0 [0–105] per million patients, P 0.04), liver toxicity (0 [0–1620) vs. 0 [0–172] per million patients, P 0.002), insomnia (0 [0–4230] vs. 0 [0–390] per million patients, P 0.03], and other neurological (0 [0–1170] vs. 0 [0–120] per million patients, P 0.02) were reported more frequently by nonrheumatologists [Supplementary Table 1]. There were no such differences in ADRs noticed for COVID-19 indication.
Figure 2: Adverse effects encountered by respondents with hydroxychloroquine prescription for rheumatic diseases and COVID-19

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Intergroup comparisons (rheumatologists versus others)

Rheumatologists prescribed HCQ more frequently (200 vs. 30 prescriptions per month) irrespective of indication for usage, while other specialists prescribed HCQ more frequently for COVID-19 (38% vs. 24%, P 0.005). While most rheumatologists prescribed HCQ at 5 mg/kg (70%), and most (72%) would never use doses > 400 mg/day, this was not true for nonrheumatologists (25% used HCQ at doses higher than 5 mg/kg).

Rheumatologists often conducted eye examinations such as baseline fundus examination (66%), OCT (61%), and visual field testing (47%) before prescribing HCQ, but not ECG (76%) in most cases. Most other investigations (hemogram, liver functions, and renal functions) were ordered more frequently by specialists other than rheumatologists before the initiation of HCQ [Supplementary Table 2]. Rheumatologists observed greater ADRs in the elderly and middle-aged patients (48% and 57% respectively), while in young adults there was no difference in the ADRs observed by all doctors.



Similar proportions (50% and 60%) of rheumatologists and other specialists were on HCQ for COVID-19 prophylaxis, at doses that varied from 100 mg OD to 400 mg OD. However, rheumatologists were less likely to prescribe HCQ for COVID-19 prophylaxis (OR 0.45, P 0.002) to family and friends, although the opinion on efficacy, safety, and drug interactions of the drug was largely similar in the two groups, [Supplementary Table 2] although rheumatologists were less likely to think that both HCQ and chloroquine are unsafe (0 vs. 3%, OR 0.04 [0.0-.87], P 0.04]. Rheumatologists reportedly faced a greater challenge in drug procurance (88% vs. 66%, OR 2.6) for their patents during the pandemic.


  Discussion Top


Our survey comprising predominantly of rheumatologists (71.2%) underscores their vast experience with HCQ usage, in patients with and without COVID-19. ADRs were more frequent in non-COVID-19 indications than for COVID-19. The most common ADRs were GI intolerance and skin pigmentation. Cardiac toxicity was rarely reported for COVID-19 and non-COVID indications. ADRs other than cutaneous and visual effects were reported more often by physicians other than rheumatologists Prescription practices varied among rheumatologists and non-rheumatologists with stricter adherence to 5 mg/kg dose, more frequent eye screening before HCQ initiation and a less frequent prescription for COVID-19 prophylaxis among the former.

HCQ has reduced levels of tissue accumulation, with the maximum tolerable dose previously being reported as 1200 mg.[14] In our study, rheumatologists were less likely to prescribe HCQ at doses >400 mg.[15] Rheumatologists supported the inefficacy of HCQ for treatment of COVID-19, with only 13% thinking that it may reduce mortality in COVID-19. Furthermore, not only did rheumatologists prescribe HCQ to lesser people on average for COVID-19 than nonrheumatologists (10 vs. 29, P = 0.012), but they were also more reluctant to prescribe HCQ for COVID-19 prophylaxis as compared to nonrheumatologist (44% vs. 26%, P = 0.002) as well. Thus, this shows that perhaps due to experience and more familiarity with the drug, rheumatologists were more likely to understand the true use of HCQ for COVID-19.

Another important factor leading to the panel recommending against HCQ was the safety profile of the drug. HCQ is known to cause ADRs across several organ systems, with cardiac effects being most concerning-particularly QTc prolongation, Torsade e Pointes, cardiac death, and ventricular arrythmias, more so at higher doses.[16] However, paradoxically, a recent systematic review by Prodromos et al. concluded that HCQ and azithromycin combination had a cardioprotective effect instead by decreasing the risk of cardiac events and cardiac-related mortality.[17] Our study supports this finding since cardiac arrhythmias was rarely reported by both rheumatologists and nonrheumatologists in COVID and non-COVID patients. In fact, interestingly, ADRs due to usage of HCQ for COVID-19 were seldomly seen (0 per million prescriptions), with the most common reported ADR being GI intolerance and skin pigmentation. This may be confounded by the longer duration of use (and follow-up) of HCQ for non-COVID-19 indications. Yet for non-COVID indications, multiple ADRs were much more frequently reported by both rheumatologists and non-rheumatologists. Although there is scientific evidence supporting that patients receiving HCQ for COVID-19 are at increased risk of QTc prolongation,[18] it should be noted that the COVID-19 virus tropism and interaction with the RAAS system, via the ACE-2 receptor, may augment an inflammatory response and cardiac aggression.[19] Therefore, our study supports that cardiac-related events are infrequent with HCQ usage for COVID-19. However, the observations of the respondents may be confounded by the duration of patient follow-up.

