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Predictors of treatment success in smoking cessation with varenicline combined with nicotine replacement therapy v. varenicline alone.

Tobacco dependence is a global epidemic and a major preventable cause of morbidity and mortality. The World Health Organization reported that nearly 6 million tobacco-related deaths occur annually. [1] Despite the well-known benefits of smoking cessation, it remains a challenge for many smokers who attempt to quit. Approximately 70% of smokers want to discontinue smoking; [2] however, only 3-5% of those who attempt to do so without assistance remain abstinent in the long term. [3] Behavioural interventions and pharmacotherapy are effective methods in smoking cessation, [4] and when combined, are even more efficacious. [5] Commonly used pharmacotherapies include nicotine replacement therapy (NRT), bupropion and varenicline. All have been proven to be efficacious to varying degrees.

Studies investigating factors that predict smoking cessation success have identified the following: male gender, older age, older age at initiation of smoking, lower nicotine dependency, lower exhaled carbon monoxide levels, fewer cigarettes smoked per day and higher confidence with regard to quitting (self-efficacy). Heavier smokers and smokers with a high nicotine dependency in particular are more likely to continue smoking. [6-15] A tobacco user who smokes at least 20 cigarettes per day is generally considered to be a heavy smoker. The level of nicotine dependence may be assessed with the Fagerstrom test for nicotine dependence (FTND)-a frequently used questionnaire scored out of 10, with a score of at least 7 denoting high dependency. [16] Reasons for successful cessation include health concerns and the high cost of cigarettes. [17] The motivation for continued smoking may also contribute-smoking for pleasure or reward (positive reinforcement), or to relieve a negative state (negative reinforcement). [18]

A recent study reported that combining varenicline and bupropion improved abstinence rates in heavier smokers and in persons with a high nicotine dependency. [19] This suggests that combination therapies may improve success rates in these difficult groups.

In a recent randomised controlled trial (RCT), we established that varenicline combined with NRT was more effective than varenicline alone, with a favourable safety profile. [20] We performed a post-hoc analysis of the data from the original RCT to identify the independent predictors of successful abstinence at 12 and 24 weeks after the target quit date. The objective was to assist healthcare workers to select interventions according to the characteristics of the individual smoker to improve their chances of success.

Methods

Study design

We performed a post-hoc analysis of a study dataset prospectively collected from April 2011 to October 2012 at seven sites throughout South Africa (SA). The study was conducted in accordance with the principles outlined in the Declaration of Helsinki, and local and international Good Clinical Practice guidelines. Ethical approval was obtained from the Health Research Ethics Committee of Stellenbosch University (ref. no. S15/02/029). The original study methods and outcomes have been described elsewhere. [20] In the original study, 446 adult smokers were randomised to receive either varenicline 1 mg twice daily with active nicotine patches 15 mg per day (combination therapy) or varenicline twice daily with placebo patches (monotherapy) for 12 weeks, and were followed up for a further 12 weeks.

Study procedures and assessment

In the current analysis, all randomised participants who were administered at least one dose of both medications were included in the study population. They were categorised by specific baseline characteristics, including age, sex, age at smoking initiation, cigarette consumption per day, nicotine dependence as measured by the FTND and motivation for continued smoking using the reinforcement assessment, and were followed up until weeks 12 and 24. The measures of cessation included 7-day point prevalence abstinence, referring to the preceding 7 days, and continuous abstinence-a prolonged period of at least 4 weeks before the assessment date. At week 12, the 7-day point prevalence abstinence rate (PPAR) and the 4-week continuous abstinence rate (CAR) for weeks 9-12 were evaluated. At week 24, the 7-day PPAR and CAR for weeks 9-24 were also measured. Abstinence from tobacco was self-reported using the Nicotine Use Inventory (NUI), which evaluates tobacco or nicotine use (other than that provided) since the last contact and the preceding 7 days. This was biochemically confirmed by exhaled carbon monoxide measurements of <10 parts per million. Participants who missed the visits at weeks 12 and 24 were considered smokers at those time points, and those who discontinued the study or were lost to follow-up were also considered smokers.

Statistical aspects

The data were analysed using Stata version 13.1 (StataCorp., USA). Univariate logistic regression was used to do a crude analysis of the entire study population to identify predictors of abstinence for each of the four outcomes. Participants for whom the relevant baseline data were missing, were excluded from that particular category for univariate analysis as per protocol.

