1. “Smoking-related lung diseases”
AIM OPD
Lizzy Oelsner (eco7)

2. Leading causes of death, US, 2015
Heart disease remains the leading cause of death, yet survival is improving
By contrast, chronic lower respiratory diseases (CLRD), which include COPD and asthma, have risen to become the third leading cause of death
Differences in mortality trends for heart versus lung diseases are poorly understood
Heart disease
Other
Cancer
Chronic lower respiratory diseases
NCHS, Health, United States, 2016.

3. Reduced heart disease mortality
Heart disease deaths, US
Mortality declines attributed in modeling studies to
Improved survival (10%)
2◦ prevention (25%)
1◦ prevention (12%)
Risk factor distribution (44%)
Dalen JE, Am J Med Ford ES, N Engl J Med Ergin E, Am J Med 2004.

4. “Unexplained” rise in COPD mortality
Women
Men
COPD deaths among current smokers, US cohorts
Attained age
Causes of worsening COPD mortality are unknown
2◦ prevention limited
1 ◦ prevention lacking
Contrary to marked improvements in smoking
Thun MJ, N Engl J Med 2013.

5. Smoking kills 443,000 per year in US
Leading preventable cause of death

6. Smoking killed 100,000,000 in 20th C.
Smoking-related deaths in WHO regions, 2012
Anticipated to cause 1 billion deaths in 21st Century if current trends continue
>25% of male deaths due to smoking in Russia, Eastern Europe, Turkey

7. Key takeaways for medical practice
It is important to know how to diagnose and treat COPD
It is extremely important to promote smoking cessation

8. How do you diagnose COPD?

9. How do you diagnose COPD?
Post-bronchodilator FEV1/FVC < 0.70
“In patients with appropriate symptoms and significant exposures to noxious stimuli”

10. What’s “appropriate” and “significant”?
Chronic Bronchitis
Emphysema
Chronic obstructive pulmonary disease
Asthma
Classical risk factors (e.g., smoking, ratio < 0.7) neither necessary nor sufficient, e.g.,
COPD in nonsmokers
“Symptomatic smokers”
Increased mortality in emphysema
Adapted from AJRCCM, 1995
CDC. Terzikhan N, Eur J Epidemiol, Woodruff PG, NEJM, 2016.

11. What’s “appropriate” and “significant”?
Fletcher and Peto, 1977
Lange P, NEJM 2015

12. Should you screen for COPD?

13. Should you screen for COPD?

14. How do you classify COPD severity?

15. How do you classify COPD severity?

16. How do you classify COPD severity?
“CAT”

17. How do you treat (outpatient) COPD?

18. How do you treat (outpatient) COPD?

19. How do you treat (outpatient) COPD?B

20. How do you treat (outpatient) COPD?B

21. How do you treat (outpatient) COPD?

22. How do you treat (outpatient) COPD?

23. How do you treat (outpatient) COPD?

24. Major recent trials in COPD
TORCH
NEJM 2007
ICS+LABA improves FEV1, exacerbations, health status (not mortality) in COPD
UPLIFT
NEJM 2008
LAMA improves FEV1, QOL, exacerbations (not rate of decline in FEV1)
M2-127,
M2-128,
REACT,
RE2SPOND
Lancet 2009
Lancet 2015
AJRCCM 2016
Roflumilast improves FEV1 in mod/severe COPD versus LABA or LAMA
Decreases AECOPD and hospitalization over ICS+LABA+LAMA if CB and severe --
COLUMBUS
NEJM 2011
Lancet RM 2014
Azithromycin (in addition to usual care) decreases AECOPD and improves QOL (increases hearing deficit)
WISDOM
NEJM 2014
Withdrawing ICS from ICS+LABA+LAMA does not increase AECOPD in severe COPD (but may decrease FEV1)
FLAME
NEJM 2016
LABA+LAMA superior to ICS+LABA for AECOPD prevention
TRILOGY
Lancet 2016
ICS+LABA -> ICS+LABA+LAMA improves lung function and decreases exacerbations in mod-severe COPD with exacerbations

25. Other treatment considerations
ALL:
SMOKING CESSATION
VACCINATION
INHALER TECHNIQUE
EDUCATION
ACTIVITY
GOC
SOME:
NAC
A1AT
OPIATES
NUTRITION
LTOT
NIPPV CT
LVRS
BULLECTOMY
TRANSPLANT
NOT INDICATED FOR COPD PER SE:
THEOPHYLLINE
ANTITUSSIVES
VASODILATORS
STATINS

26. Total population ~ 320 mn / 100%
Smoking
Total population ~ 320 mn / 100%
CDC, Law & Tang, Arch Intern Med Stead LF, Cochrane, Cahill, Cochrane, 2013.

