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Chronic obstructive pulmonary disease (COPD) is a group of disorders characterised by a progressive and poorly reversible limitation of airflow which is associated with persistent inflammation of lungs. It encompasses chronic bronchitis which is accompanied by hypersecretion of mucus and emphysema with destruction of alveolar walls.
With an estimate of 210 million people suffering from it worldwide, COPD is the fourth-leading cause of death with 3 million people died, which approximates to 5% of global mortality, as stated by World Health Organisation 1,2,3. It is expected to increase by more than 30% to be ranked third by 2020 according to the global burden of disease studies. In UK, over 2 million people suffered from this disease with NHS claiming it to be ranked fifth in total reported death in UK 4. Analysis also showed that the estimates of prevalence of COPD differ from 1% to 4% of the population, more men suffered from COPD than women and mostly affecting citizens over 45 years old. As for the morbidity rate, over 110000 people were hospitalised in England alone with a total of 1 million in-patient bed days per annum. With 200 patients per GP and costs of over £800 million per annum, COPD is one of the most important cause of mortality and morbidity in UK and every other country. Compared to respiratory problems, cardiovascular (CV) death is the major cause of mortality in people suffering COPD, with increased cardiac deaths depending on its severity 5. This may be due to its underlying systemic inflammation and the reason both diseases share some similar risk factors like age and smoking 6.
One of the primary pharmacological agents used as symptomatic relief for COPD is inhaled anticholinergics. It remains to be one of the most widely used drugs for COPD with over 2 million prescriptions dispensed in 2007 in England alone. The use of inhaled muscarinic antagonists was also well-established as it is recommended in most COPD guidelines such as National Institute for Clinical Excellence (NICE), Global Initiative for Chronic Obstructive LungÂ Disease (GOLD), European Respiratory Society/American Thoracic Society (ERS/ATS), Canadian Thoracic Society and General Practice Airways Group Publication (GPIAG) for management of COPD and as an additional treatment for stage 4 of British Thoracic Society guidelines for treatment of chronic asthma 7-12. Studies had also shown that antimuscarinic agents improve lung function, exercise tolerance, and quality of life (QOL), and reduce number of exacerbations and respiratory symptoms 13. Muscarinic antagonists had also been shown to reduce hospitalisations by 30% and respiratory deaths by 70% 14.
Anticholinergic drugs are direct antagonists at muscarinic acetylcholine receptors 15. These drugs have various parasympatholytic actions at different site of actions such as heart, bladder and lung. Thus, some of the common side effects for these drugs are dry mouth with rare side effects include tachycardia and palpitation 16. Therefore, different routes of delivery and kinetic properties are utilised to achieve different effects.
One of the routes to deliver the drugs directly to lungs is via inhalation which was believed to have less systemic side effects. Inhaled therapy may also causes paroxysmal bronchospasm though rare. There are two types of inhaled anticholinergics currently available in the BNF; the short-acting ipratropium bromide and the long-acting tiotropium bromide; with the former drug also available as combination inhalers with Î²2-agonists 16. Ipratropium is indicated for short-term relief in mild COPD. Its onset of action is over 30-60 minutes; duration of action of 3-6 hours and usually given 1-2 puffs 3-4 times per day 15. Another short-acting anticholinergic inhaler, oxitropium, is not available in UK. As for the latter drug, tiotropium is used for the management of COPD and not suitable as a reliever for acute bronchospasm even though it has the same onset of action. Its main advantage is that it can be given once-daily due to its long half-life (24 hours), making it the preferred choice for COPD.
Inhaled anticholinergics, also known as antimuscarinic bronchodilators, are particularly used as relief of acute and chronic bronchospasm. They help reduce bronchospasm by working as antagonists at M3 muscarinic acetylcholine receptors 15. The short-acting agents act at M2 receptors which are located in heart and responsible for control of heart rate, conduction velocity of AVN and contraction of heart muscle 15. This may explain the reason as to why more studies associate increased CV risk in ipratropium which will be mentioned later. On the other hand, tiotropium is more selective for M3 and M1 receptors 18. As parasympathetic nervous system has bronchoconstricting action in the lungs, blocking muscarinic receptors have bronchodilatory action to help relax and prevent narrowing of the airways. The degree of bronchodilatation caused by these agents is less than Î²-agonists but the relative contribution of cholinergic system is greater for COPD. Therefore, antimuscarinic inhalers are the therapeutic foundation in the management of COPD, in conjunction with short-acting Î²2-agonists 7. When comparing both drugs, tiotropium has better efficacy, less side effects, better compliance and lower discontinuation rates than its short-acting counterpart 38,39.