Multivariate logistic regression was used to measure the association between all the baseline characteristics and abstinence rates at weeks 12 and 24, adjusting for the treatment received. To include all participant data in the models for multivariate analysis, missing data were coded as missing and included in the models as a separate category. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and statistical significance was indicated at p<0.05.

Results

A total of 446 participants were randomised, 435 of whom were included-216 in the combination therapy arm, and 219 in the monotherapy arm. Their baseline characteristics have been reported elsewhere. [20] No statistically significant differences in baseline predictors were found between the participants in the active treatment group and those in the placebo group. Missing baseline data were minimal and comparable across treatment arms (<2%).

The short-term (7-day point prevalence) and long-term (continuous) abstinence rates in each treatment arm according to baseline characteristics are shown in Table 1. In keeping with our previous findings, the active group had a higher abstinence rate than the placebo group across all categories. [20]

In the univariate analysis conducted at 12 and 24 weeks, CARs were significantly higher in light smokers than in heavy smokers at both time points, and in older participants than in those <50 years of age at the 24-week time point (Table 2). These associations remained significant in the multivariate analysis. The only predictor of PPAR was younger age-at 12 weeks. In the sample, heavily nicotine-dependent participants were more likely to continue smoking than those who were less nicotine dependent; however, this difference was not statistically significant, indicating no population differences. No other factors significantly predicted successful smoking cessation, including sex, age at smoking initiation and motivation for continued smoking, i.e. the reinforcement assessment.

The multivariate analysis did not markedly change the ORs for all variables, except for identifying younger age as a predictor of the 12-week CAR.

Participants who started smoking after the age of 20 had a relatively poorer response on varenicline alone (CAR 22.2%) than those on combination therapy (CAR 39.1%) (p<0.01).

Discussion

The original study confirmed that the addition of NRT improved smoking cessation success at both time points. The only other significant predictors of success identified in the current analysis were older age and lower daily cigarette consumption.

The reasons for smoking cessation, self-efficacy (a participant's belief in his/her ability to succeed) and level of motivation were not assessed, but it may be that older persons are more likely to be motivated to quit because of health concerns. Younger persons may consider future opportunities to quit and be less committed or motivated. [11] Preparedness for the challenges of tobacco abstinence was not assessed, but quit attempts were well supported by smoking cessation counselling during all visits before and after quitting.

The finding that heavier smokers had lower abstinence rates than those who smoked fewer cigarettes per day is in keeping with previous research; [7,8,10-12] however, it contrasts with a recent study, where a combination of varenicline and bupropion improved abstinence in heavy smokers and in those who were more nicotine dependent. [19] This may be due to the average daily cigarette consumption in this study population being lower, as was the average FTND. The data from our study did not suggest that combination therapy (varenicline and NRT) conferred any benefit to heavy and more-dependent smokers.

Unlike previous research, which indicated that lower levels of nicotine dependence were associated with increased abstinence, [7,9-11,14] we did not observe this. We investigated whether highly dependent smokers would benefit more, but unexpectedly there were fewer patients with high dependence. Studies have also found that men are more likely to abstain than women; [7-10,12] however, we could not confirm this-perhaps because we had a greater number of female participants.

Despite the original study findings in favour of the addition of NRT to varenicline, we found little difference in the ORs between univariate and multivariate analyses, suggesting that the addition of nicotine replacement to varenicline did not markedly alter the predictors of abstinence. Baseline characteristics that predicted success in participants who received varenicline alone were found to be similar to those of the group who received both varenicline and NRT.

There may be other factors that contribute to smoking cessation success. Genetic studies of variations in the nicotine-receptor gene cluster CHRNA5-CHRNA3-CHRNB4 found that although smokers with the high-risk haplotype had a heightened response to pharmacotherapy, they were more likely to relapse than the low-risk group. [21] Recent research also found that the therapeutic response to a nicotine patch and varenicline is influenced by the nicotine metabolite ratio (NMR), a genetically influenced biomarker measuring the ratio of two nicotine metabolites produced during smoking. [22] Participants with a normal metabolism had better abstinence rates when receiving varenicline, whereas those with a slow metabolism fared better on nicotine patches. Genetic factors and NMR were not assessed in the current study, but correcting for this ratio may change the predictors of success. From a behavioural science perspective, another recent study found that financial incentives were associated with successful smoking cessation and that harnessing the individual's aversion to loss in a cessation programme may encourage a change in smoking behaviour. [23]

