Fardet, L

Nazareth, I

Petersen, I

UCL Discovery

1    Association between chronic quinine exposure and all-cause mortality  Laurence Fardet MD PhD 1, Irwin Nazareth MD PhD 2, Irene Petersen PhD 2 1 EA 7379 EpiDermE, Université Paris Est Créteil,  France 2 University College London, Department of Primary Care and Population Health, London, UK    Correspondence:   Laurence Fardet Hopital Henri Mondor 51 Avenue du Maréchal de Lattre de Tassigny 94010 Créteil France laurence.fardet@aphp.fr phone: +33 149814506  Manuscript word count:   649 Date of revision: February 07th 2017 2  Background Quinine has been used since the 1930s to treat idiopathic muscular cramps. However, in 2006, because of efficacy and safety issues, the U.S. Food and Drug Administration cautioned about this off-label use of quinine, citing “665 reports of adverse events with serious outcomes (…), including 93 deaths”.1 Despite warnings, quinine is still prescribed to individuals with idiopathic muscular cramps. Further, many drinks such as bitter lemon or tonic waters contain quinine, and hence, many are exposed to quinine daily. This study explored the association between long-term quinine exposure and all-cause mortality.  Methods  This study used data recorded in The Health Improvement Network (THIN), a UK primary care database containing anonymized data on more than 12 million individuals representative of the UK population.2 Adults who received incident quinine sulfate/bisulfate/dihydrochloride prescriptions for idiopathic muscular cramps or restless leg syndrome for at least one year from January 1990 to December 2014 (last follow-up December 2015) at a mean dosage ≥100 mg/day were considered to be exposed. The ‘start date’ (i.e., start of at-risk period) was defined as the first day of the first prescription of quinine. Individuals with muscular cramps or restless leg syndrome, never exposed to quinine or its derivatives, and with at least one year follow-up after a randomly selected ‘start date’ were eligible to be included in the unexposed sample. Three unexposed individuals were selected for every exposed individual. The samples were stratified in term of sex and age. Groups’ characteristics were compared using the Chi2 test or the Wilcoxon rank-sum test. The primary outcome (i.e., all-cause mortality) was compared between the exposed and the unexposed populations using Cox proportional hazards models adjusted on socio-demographic data, underlying conditions and concomitant prescriptions. Post-hoc subgroup analyses were conducted according to age and 3  to amount of exposure. The proportional hazards assumption for Cox models was checked graphically using the Schoenfeld residuals. All analyses were done using Stata 14.0. A two-sided p-value ≤0.05 denoted statistical significance. The scheme for THIN to obtain and provide anonymous patient data was approved by a national ethic Committee in 2002. The need for informed consent was waived.   Results  The study population was made of 175,195 individuals (median age (IQR): 70 (61-78) years, women: 57.8%, median follow-up: 5.7 (3.1-8.9) years) (Table 1). There were 11,598 deaths (4.2 per 100 person-years) among the 44,699 exposed individuals versus 26,753 (3.2 per 100 person-years) among the 130,496 unexposed individuals (adjusted HR: 1.24 (95%CI, 1.21-1.27)). The increase in the risk of death was more pronounced in those under 50 years of age (adjusted HR: 3.06 (2.51-3.73)), whatever the indication for prescription (Table 2). A dose-effect was found (adjusted HRs: 1.25 (1.20-1.30), 1.83 (1.72-1.94), and 2.24 (1.95-2.58), respectively for exposure 200-299, 300-399 and ≥400 mg/day by comparison to <200 mg/day, p-value for trend <0.001).  Discussion Quinine compared to placebo is effective in reducing both cramps number and intensity.3 Individuals included in this study received on average more than 100 mg/day of quinine, equivalent to a daily consumption of one liter of bitter lemon or tonic waters. 