Side effects of inhaled anticholinergics
As stated earlier, it is plausible that even inhaled route might cause serious cardiac adverse effect due to its anticholinergic properties although clinical trials showed they are rare and have limited systemic bioavailability 17,19. The summary of product characteristics for short-acting ipratropium enlisted palpitations, supraventricular tachycardia (SVT) and atrial fibrillation as rare side effects with tachycardia as uncommon 20. Tachycardia and palpitations are listed as rare adverse effects for tiotropium inhalers 21. The common side effects reported in both are dry mouth and urinary retention which are thought to be of non-importance as they are reversible. In UK, drug's safety is regulated by Medicines and Healthcare products Regulatory Agency (MHRA) and Commissions on Human Medicine (CHM). Through the Yellow Card Scheme, cardiac disorders account for 16% out of total adverse drug reactions (ADR) reports and 27% fatality out of total fatal ADR reported for tiotropium from 1963 to 2010 36. As for ipratropium, only 9% of cardiac disorder was reported from overall ADR and 14% deaths were due to CV disorders 37. Different types of CV side effects and its number of events had been summarised in Table 1 according to the 2 types of antimuscarinic inhalers. Both types had been shown to exhibit absorption and excretion via urine to produce systemic cardiac adverse effects as those observed in oral administration 24,25. One mechanism has been suggested. A proportion of drugs may be swallowed during inhalation, not reaching its desired target. Even though the drugs exhibit poor absorption, it may still be absorbed and bind to M2 receptors located in the heart to give rise to cardiac side effects mentioned above.
Table 1 Comparison of reported adverse effect through Yellow Card Scheme from MHRA between short-acting Ipratropium and long-acting Tiotropium in UK 36,37.
Types of CV Disorders
Cyanosis & palpitations
Coronary artery disease
Angina and MI
Left ventricular failure
Rate and rhythm disorders (Arrhythmia, bradycardia & tachycardia)
Supraventricular arrhytmias (AF, sinus & supraventricular tachycardia)
Ventricular arrhytmias (ventricular fibrillation & tachycardia) & cardiac arrest
AV block & conduction disorder
Right ventricular failure
Evidences that inhaled anticholinergics cause CV adverse effects
The cardiac concern started a decade ago as Lung Health Study (LHS) discovered that ipratropium group had a higher number of mortality due to CVD when compared to control group (n=5887; P=0.027) 22. Coronary heart disease mortality and combination of fatal/non-fatal CV mortality were greater but not statistically significant (P=0.084 and P=0.156). Another interesting observation was that hospitalisation for SVT in treated group was found to be greater. However, the paper had many limitations, making its findings ambiguous but it served as a catalyst to more studies being carried out. In this case scenario, the concern was re-addressed by a junior doctor asking if inhaled anticholinergics can cause cardiac side effects. To answer this question, a further two randomised controlled trials (RCTs), an observational study and several meta-analyses were analysed.
For the first RCT, it was published by LHS involving 5887 smokers 30. This 5-year study showed that short-acting ipratropium was associated with increased hospitalisation and deaths due to CV problems by two-fold as compared with control though not statistically significant. Another interesting observation is that hospital admission was mainly due to SVT, one of ipratropium's adverse effects. However, multiple comparisons in this trial may result in false positive data.