Our study has limited generalisability, as we enrolled mostly healthy persons without a history of psychiatric illness in the previous 2 years. Our findings are nonetheless similar to those of studies resembling real-life situations. [7,15] The overall attrition rate of 36.1% may have affected the outcomes, but attrition was similar across the two treatment arms (33.3% in the active arm v. 38.8% in the placebo arm) and is comparable to that in previous studies. The results may have been underestimated by defining all participants who withdrew, defaulted on visits or were lost to follow-up as smokers, but this is in keeping with previous research and the high likelihood of treatment failure in such subjects. [19] We did not assess the effect of the financial cost of continued smoking on abstinence rates and smoking behaviour, but as our study was conducted during a worldwide economic recession, this may have influenced the predictors of successful cessation attempts. We could also not specifically evaluate the potential impact of the level of education and smoking status of participants' partners on smoking cessation.

Conclusion

Advanced age and lower daily cigarette consumption are associated with a higher likelihood of abstinence in patients who receive varenicline, regardless of the addition of NRT. Future studies should consider genetic factors, NMR, effect of personal resources, financial implications and local tobacco regulations, and possibly also novel ways of incentivising subjects.

Acknowledgements. Prof. Eric D Bateman, Prof. Richard N van Zyl-Smit, Drs Axel Bruning, John A O'Brien, Clifford Smith, Mohamed S Abdool-Gaffar and Shaunagh Emanuel, who contributed to the data collection of the original study.

Author contributions. All authors contributed to the study concept and design. FN had full access to all study data and performed analyses and interpretation with the assistance of EMI and TME. FN drafted the manuscript with support from all authors. The study was supervised by EMI.

Funding. None.

Conflicts of interest. None.

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Accepted 26 September 2017.

F Noor, (1) MB ChB, MSc; C F N Koegelenberg, (1) MB ChB, MMed (Int), FCP (SA), FRCP (UK), Cert Pulm (SA), PhD; T M Esterhuizen, (2) MSc; E M Irusen, (1) MB ChB, FCP (SA), PhD

(1) Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa

(2) Centre for Evidence-based Health Care, Stellenbosch University, Cape Town, South Africa

Corresponding author: C F N Koegelenberg (coeniefn@sun.ac.za)
Table 1. Abstinence rates in each treatment arm according to baseline
characteristics

Baseline                      Treatment
characteristics               arm          Total

Age, years
  [greater than or equal      Active       94
    to] 50                    Placebo      90
  <50                         Active       122
                              Placebo      129
Sex
  Male                        Active       87
                              Placebo      83
  Female                      Active       129
                              Placebo      136
Cigarettes/day, n
  [greater than or equal      Active       85
    to] 20                    Placebo      93
  <20                         Active       131
                              Placebo      126
Level of nicotine
dependence *
  FTND [greater than or       Active       12
    equal to] 7               Placebo      15
  FTND <7                     Active       202
                              Placebo      201
Age at smoking
initiation, years
  [greater than or equal      Active       46
    to] 20                    Placebo      54
  <20                         Active       170
                              Placebo      165
Reinforcement
assessment ([dagger])
  NR                          Active       44
                              Placebo      52
  PR                          Active       54
                              Placebo      49
  NR + PR                     Active       95
                              Placebo      97
  N/A                         Active       20
                              Placebo      19

                                                     12 weeks

Baseline                      Treatment    7-day PPAR,    CAR 9-12
characteristics               arm          n (%)          weeks, n (%)