27. Total population ~ 320 mn / 100%
Smoking
Total population ~ 320 mn / 100%
Current smokers ~ 40 mn / 17%
CDC, Law & Tang, Arch Intern Med Stead LF, Cochrane, Cahill, Cochrane, 2013.

28. Quitting
Prevalence of interest in quitting, past year quit attempt, and recent smoking cessation among adult smokers aged ≥18 years, --- National Health Interview Survey, United States, 2010
Interested in quitting
Past year quit attempt
Recent cessation %
(95% CI)
Overall
68.8
( )
52.4
( )
6.2
( )
Almost half who try to quit without support will not manage to stop for even a week, and fewer than 5% remain abstinent at one year after quitting
Only about 4% to 7% of people are able to quit smoking on any given attempt without medicines or other help.
Definitions of quitting : The gold standard outcome of continuous abstinence (West 2005) was used by two authors (Lipkus 2004; Peterson 2009). Other continuous measures included 90-day abstinence (Myers 2005) and "prolonged abstinence" (Moolchan 2005). Point prevalence measures were in the majority and these ranged from cessation for longer than one day (NoT FL 2001; NoT NC 2002; NoT WV 2004; Hoffman 2008) to 30 day cessation (Chan 1988; Aveyard 2001; Project EX ; Hollis 2005; Kelly 2006; Project EX Russia 2013). The most common outcome measure was seven-day point prevalence (Aveyard 2001; Brown 2003; Robinson 2003; Killen 2004; Lipkus 2004; Colby 2005; Moolchan 2005; Myers 2005; Muramoto 2007; NoT AL 2008). One study defined cessation as two sequential reports of seven-day point prevalence at four months and eight months from the start of the intervention (Lipkus 2004).
Hughes JR et al. Addiction 2004;99(1):29-38.

29. Smoking Total population ~ 320 mn / 100% Current smokers ~ 40 mn / 17%
Attempted to quit ~ 20 mn / 8%
Still abstinent at 1 year ~ 1 mn / <1%
CDC, Law & Tang, Arch Intern Med Stead LF, Cochrane, Cahill, Cochrane, 2013.

30. Why so hard to quit?

31. 5 major steps to intervention

32. 5 major steps to intervention
Ask – do you smoke?

33. 5 major steps to intervention
Ask – do you smoke?
Advise – you should quit!

34. Benefits of quitting Affects multiple (all?) organ systems
Acute and chronic effects
Some reversibility observed

35. Smoking Total population ~ 320 mn / 100% Current smokers ~ 40 mn / 17%
Attempted to quit ~ 20 mn / 8%
Still abstinent at 1 year ~ 1 mn / <1%
CDC, Law & Tang, Arch Intern Med Stead LF, Cochrane, Cahill, Cochrane, 2013.

36. Smoking MD encourages x 1 Total population ~ 320 mn / 100%
Still abstinent at 1 year ~ 1 mn
(-2% ARR of smoking)
Current smokers ~ 40 mn / 17%
Attempted to quit ~ 20 mn / 8%
Still abstinent at 1 year ~ 1 mn / <1%
CDC, Law & Tang, Arch Intern Med Stead LF, Cochrane, Cahill, Cochrane, 2013.

37. Smoking MD encourages x 1 Total population ~ 320 mn / 100%
Still abstinent at 1 year ~ 1 mn
(-2% ARR of smoking)
MD frequently encourages…
Current smokers ~ 40 mn / 17%
Still abstinent at 1 year ~ 2 mn
(-5% ARR of smoking)
Attempted to quit ~ 20 mn / 8%
Still abstinent at 1 year ~ 1 mn / <1%
CDC, Law & Tang, Arch Intern Med Stead LF, Cochrane, Cahill, Cochrane, 2013.