One recently published meta-analysis involving 17 RCTs selected out of 103 trials reported that inhaled antimuscarinics (ipratropium and tiotropium) increased CVD risk in COPD patients when compared with placebo or other comparators (Î²-agonist and combination therapy) 26. In this large systematic review (n=14783) and trial duration from 6 weeks to 5 years, patients using inhaled antimuscarinics had 58% increased risk for composite of non-fatal MI, CV death or stroke (1.8% vs 1.2%;Relative Risk (RR) 1.58;[95% CI 1.21-2.06];P<0.001) than placebo. In subgroup analysis, antimuscarinic inhalers were found to be associated with increased MI risk (1.2% vs 0.8%;RR 1.53;[95% CI 1.05-2.23];P=0.03) and CV death (0.9% vs. 0.5%;RR 1.80;[95% CI 1.17-2.77];P=0.008). There was no significant increased in stroke risk (0.4% vs 0.5%, RR 1.46 [95% CI 0.81-2.62]; P=0.20). One important finding from this study is that no significant increased of the composite end-point was found in 12 short-term trials (less than 26 weeks). The increased is only statistically significant (2.9% vs. 1.8%; RR 1.73, 95% CI 1.27 to 2.36; P<0.001) for 5 long-term trials (more than 6 months) with 73% of increased heart problems. In short, this study supported the association between inhaled anticholinergics and CV events as shown in Figure 1 below. It also suggests that patients using inhaled anticholinergics as long-term therapy had a higher chance of developing CV side effects.
Figure 1 Blobbogram on overall meta-analyses adapted from Singh S et al study of inhaled anticholinergic drugs on risks of cardiac events composite (CV death, MI and stroke) 26. Data represents relative risks (with respective 95% CI). Size of the data markers indicates weight of the study. Relative risks of more than one show increased in risks. â€ represents statistical significance.
Nevertheless, every meta-analysis had its limitation. Biased may be introduced as the placebo group had a mixture of drugs as Î²-agonists may increase CV events whereas IHC may lower events 27,28. Over 50% of the overall patient included in meta-analysis came from LHS. High discontinuation rates in several trials up to 42% and more drop-out in placebo group may result in over-estimate of CV risk and weak statistical power. As the individual trials were not designed to observe CV risks, there may be discrepancies over the reported outcomes. In addition, CV deaths reported in the study were too few, suggesting that the increased risk may not be important clinically. Many of the trials were not large and long-term with only 5 long-term trials, contributing to its few events. The small number of events and wide range of 95% confidence intervals raise uncertainty about the precision of the results.
Lee et al conducted a randomised nested case-control study involving 32130 patients and 320501 placebos to investigate the link between various COPD medicines (ICS, ipratropium, theophylline and Î²-agonists) and different means of mortality (all-cause, CV and respiratory deaths). For CV death, a 34% increased risk with ipratropium (odd ratio 1.34, 95% CI 1.22-1.47) was reported. However, this study had age restriction over 65 years old and did not measure two important CV risk predictors (lung function and smoking status). Nevertheless, the above recent findings raised questions over the use of inhaled antimuscarinics as primary therapy for COPD as recommended in most guidelines.
Evidences that anticholinergics do not increase CV side effects
UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) study published a large, prospective, long-term (4 years), double-blinded RCTs which involves 5993 participants and 37 countries. The study did not demonstrate any increased risk for overall cardiac adverse events (3.56% vs 4.21%; RR 0.84; [95% CI 0.73-0.98]; P<0.05) 29. From Figure 2 below, only congestive cardiac failure and MI showed statistical significance which favours placebo. Moreover, tiotropium was found to lower exacerbations by 15% in terms of number over patientâ€‘year (P<0.001), improve lung function (through measurement of FEV1) and QOL by 2.7 point score according to St. George's Respiratory Questionnaire (95% CI 2.0-3.3; P<0.001). In contrast to the above trials, this study provides evidence on the safety and effectiveness of tiotropium in COPD though it had its own limitations. Some of the limitations are it did not include CV end-points, inclusion of moderate-to-severe COPD only, high drop-out rates (36% for tiotropium and 45% for placebo) and most importantly, funded by Boehringer Ingelheim, the company who marketed the drug. This may be the reason why safety data was incomplete as it may be unfavourable to the funder.
Figure 2 Blobbogram on incidence rate of tiotropium with cardiac side effects per 100 patient-years adapted from UPLIFT trial 29. Data represents relative risks (with respective 95% CI). Size of the data markers indicates weight of the study. Relative risks of less than one favour tiotropium group. â€ represents statistical significance.