Age, years
  [greater than or equal      Active       61 (64.89)     52 (55.32)
    to] 50                    Placebo      35 (38.89)     28 (31.11)
  <50                         Active       55 (45.08)     47 (38.52)
                              Placebo      52 (40.31)     42 (32.56)
Sex
  Male                        Active       43 (49.43)     38 (43.68)
                              Placebo      31 (37.35)     25 (30.12)
  Female                      Active       73 (56.59)     61 (47.29)
                              Placebo      56 (41.18)     45 (33.09)
Cigarettes/day, n
  [greater than or equal      Active       45 (52.94)     35 (41.18)
    to] 20                    Placebo      31 (33.33)     20 (21.51)
  <20                         Active       71 (54.20)     64 (48.85)
                              Placebo      56 (44.44)     50 (39.68)
Level of nicotine
dependence *
  FTND [greater than or       Active       4 (33.33)      3 (25.00)
    equal to] 7               Placebo      4 (26.67)      4 (26.67)
  FTND <7                     Active       111 (54.95)    95 (47.03)
                              Placebo      83 (41.29)     66 (32.84)
Age at smoking
initiation, years
  [greater than or equal      Active       29 (63.04)     24 (52.17)
    to] 20                    Placebo      24 (44.44)     20 (37.04)
  <20                         Active       87 (51.18)     75 (44.12)
                              Placebo      63 (38.18)     50 (30.30)
Reinforcement
assessment ([dagger])
  NR                          Active       23 (52.27)     20 (45.45)
                              Placebo      18 (34.62)     15 (28.85)
  PR                          Active       29 (53.70)     24 (44.44)
                              Placebo      24 (48.98)     16 (32.65)
  NR + PR                     Active       53 (55.79)     44 (46.32)
                              Placebo      40 (41.24)     35 (36.08)
  N/A                         Active       10 (50.00)     10 (50.00)
                              Placebo      5 (26.32)      4 (21.05)

                                                     24 weeks

Baseline                      Treatment    7-day PPAR,    CAR 9-24
characteristics               arm          n (%)          weeks, n (%)

Age, years
  [greater than or equal      Active       50 (53.19)     40 (42.55)
    to] 50                    Placebo      23 (25.56)     18 (20.00)
  <50                         Active       44 (36.07)     31 (25.41)
                              Placebo      40 (31.01)     24 (18.60)
Sex
  Male                        Active       34 (39.08)     28 (32.18)
                              Placebo      24 (28.92)     15 (18.07)
  Female                      Active       60 (46.51)     43 (33.33)
                              Placebo      39 (28.68)     27 (19.85)
Cigarettes/day, n
  [greater than or equal      Active       34 (40.00)     24 (28.24)
    to] 20                    Placebo      21 (22.58)     12 (12.90)
  <20                         Active       60 (45.80)     47 (35.88)
                              Placebo      42 (33.33)     30 (23.81)
Level of nicotine
dependence *
  FTND [greater than or       Active       3 (25.00)      2 (16.67)
    equal to] 7               Placebo      3 (20.00)      3 (20.00)
  FTND <7                     Active       89 (44.06)     68 (33.66)
                              Placebo      59 (29.35)     39 (19.40)
Age at smoking
initiation, years
  [greater than or equal      Active       24 (52.17)     18 (39.13)
    to] 20                    Placebo      19 (35.19)     12 (22.22)
  <20                         Active       70 (41.18)     53 (31.18)
                              Placebo      44 (26.67)     30 (18.18)
Reinforcement
assessment ([dagger])
  NR                          Active       21 (47.73)     16 (36.36)
                              Placebo      13 (25.00)     10 (19.23)
  PR                          Active       20 (37.04)     15 (27.78)
                              Placebo      18 (36.73)     10 (20.41)
  NR + PR                     Active       42 (44.21)     31 (32.63)
                              Placebo      29 (29.90)     20 (20.62)
  N/A                         Active       8 (40.00)      8 (40.00)
                              Placebo      3 (15.79)      2 (10.53)

PPAR = point prevalence abstinence rate; CAR = continuous abstinence
rate; FTND = Fagerstrom test for nicotine dependence; NR = negative
reinforcement (smoking to avoid a negative state); PR = positive
reinforcement (smoking for pleasure); N/A = not applicable (never
tried to quit).

FTND not done--2 (0.93%) in active group, and 3 (l.37%) in placebo
group.

([dagger]) Reinforcement assessment not done--3 (1.39%) in active
group, and 2 (0.91%) in placebo group.