Our study showed that both rheumatologist and nonrheumatologists encountered drug toxicity mostly in middle-aged and elderly, and the least in children. In fact, due to the risk of cardiac toxicity, baseline ECGs are also recommended to estimate QTc intervals in patients receiving HCQ by cardiology society[20] but conditionally recommended in selective patients by rheumatology societies.[21] Furthermore, due to the risk of retinal toxicity, the American College of Rheumatology (ACR) guidelines recommend that individuals should get complete baseline ophthalmic examinations done within the 1st year of HCQ usage for enabling early retinopathy detection.[22] Although our study showed that retinopathy and ocular complications were less frequently reported with HCQ use, most rheumatologists did perform baseline fundus examination (66%), OCT (61%), and visual field testing (47%), but a majority of them did not perform baseline ECG (76%) as rheumatology guidelines do not mandate same. Nonrheumatologists were more likely to perform baseline ECG, and surprisingly hemograms, liver functions, and renal functions were ordered more frequently by them too before initiation of HCQ. This discrepancy between baseline screening tests, calls for more awareness and enforcement regarding the performance of baseline ECGs among rheumatologist and ophthalmic examinations among nonrheumatologists, to ensure optimum safety and decrease the risk of complications in patients receiving HCQs. With the rarity of cardiac events, we suggest that even routine ECG at baseline is not needed for short-term use of HCQ, especially for COVID-19.

In addition, there is a need to increase awareness and knowledge regarding HCQ drug interactions and the safety of antimalarials usage in COVID-19 and RDs. This is all the more important since despite the Food and Drug Administration now advising against the use of HCQ for COVID-19,[23] the recommendation of HCQ usage by The National Task Force for COVID-19 by the Indian Council of Medical Research is still being implemented in India where the number of deaths due to COVID-19 remain distressingly high.[24] In our study, both rheumatologists and nonrheumatologists had similar responses regarding the use of macrolides with HCQ, with a majority in both being uncertain regarding the safety of such a combination. Similarly, a majority of both groups responded that HCQ was safe for the treatment of RDs but were unsure about chloroquine. Yet in the setting of COVID-19, both drugs were considered safe by a majority in both physician groups. These physician perceptions may be shaped by reading patterns and amid the ensuing “infodemic,” it may be difficult to control the flux of information and find valid and reliable information to make sound judgments.[25]

There are variable clinical features of COVID-19 seen in patients with systemic RDs, with insufficient data to determine whether underlying RDs may affect COVID-19 presentation. According to the management guidelines released by the ACR, for RD patients with suspected or confirmed COVID-19, HCQ usage may be continued with a cautious outlook for cardiotoxicity.[26] Hence, in COVID-19 use of HCQ may be continued as normal, with the dosage and management being individualized for each patient, keeping factors such as COVID-19 disease severity, COVID-19 symptoms, and RD presentation in mind. While more evidence has emerged since this study was conducted, and with HCQ seeming to no longer be useful for treating COVID-19, the perceived safety of HCQ remains a valid concern in a large population of individuals with RDs, a significant proportion of whom are continuing to use HCQ for effective treatment.

The limitations of this study are typical of survey-based studies; most common being an estimated oversimplification of social reality. A convenience sampling can introduce a significant nonresponder bias in a survey.[27] The study can only depict information from a single point in time and it is difficult to measure changes in this population. Furthermore, as this is an online survey design, the responses are contingent primarily on the ability to recall and may, thus it may be subject to recall bias. Further, most respondents were rheumatologists, which could skew the experiences toward the safety of HCQ usage. However, due to strict lockdowns and social distancing protocols, directly recording responses from participants was not possible. This being a pilot study to test the hypothesis, we hope that larger well-structured studies may validate the observations obtained.


  Conclusions Top


Most ADRs are rare with HCQ use in our respondent population with a large user experience. HCQ use was considered unsafe by one-thirds in the setting of COVID-19 but not outside it, lesser so by rheumatologists.

Prescription practices varied among rheumatologists and nonrheumatologists with stricter adherence to 5 mg/kg dose, more frequent eye screening before HCQ initiation and a less frequent prescription for COVID-19 prophylaxis among the former. Rheumatologists were less likely to investigate preprescription and reportedly faced a greater challenge in drug procurance for their patients during the pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

 
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    -  Naveen R
    -  Verma A
    -  Raza HA
    -  Chengappa K G
    -  R Naidu G S
    -  Sharma S
    -  Goel A
    -  Misra DP
    -  Sharma A
    -  Gupta L
    -  Agarwal V
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