38. Effective behavioral interventions
Utilize the “5 As” at every clinic visit
Self-help therapy
Apps, Web, and mobile interventions
Motivational interviewing
Individual therapy (training in practical problem-solving skills)
Telephone therapy
Group therapy (provides mutual support from others)
Acupuncture, hypnosis (evidence is insufficient)
What behavioral interventions are effective? At every clinic visit, physicians should utilize the “5 As” as outlined above (18). Behavioral interventions can range from briefly asking patients about smoking habits to multiple counseling sessions. Individual therapy, group therapy, and telephone quitlines have all been found to aid in smoking cessation.
Self-Help Therapy
A meta-analysis of the effectiveness of self-help materials with no other treatment showed no evidence of benefit of standard structured materials (n = ; relative risk [RR], 1.06 [CI, 0.95– 1.18]). Materials tailored to individual smokers are more effective than nontailored materials, although the absolute size of effect is still small. Standard self-help materials provide no additional benefit when used with other interventions, like clinician advice or nicotine replacement therapy (NRT) (25).
Apps, Web, and Mobile Interventions Some of the most recent self-help tools include apps, mobile, and Web-based programs. Although the recommendations of many of these tools are not based on evidence, they can reach a large number of tobacco users with little potential downside. Thus, they could still have an effect, even if the individual benefit is small.
A review of 28 studies with more than participants of Internet programs showed that interactive and individually tailored interventions had significant effects (RR, 1.48 [CI, 1.11–2.78]) (26).
Five studies of 9000 participants showed that mobile phone interventions increased long- term quit rates better than control programs (RR, 1.71 [CI, 1.47–1.99]). The degree of benefit seems to correlate with adherence to evidence-based guidelines (27).
Motivational Interviewing
Motivational interviewing is a collaborative, goal-oriented style of communication with particular focus on a person's own reasons for change. These techniques can be useful in moving current tobacco users along a continuum of readiness to quit.
A meta-analysis of 14 studies published be- tween 1997 and 2008 involving more than smokers showed that motivational interviewing vs. brief advice or usual care yielded a modest, but significant, increase in quitting (RR, 1.27 [CI, 1.14 –1.42]) (28).
Individual Therapy
Individualized counseling by health care providers improves quit rates, and counseling intensity and quitting success has a strong dose–response relation. The OR was 1.6 (CI, 1.2–2.0) for cessation with low-intensity counseling (3–10 minutes) and 2.3 (CI, 2.0 –2.7) with high-intensity counseling (>10 minutes). Programs that delivered 4 or more sessions were the most beneficial (18). Training in practical problem-solving skills seems to be effective for smoking cessation. Such training included recognizing danger situations (e.g., being around smokers, cues and urges), developing coping skills (e.g., anticipate and avoid triggers, cognitive strategies to reduce negative moods and stress, and altering routines), and providing basic information (e.g., even a single puff can cause a full relapse, withdrawal symptoms may persist). Smokers may also benefit from social support provided in the context of cessation treatment (29).
Telephone Therapy
Individual telephone counseling is a popular way to administer support and reinforcement. It can reach a large number of tobacco users and is not as limited by geographic barriers. Both proactive (initiated by patients) and reactive (arranged by clinicians) telephone counseling helps smokers interested in quitting (24). Telephone quitlines provides smokers with important access to support, and call-back counseling enhances their usefulness. There is a dose–response relation—1 or 2 brief calls are less likely to provide a measurable benefit, whereas 3 or more calls has even better success. Quit rates were higher for groups receiving multiple sessions of proactive counseling (9 studies, > participants; RR for cessation at longest follow-up, 1.37 [CI, 1.26 –1.50]) (30).
Group Therapy
Group therapy provides mutual support from others having similar experiences and enables pooling of collective knowledge of previously effective behavioral methods. Group therapy is more effective than self-help and other less-intense interventions. Adding group therapy to other forms of treatment, like NRT, may provide additional benefit.
In a meta-analysis of group treatment, cessation increased with use of a group program (OR, 2.04 [CI, 1.60 –2.60]) compared with self-help or low-intensity treatments. There was no evidence that group therapy was more effective than similarly intense individual counseling (31).
Other Nondrug Therapies
Alternative interventions marketed for smoking cessation, such as acupuncture and hypnosis, are numerous; however, sup- port for their use is insufficient.
A review of 38 studies of the effectiveness of acupuncture compared with sham acupuncture for smoking cessation found an RR for the short-term effect of acupuncture of 1.22 (CI, 1.08–1.38) and an RR for the long-term of 1.10 (CI, 0.86 –1.40). There was no consistent evidence that acupuncture, acupressure, or laser therapy had a sustained benefit on smoking cessation for 6 or more months (32).
A review of 11 randomized, controlled trials compared hypnotherapy with 18 control interventions. The benefit of hypnotherapy on smoking cessation found in uncontrolled studies was not validated in this analysis (33).