Table 2. Predictors of smoking cessation success at weeks 12 and 24

                                                  Univariate

Predictors                                        7-day PPAR
                                         OR (95% CI)      p-value

12 weeks (CAR 9-12 weeks)
  Combination therapy                    1.76             0.004
  v. monotherapy                         (1.20-2.57)      ([section])

  Age ([greater than or equal to]        1.47             0.049[section]
  50 v. <50), years                      (1.00-2.15)

  Sex (male v. female)                   0.81             0.29
                                         (0.55-1.20)

  Cigarettes/day                         1.31             0.17
  (<20 v. [greater than or equal to]     (0.89-1.93)
  20), n ([dagger])

  FTND (<7 v. [greater than or equal     2.20             0.07
  to] 7) ([double dagger])               (0.94-5.15)

  Age started smoking                    1.39             0.15
  ([greater than or equal to] 20 v.      (0.89-2.18)
  <20), years

  Reinforcement                          1.42             0.22
  assessment, PR v. NR                   (0.81-2.49)

  Reinforcement assess-                  1.26             0.36
  ment, NR + PR v. NR                    (0.77-2.06)

24 weeks (CAR 9-24 weeks)
  Combination therapy                    1.91             0.001[section]
  v. monotherapy                         (1.28-2.84)

  Age ([greater than or equal to]        1.31             0.18
  50 v. <50), years                      (0.88-1.94)

  Sex (male v. female)                   0.87             0.49
                                         (0.58-1.30)

  Cigarettes/day                         1.47             0.06
  (<20 v. [greater than or equal to]     (0.98-2.21)
  20), n ([dagger])

  FTND (<7 v. [greater than or equal     2.03             0.14
  to] 7) ([double dagger])               (0.80-5.15)

  Age started smoking                    1.46             0.10
  ([greater than or equal to] 20 v.      (0.93-2.31)
  <20), years

  Reinforcement                          1.07             0.83
  assessment, PR v. NR                   (0.60-1.90)

  Reinforcement assess-                  1.07             0.80
  ment, NR + PR v. NR                    (0.64-1.78)

                                                  Univariate

Predictors                                            CAR
                                         OR (95% CI)      p-value

12 weeks (CAR 9-12 weeks)
  Combination therapy                    1.80             0.003
  v. monotherapy                         (1.22-2.66)      ([section])

  Age ([greater than or equal to]        1.40             0.09
  50 v. <50), years                      (0.95-2.07)

  Sex (male v. female)                   0.88             0.54
                                         (0.59-1.31)

  Cigarettes/day                         1.78             0.005
  (<20 v. [greater than or equal to]     (1.19-2.67)      ([section])
  20), n ([dagger])

  FTND (<7 v. [greater than or equal     1.90             0.15
  to] 7) ([double dagger])               (0.79-4.6)

  Age started smoking                    1.32             0.23
  ([greater than or equal to] 20 v.      (0.84-2.08)
  <20), years

  Reinforcement                          1.11             0.73
  assessment, PR v. NR                   (0.62-1.97)

  Reinforcement assess-                  1.22             0.44
  ment, NR + PR v. NR                    (0.74-2.02)

24 weeks (CAR 9-24 weeks)
  Combination therapy                    2.06             0.001
  v. monotherapy                         (1.33-3.20)      ([section])

  Age ([greater than or equal to]        1.64             0.03
  50 v. <50), years                      (1.07-2.53)      ([section])

  Sex (male v. female)                   0.94             0.80
                                         (0.61-1.47)

  Cigarettes/day                         1.69             0.02
  (<20 v. [greater than or equal to]     (1.07-2.65)      ([section])
  20), n ([dagger])

  FTND (<7 v. [greater than or equal     1.59             0.36
  to] 7) ([double dagger])               (0.59-4.31)

  Age started smoking                    1.30             0.30
  ([greater than or equal to] 20 v.      (0.79-2.13)
  <20), years

  Reinforcement                          0.86             0.65
  assessment, PR v. NR                   (0.46-1.63)

  Reinforcement assess-                  0.97             0.93
  ment, NR + PR v. NR                    (0.56-1.69)

                                                 Multivariate *

Predictors                                        7-day PPAR
                                         OR (95% CI)      p-value

12 weeks (CAR 9-12 weeks)
  Combination therapy                    --               --
  v. monotherapy

  Age ([greater than or equal to]        1.49             0.056
  50 v. <50), years                      (0.99-2.23)

  Sex (male v. female)                   0.83             0.36
                                         (0.55-1.24)

  Cigarettes/day                         1.29             0.23
  (<20 v. [greater than or equal to]     (0.85-1.96)
  20), n ([dagger])