4  Short term quinine exposure may lead to life threatening adverse events such as thrombocytopenia, hypoglycemia, or cardiac arrhythmia.3 In a recent study, the incidence rate ratio of death in individuals with heart failure initiating quinine for leg cramps was 1.19 (1.14-4  1.24) when compared to unexposed patients.5 Mortality of long-term users was not compared to mortality of short-term users.5  The findings have limitations. Cramps may be due to underlying conditions or unmeasured confounders that predispose patients to higher mortality rather than exposure to quinine per se. No data was available regarding quinine beverages consumption. A competing risk may explain the lower increase of risk in the elderly but as death certificates were not accessible the mortality causes are unknown.  Quinidine, an isomer of quinine increases by three-fold the risk of deaths by comparison to placebo or no treatment.6 These deaths are mainly explained by sudden cardiac arrests.6    Acknowledgment Laurence Fardet had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.  Dr. Fardet, Dr Nazareth and Dr Petersen have nothing to disclose. There are no financial or material supports for this work.  5  References 1- Food and Drug Administration, Department of Health and Human Services. Drug products containing quinine; enforcement action dates. Federal Register 2006;71:75557–75560. Available at http://www.fda.gov/OHRMS/DOCKETS/98fr/06-9713.htm. Last acceded January 2017. 2- Blak BT, Thompson M, Dattani H, Bourke A. Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. Inform Prim Care. 2011;19:251-5 3- Katzberg HD, Khan AH, So YT. Assessment: symptomatic treatment for muscle cramps (an evidence-based review): report of the therapeutics and technology assessment subcommittee of the American academy of neurology. Neurology. 2010;74:691-6 4- Feas X, Brasic JR, Fente CA, Cepada A. La quinina y sus posibles implicaciones toxicológicas. Análysis de aguas tónicas en España. Rev Esp Nutr Comunitaria 2009;15 :97-102 5- Gjesing A, Gislason GH, Christensen SB, et al. Use of quinine and mortality-risk in patients with heart failure--a Danish nationwide observational study. Pharmacoepidemiol Drug Saf. 2015;24:310-8  6- Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation. 1990;82:1106-166  Table 1: Characteristics of the study population  Exposed (n=44,699) Unexposed (n=130,496) p-value Age, median [IQR], years  71 (61-78) 70 (61-78) <0.001 Female, n (%)   25,818 (57.8) 75,379 (57.8) 0.98 ‘Start date’, median [IQR] Jul 2006 (Feb 2003-Sept 2009) Jul 2006  (Apr 2003-Oct 2009) <0.001 Duration of follow-up after ‘start date’, median [IQR], years   5.5 (3.0-8.7)  5.7 (3.1-8.9) <0.001 Time between end of exposure and end of follow-up, , median [IQR], days 25 (0-310) - - Quinine dosage, median [IQR], mg/day 203 (163-252) - - Underlying diseases, n (%)    0.04   Idiopathic muscular cramps 42,865 (95.9) 125,424 (96.1)   Restless leg syndrome 1,834 (4.1) 5,072 (3.9) Smoking status, n (%)    <0.001   Non-smokers  18,597 (41.6) 64,707 (49.6)   Ex-smokers 16,622 (37.2) 41,636 (31.9)   Smokers 7,814 (17.5) 20,214 (15.5)   Missing 1,666 (3.7) 3,939 (3.0) BMI, median [IQR], kg/m2 27.6 (24.2-31.6) 26.9 (24.0-30.4) <0.001 Past history of, n (%)            Cancer 5,976 (13.4) 16,984 (13.0) 0.06   Hematological malignancy 593 (1.3) 1,069 (0.8) <0.001   Hypertension 19,748 (44.2) 53,046 (40.7) <0.001   Diabetes 8,522 (19.1) 15,645 (12.0) <0.001   Coronary artery disease 9,199 (20.6) 21,424 (16.4) <0.001   Congestive heart failure 2,610 (5.8) 5,696 (4.4) <0.001   Peripheral ischemic vascular disease 2,351 (5.3) 5,766 (4.4) <0.001   Cardiac conduction disorder 239 (0.5) 958 (0.7) 0.60   Cardiac dysrythmia 3,309 (7.4) 11,242 (8.6) <0.001   Amyotrophic lateral sclerosis 64 (0.1) 18 (0.01) <0.001   Multiple sclerosis 207 (0.5) 753 (0.6) 0.005   Muscular dystrophya 13 (0.03) 17 (0.01) 0.03 Number of prescriptions of, n (%)      Diuretics b 0 (0-27) 0 (0-25) <0.001   Beta blockers b 0 (0-18) 0 (0-18) <0.001 7    Calcium channel blockers  0 (0-17) 0 (0-15) <0.001   Including diltiazem c 0 (0-2) 0 (0-1) <0.001   B complex vitamin c 0 (0-0) 0 (0-0) <0.001   Statins b 0 (0-16)  0 (0-13) <0.001   Oral glucocorticoids b  0 (0-2) 0 (0-1) <0.001   Non steroidal anti-inflammatory drugs 0 (0-15) 0 (0-9) <0.001  Continuous variables are reported as medians and interquartile ranges except for medication prescriptions which are reported as medians and 5%-95% ranges a including Steinert’s disease, nemaline body disease, Becker muscular dystrophy b can induce idiopathic muscular cramps c recommended for idiopathic muscular cramp treatment  8  Table 2: All-cause deaths in the exposed and unexposed populations  Exposed N (%) Unexposed N (%) Crude Hazard Ratios (95% CI) Adjusted Hazard Ratios (95% CI) Overall population     All individuals        n 44,699 130,496     Deaths, n (%) 11,598 (26.0) 26,753 (20.5) 1.32 (1.29-1.35) 1.24 (1.21-1.27) Individuals aged ≤ 50 y       n 3,361 10,374     Deaths, n (%) 258 (7.7) 198 (1.9) 4.16 (3.46-5.01) 3.06 (2.51-3.73) Individual aged 51-70 y       n 18,935 56,280     Deaths, n (%) 3,069 (16.2) 5,957 (10.6) 1.60 (1.53-1.67) 1.37 (1.31-1.43) Individuals aged > 70 y       n 22,403 63,842     Deaths, n (%) 8,271 (36.9) 20,598 (32.3) 1.20 (1.17-1.23) 1.16 (1.13-1.19) Individuals with muscular cramps        All individuals        n 42,865 125,424     Deaths, n (%) 11,138 (26.0) 25,810 (20.6) 1.32 (1.29-1.35) 1.24 (1.21-1.27) Individuals aged ≤ 50 y       n 3,156 9,759     Deaths, n (%) 248 (7.9) 188 (1.9) 4.23 (3.50-5.12) 3.06 (2.50-3.76) Individuals aged 51-70 y       n 18,186 54,109     Deaths, n (%) 2,952 (16.2) 5,750 (10.6) 1.60 (1.53-1.67) 1.36 (1.30-1.42) Individuals aged > 70 y        n 21,523 61,556     Deaths, n (%) 7,938 (36.9) 19,872 (32.3) 1.20 (1.17-1.23) 1.16 (1.13-1.19) Individuals with restless leg syndrome     9    All individuals        n 1,834 5,072     Deaths, n (%) 460 (25.1) 943 (18.6) 1.35 (1.21-1.51) 1.22 (1.09-1.36) Individuals aged ≤ 50 y       n 205 615     Deaths, n (%) 10 (4.9) 10 (1.6) 2.95 (1.22-7.08) 2.82 (1.17-6.81)a Individuals aged 51-70 y       n 749 2,171     Deaths, n (%) 117 (15.6) 207 (9.5) 1.64 (1.31-2.06) 1.54 (1.22-1.95) Individuals aged > 70 y       n 880 2,286     Deaths, n (%) 333 (37.8) 726 (31.8) 1.19 (1.05-1.36) 1.11 (1.02-1.21)  All adjusted models were adjusted on age and sex. All the following variables were further considered to be included in the Cox multivariable models: BMI (<18, 18-24.9, 25-29.9, ≥ 30 kg/m2), Townsend deprivation score (categorical), smoking status (non smoker, ex-smoker, smoker, missing), history of cancer (yes/no), hematological malignancy (yes/no), diabetes (yes/no), hypertension (yes/no), coronary artery disease (yes/no), congestive heart failure (yes/no), peripheral ischemic vascular disease (yes/no), cardiac conduction disorders (yes/no), cardiac dysrythmias (yes/no), amyotrophic lateral sclerosis (yes/no), multiple sclerosis (yes/no), or muscular dystrophies (yes/no), number of prescriptions of diuretics, beta blockers, calcium channel blockers (including diltiazem), oral glucocorticoids, and oral non-steroidal anti-inflammatory drugs (continuous or categorical depending of the log likelihood ratio test results). Some first-order interaction terms (e.g., interactions between group and sex, coronary artery disease and congestive heart failure, coronary artery disease and peripheral ischemic vascular disease) were also considered to be included in the models. Variables to be kept in the models were selected using manually stepwise procedures with backward selection. The final models were selected as those that provided the lowest Akaike information criterion and Bayesian information criterion. All HRs were statistically significant (all p-values <0.001except for adjusted HR regarding those >70 year-old with restless leg syndrome p-value=0.02). a Adjusted on age and sex only  

Association Between Long-term Quinine Exposure and All-Cause Mortality

Laurence Fardet

Irwin Nazareth

Irene Petersen

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JAMA

http://discovery.ucl.ac.uk/1557028/1/Nazareth_assoc_between%20long%20term%20Quinine.pdf

Association Between Long-term Quinine Exposure and All-Cause Mortality

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