39. 5 major steps to intervention
Ask – do you smoke?
Advise – you should quit!
Assess – are you ready?

40. 5 “R’s” for the “unready” (aka motivational interviewing)
Relevance – how is quitting relevant to you?
Risks – what are smoking’s negative consequences for you?
Rewards – what would be some benefits of quitting for you?
Roadblocks – why not?
Repetition – never give up!

41. 5 major steps to intervention
Ask – do you smoke?
Advise – you should quit!
Assess – are you ready?
Assist – can I prescribe anything to help?

42. Some drugs for treatment of tobacco dependence
Formulations
Maintenance dose
Cost (30 d)
Nicotine replacement therapy (NRT)
Patch
7, 14, 21 mg/24hr
1 patch/d
$40.70
Nasal spray
0.5 mg/spray
2 sprays 8-40x/d
$304.90
Inhaler
10 mg cartridge
4-6 cartridges/d
$290.40
Gum
2, 4 mg/piece
8-24 pieces/d
$77.20
Lozenge
2, 4 mg/lozenge
8-20 lozenges/d
$72.00
Dopaminergic / Noradrenergic Reuptake Inhibitors
Bupropion SR
100*, 150, 200* mg
150 mg BID**
$27.00
Wellbutrin SR *
$377.20
Zyban
150 mg
$236.00
Nicotine receptor partial agonist
Varenicline
0.5, 1 mg
1 mg BID***
$157.50
*Not FDA approved for smoking cessation.
**Start with 150mg once daily x 3 d.
***Start with 0.5mg daily x 3 d, then 0.5 mg BID x 4 days.
The Medical Letter, Vol. 58 (1489), Feb

43. Network meta-analysis of cessation Rx
267 trials, >100K smokers
6-month abstinence
Cahill, Cochrane, 2013

44. Network meta-analysis
The network
Some issues

45. Other considerations Bupropion NRT
Concern re: concomitant smoking less valid than believed
Use caution within 2 weeks of recent MI, severe angina, or life-threatening arrhythmias
Bupropion
Contraindicated: recent history of seizures
Drug interactions with antipsychotics and MAO inhibitors or drugs with MAO inhibitor-like activity
Associated with hypertension (monitor blood pressure)
Varenicline
Concerns regarding neuropsychiatric effects (or not???) and possibly cardiovascular events
Use cautiously in patients with renal impairment
Are there conditions that contraindicate or caution against pharmacologic therapy?
NRT
Side effects vary based on the type of NRT (18, 39, 40). For example, the patch can cause rashes, the gum nausea, and the nasal spray nasal irritation. Concerns about this therapy with concomitant smoking are less valid than previously believed. The revised labeling for over-the-counter NRT suggests that there are no significant safety concerns in using more than 1 nicotine-containing product (multiple NRTs or NRT with a cigarette). Although people should be encouraged not to smoke while receiving NRT, if they have a cigarette they should not remove the nicotine patch. Instead, they should keep the patch on and discontinue smoking.
NRT should be used with caution within 2 weeks of a recent myocardial infarction, severe angina, and life-threatening arrhythmias (40). In these patients, the potential adverse risks of NRT should be weighed against those of continued smoking. This decision should probably be made in conjunction with a cardiologist. NRT seems to be safe in persons with stable coronary disease (40). Nicotine may be safer than smoking during pregnancy, but it may be advisable to initially attempt to stop smoking without NRT. However, if a pregnant smoker continues to smoke, the potential risk of medications should be weighed against the known harm of continued smoking.
Bupropion
The most common side effects for bupropion include insomnia, anxiety, dry mouth, headache, and rash (39). Bupropion is contraindicated in persons with a recent history of seizures, eating disorders, or other conditions that lower the seizure threshold. The seizure rate with bupropion is about 1 per 1000 persons treated. Drug interactions with antipsychotics and monoamine oxidase (MAO) inhibitors or drugs with MAO inhibitor-like activity (e.g., furazolidone, linezolid, procarbazine, or selegiline) have been reported. Similarly, other drugs that can lower the seizure threshold should be used with caution or avoided in patients receiving bupropion (18). Blood pressure should be monitored because bupropion has been associated with hypertension. Multiple forms of the drug should not be administered together. Meta-analysis of bupropion studies found no excess of neuropsychiatric (RR, 0.88 [CI, 0.31–2.50]) or cardiovascular events (RR, 0.77 [CI, 0.37–.59]) (34).
Varenicline
The most common side effects of varenicline include nausea, sleep disturbances, and gastrointestinal symptoms. These are improved by taking varenicline with food and adequate water. Clinicians should use varenicline cautiously in patients with renal impairment, and dosage adjustments may be necessary. No adequate, well-controlled studies of varenicline
have been done in pregnant women.
There have been concerns regarding varenicline and cardio- vascular events. An initial meta-analysis found a slightly increased rate of cardiovascular adverse events (1.06 vs. 0.82%) (41). However, whether this difference is clinically significant is unclear. Two subsequent reviews, which included 8 additional studies that had been excluded, did not show any significant increase in events (0.63 vs. 0.47% event rate) or risk (RR, 1.26 [CI, 0.62–2.56]) (34, 42).
The most notable concerns regarding varenicline have been neuropsychiatric effects (erratic and hostile activity, depressed mood, and suicidal behavior), for which it currently carries a “black-box” warning. Subsequent analyses of available trial data and large cohorts of patients in primary care have not demonstrated the same risk for neuropsychiatric events (34, 43, 44). Therefore, clinicians should weigh the initial concerns from postmarketing surveillance with the lack of adverse events seen in more controlled studies and appropriately monitor mood and behavior.