  FTND (<7 v. [greater than or equal     1.80             0.19
  to] 7) ([double dagger])               (0.74-4.35)

  Age started smoking                    1.25             0.36
  ([greater than or equal to] 20 v.      (0.78-1.99)
  <20), years

  Reinforcement                          1.32             0.35
  assessment, PR v. NR                   (0.74-2.34)

  Reinforcement assess-                  1.25             0.39
  ment, NR + PR v. NR                    (0.75-2.08)

24 weeks (CAR 9-24 weeks)
  Combination therapy                    --               --
  v. monotherapy

  Age ([greater than or equal to]        1.41             0.11
  50 v. <50), years                      (0.93-2.15)

  Sex (male v. female)                   0.94             0.79
                                         (0.62-1.44)

  Cigarettes/day                         1.38             0.14
  (<20 v. [greater than or equal to]     (0.90-2.14)
  20), n ([dagger])

  FTND (<7 v. [greater than or equal     1.59             0.35
  to] 7) ([double dagger])               (0.60-4.18)

  Age started smoking                    1.42             0.15
  ([greater than or equal to] 20 v.      (0.88-2.28)
  <20), years

  Reinforcement                          1.02             0.95
  assessment, PR v. NR                   (0.56-1.86)

  Reinforcement assess-                  1.08             0.78
  ment, NR + PR v. NR                    (0.64-1.83)

                                                 Multivariate *

Predictors                                            CAR
                                         OR (95% CI)      p-value

12 weeks (CAR 9-12 weeks)
  Combination therapy                    --               --
  v. monotherapy

  Age ([greater than or equal to]        1.52             0.049
  50 v. <50), years                      (1.00-2.31)      ([section])

  Sex (male v. female)                   0.93             0.74
                                         (0.62-1.41)

  Cigarettes/day                         1.86             0.005
  (<20 v. [greater than or equal to]     (1.21-2.87)      ([section])
  20), n ([dagger])

  FTND (<7 v. [greater than or equal     1.39             0.48
  to] 7) ([double dagger])               (0.55-3.52)

  Age started smoking                    1.17             0.51
  ([greater than or equal to] 20 v.      (0.73-1.89)
  <20), years

  Reinforcement                          1.04             0.89
  assessment, PR v. NR                   (0.58-1.89)

  Reinforcement assess-                  1.23             0.43
  ment, NR + PR v. NR                    (0.73-2.08)

24 weeks (CAR 9-24 weeks)
  Combination therapy                    --               --
  v. monotherapy

  Age ([greater than or equal to]        1.79             0.01
  50 v. <50), years                      (1.13-2.84)      ([section])

  Sex (male v. female)                   1.02             0.94
                                         (0.64-1.62)

  Cigarettes/day                         1.83             0.02
  (<20 v. [greater than or equal to]     (1.12-2.98)      ([section])
  20), n ([dagger])

  FTND (<7 v. [greater than or equal     1.21             0.72
  to] 7) ([double dagger])               (0.43-3.45)

  Age started smoking                    1.17             0.54
  ([greater than or equal to] 20 v.      (0.70-1.97)
  <20), years

  Reinforcement                          0.82             0.55
  assessment, PR v. NR                   (0.42-1.58)

  Reinforcement assess-                  0.99             0.98
  ment, NR + PR v. NR                    (0.56-1.76)

PPAR = point prevalence abstinence rate; CAR = continuous abstinence
rate; OR = odds ratio; FTND = Fagerstrom test for nicotine dependence;
NR = negative reinforcement (smoking to avoid a negative state); PR =
positive reinforcement (smoking for pleasure); N/A = not applicable
(never tried to quit).

* Adjusted for treatment and all other factors in the model.

([dagger]) <20 cigarettes/day indicates light smokers; [greater than
or equal to] 20 cigarettes/day indicates heavy smokers.

([double dagger]) FTND <7 indicates less nicotine dependence, and
[greater than or equal to] 7 indicates heavy nicotine dependence.

([section]) Statistically significant.
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Title Annotation:RESEARCH
Author:Noor, F.; Koegelenberg, C.F.N.; Esterhuizen, T.M.; Irusen, E.M.
Publication:South African Medical Journal
Article Type:Author abstract
Date:Dec 23, 2017
Words:4780
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