A more recent meta-analysis published by Oba et al in 2009 reported that inhaled tiotropium had lower risk of fatal and non-fatal CV events (RR 0.91;95% CI 0.77-1.07) than placebo 31. However, majority of the 13 trials chosen was short-term trials, result is not statistically significant and most weight of the pooled analysis was from UPLIFT trial. Another meta-analysis released after UPLIFT trial also reported similar findings. The study by Rodrigo et al had similar limitation with 80% of the data from UPLIFT, 10% from LHS and only 10% for the rest, suggesting that results may be biased to the large UPLIFT trial, eliminating any possibilities of cardiac risks 32.
Earlier this year, US Food and Drug Administration (FDA), the regulatory body for drug safety in US, released a follow-up to its 2008 early communications on the ongoing safety review of tiotropium. In 2008, FDA reported that anticholinergic inhalers were linked to a small increased risk of stroke (0.8% vs 0.6%; RR 1.34) in a pooled analysis from 29 trials (n=13500) 23. In the same year, FDA also found increased risk of CV death, MI or stroke after reviewing 2 additional papers 26,35. However, FDA reversed its early claim after analysing UPLIFT trial and stated that there are no association between CV events (MI, stroke and CV deaths) and tiotropium 36. An advantage of pooled analysis is that it may offer early information on the potential issue which in this case is safety. However, they have inherent limitations such as inclusion biased that need further investigation using other sources.
Another reason which may suggest that CVD is not linked to inhaled anticholinergics is the common risk factors shared by COPD and CVD such as advanced age, hypertension and smoking 33. A new study from Columbia University Medical Center researchers found that patients with COPD of any severity were found to have diminished heart function 34. MESA project, a large ongoing cohort study, also showed a strong link between heart function and lung, suggesting that disease itself may be the cause of CVD rather than drugs such as antimuscarinics. Patients may also be on other drugs like statins and aspirin which are cardioprotective, pre-existing CVD or co-morbidities such as hypertension and dyslipideamia, and other complications as well 22,23.
Scenario and Conclusion:
There are still ongoing debates over whether inhaled anticholinergics increase or decrease CV side effects with current evidences remain inconsistent as shown above. It is not certain why the findings are conflicting among the published papers. In my opinion, there are not enough good RCTs available with majority of the published papers are meta-analyses, observational (cohort or case-control) studies and consensus opinion; which none of them are as strong as RCTs which are considered to be the strongest available evidence-based medicine. Furthermore, most clinical evidences found may not be applicable to the local population as majority did not report enough patient demographics and were US-based. These contradictory findings revels the need for more prospective, robust RCTs to provide a final conclusion on the safety of inhaled antimuscainics. Until then, a change in prescribing practice is not recommended as these drugs had been proven to reduce hospitalisations, exacerbations and improve symptoms in COPD 7,13.
If inhaled anticholinergic was prescribed, doctor should be told that it should be recommended only for short-term as one of the above study found that most risk had come from trials in which the agents were used for more than 6 months 26. Moreover, the benefits of long-term use have yet to be proven. Routine follow-up appointments and close cardiac monitoring for development of complications are also needed to eliminate any possible risks associated with CV events for patients receiving antimuscarinic therapy.
Even though there are more papers stating that inhaled anticholinergics does not increase CV risks than those supporting it, all those studies still reported small events of cardiac side effects and it is to no one's surprise due to its anticholinergic pharmacological properties. Therefore, cautions should always be practiced with inhaled antimuscarinics, particularly those with high risk or have pre-existing CVD. In the mean time, I would advise the doctor to consider these new findings of increased cardiac risk when weighing the risk: benefit ratio against each individual patient while waiting for updated guidelines or more evidence-based medicine trials to confirm the possibility of increased CV risk with inhaled antimuscarinics. Decisions regarding prescribing or changing this inhaler in COPD patients should take into consideration its effectiveness, costs, concomitant co-morbidities, concurrent drugs and others as successful use of every drugs are always a balance between their desired and risk of side effects. Patients should also have a say in managing the disease in order to achieve concordance for the management of the disease.