46. Cardiovascular risks
Estimated RR and 95% CrI From Random-Effects Network Meta-Analysis for Cardiovascular Events in Smoking Cessation RCTs (RCTs for NRT=21)
Comparison All CVD events MACEs
    NRT vs placebo (1.39–3.82) 1.95 (0.92–4.30)
    Bupropion vs placebo (0.54–1.73) 0.45 (0.21–0.85)
    Varenicline vs placebo (0.79–2.23) 1.34 (0.66–2.66)
    Bupropion vs varenicline 0.76 (0.33–1.73) 0.33 (0.16–0.87)
    Bupropion vs NRT (0.19–0.91) 0.23 (0.08–0.63)
    Varenicline vs NRT (0.25–1.27) 0.67 (0.26–1.90)
Mills EJ, Circ 2014.

47. Smoking MD encourages x 1 Total population ~ 320 mn / 100%
Still abstinent at 1 year ~ 1 mn
(-2% ARR of smoking)
MD frequently encourages…
Current smokers ~ 40 mn / 17%
Still abstinent at 1 year ~ 2 mn
(-5% ARR of smoking)
Attempted to quit ~ 20 mn / 8%
Still abstinent at 1 year ~ 1 mn / <1%
CDC, Law & Tang, Arch Intern Med Stead LF, Cochrane, Cahill, Cochrane, 2013.

48. Smoking MD encourages x 1 Total population ~ 320 mn / 100%
Still abstinent at 1 year ~ 1 mn
(-2% ARR of smoking)
MD frequently encourages…
Current smokers ~ 40 mn / 17%
Still abstinent at 1 year ~ 2 mn
(-5% ARR of smoking)
Nicotine replacement therapy…
Still abstinent at 6 months ~ 1.8 mn
(50-80% ↑ cessation rate)
Attempted to quit ~ 20 mn / 8%
Bupropion…
Still abstinent at 6 months ~ 1.8 mn (~80% ↑ cessation rate)
Still abstinent at 1 year ~ 1 mn / <1%
Varenicline…
Still abstinent at 6 months~ 2.9 mn (~180% ↑ cessation rate)
CDC, Law & Tang, Arch Intern Med Stead LF, Cochrane, Cahill, Cochrane, 2013.

49. 5 major steps to intervention
Ask – do you smoke?
Advise – you should quit!
Assess – are you ready?
Assist – can I prescribe anything to help?
Arrange – follow up within one week of quit attempt

50. Conclusions
Chronic lower respiratory diseases, including COPD, are the 4th leading cause of death
Not only in smokers!
Smoking is the most important modifiable risk factor for disease
Not only lung disease!
Advances in COPD treatment and smoking cessation strategies are urgently needed
Prevention!

51. Thank you!