Breath-actuated INhalation TheRapy: survey of phySicians’ PErCepTion (INTROSPECT) in Nepal

Abstract Objective Breath-actuated inhalers (BAIs) are gaining attention in the management of obstructive airway diseases (OADs). In Nepal, a BAI containing fluticasone propionate/salmeterol (FPS) has been available for a year. This survey is aimed at determining the perception and experience of physicians in Nepal concerning BAIs. Methods A cross-sectional, questionnaire-based survey was conducted. A total of 141 physicians participated and filled the survey. Results Most physicians felt that the right device should be easy to teach, learn and remember. They considered coordination and multiple steps as the primary challenges with pressurized metered-dose inhalers and dry powder inhalers, respectively. Most of them agreed that BAIs could address these challenges. BAIs were not only preferred by most of the physicians for asthma and chronic obstructive pulmonary disease but were also the preferred choice in newly diagnosed patients. Physicians believed that if current patients were shifted to BAIs, it could improve inhalation technique (88%) and compliance/adherence (81%). Almost all of them (92–97%) agreed that teaching the breathing technique and the cleaning process was easier and faster in BAIs. BAIs were considered easy and simple to use. Also, BAI’s dose-counter helps patients to increase adherence to inhalation therapy. Conclusions In this INTROSPECT survey, physicians in Nepal believed that BAIs could address the key challenges faced with using pMDIs and DPIs in asthma and COPD patients.


Introduction
Inhalation devices are integral to managing obstructive airways diseases (OADs) (1). Pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) are inhalation devices that have been available for decades (2). However, both of these devices have got their drawbacks when it comes to patient usage. The biggest challenge with pMDIs is the coordination between actuation and inhalation; with DPIs, it is the need for a high inspiratory flow rate for optimum drug delivery to the lungs (3). These challenges could be one of the potential reasons for poor inhaler technique and non-adherence to inhaler devices among patients with OADs, which can result in exacerbations, increased hospitalizations, poor quality of life, and increased morbidity and mortality (4).
A breath-actuated inhaler (BAI) releases the dose during inhalation due to negative pressure within the device. This overcomes the need to facilitate coordination of the actuation and inhalation as required in pMDIs (5). Furthermore, BAIs get actuated at a very low inspiratory flow rate. This also overcomes the DPI requirement of high inspiratory flow for optimal drug deposition into the lungs. Thus, BAI use may, ultimately, further improve treatment adherence and outcomes in patients with OADs (6,7).
In Nepal, a BAI (Synchrobreathe®) containing fluticasone/salmeterol (FPS) has been available for more than a year. This novel BAI with an integrated dose counter has a soft-triggering mechanism. It gets actuated at lower inspiratory flow rates of approximately 27-30 L/min (8)(9)(10). This survey was designed to gain an insight into the current trends regarding inhalation devices and to evaluate the perceptions and experiences of the physicians in Nepal regarding breath-actuated inhalation therapy in OADs.

Methods
This was a questionnaire-supported, observation-based, multi-specialty survey conducted among physicians in Nepal, who routinely manage OAD patients with inhalation therapy but may or may not be prescribing BAIs. A total of 141 physicians from different specialties (physicians [Internal Medicine] − 64.75%, chest physicians − 24.59%, general practitioners − 9.84%, and interns − 0.82%) participated in the survey. The principal investigator helped to develop the survey questionnaire ( Figure 1) and reviewed the survey protocol and consent procedures to ensure confidentiality and data safety. The randomly chosen qualified physicians for the survey were from different geographical regions of Nepal ( Figure 2) and practice settings such as academic institutions, government hospitals, private hospitals, or clinics. All the survey forms were duly undersigned and hand-filled by the participating physicians. They also signed the data-sharing consent form, allowing data from the survey to be used for publication. Cipla Ltd personnel helped distribute the survey questionnaire to the participating physicians and collected the response sheets. The average time to complete the data collection was two months. This survey aimed to gain an insight into the current trends regarding inhalation devices and to evaluate the perceptions and experiences of the physicians in Nepal regarding breath-actuated inhalation therapy in OADs. Reports related to the safety of management therapy in patients were not recorded.

Questionnaire
The survey questionnaire consisted a mix of 17 open and close ended questions with multiple choice answers. There were also a few questions based on 5-point choices, ranging from "strongly agree" to "strongly disagree." The questionnaire was designed to evaluate the perceptions and experiences of practicing in Nepal with respect to BAIs [Supplement 1].

Data collection and analysis
The filled survey forms (response sheets) were sent for data entry and statistical analysis to Sqarona Medical Communication, Mumbai, India. The summarized physician's responses were presented as unadjusted means, medians, descriptive statistics, frequency distribution, and proportions. Due to the disproportionate sample size, the total data was represented in percentages (they were considered null).

Baseline characteristics
A total of 141 physicians participated in the survey. About two-thirds of the participating physicians had a clinical practice of 10 years or below. Over half of the participating physicians practiced in hospitals and clinics, whereas 44.26% of the participants practiced only in hospitals, and a small group (2.46%) practiced only in private clinics (Table 1).

Choosing the right device
For their patients with OADs, all but two of the physicians (n = 139) believed that selecting the right device is equally important as selecting the right inhalation therapy. Most (35.97%) felt that the selection criteria for choosing the right device are "easy to teach, learn and remember." In comparison, "no requirement of coordination between breathing and actuating inhaler" and "drug can be inhaled with minimal effort" was chosen by 33.09% and 28.78% of the participants, respectively ( Figure 3).

Demonstration of inhalation techniques
Almost half of the physicians relied on the pharmacist at the nearest pharmacy or the hospital pharmacist to demonstrate the inhalation devices. Only 29% of the physicians demonstrated the inhalation device techniques, whereas another one-third would ask their assistant and supporting staff to demonstrate the inhalation techniques.

pMDIs
The physicians felt that OAD patients faced multifold challenges while using pMDIs, such as shaking the inhaler before use, coordination between actuation and inhalation, rapid inspiration, and the inability to hold their breath. Most of them (89.21%) believed coordination was the biggest challenge faced by the patients while using pMDIs.
Opinions varied among the physicians regarding prescribing an additional spacer device with pMDI for their OAD patients. Only 17% of the physicians believed that >80% of their patients would use the prescribed spacer with a pMDI. In a real-life setting, using an add-on spacer device along with a pMDI poses additional challenges such as incremental costs, social stigma, and the need for regular cleaning. Further, extra effort to assemble the spacer every time and difficulty in carrying the spacer was the two topmost challenges identified during the survey (Figure 4).

DPIs
The maximum number of physicians believed that the multiple steps involved in device preparation and inhalation (52.90%), followed by the requirement of high inspiratory flow (31.16%), were the most important challenges faced by their patients while using the DPI devices.

BAIs
Approximately 9 out of 10 physicians either agreed (50.72%) or strongly agreed (37.68%) that BAIs can address the challenges faced while using other drug  delivery systems such as pMDIs and DPIs ( Figure 5). Up to 87.69% of physicians either agreed or strongly agreed that shifting their patients from their existing devices to BAIs can improve their technique; 80.77% of physicians believed that this shifting could also improve their patients' compliance and adherence levels (Figure 6(a) and (b)). Among the participating physicians (n = 138), the majority (94.20%) said that they would prescribe BAIs to their OAD patients, while the rest would like to prescribe other drug delivery systems.
Up to 84.62% of the physicians confirmed that they prescribe BAIs to 40% of their OAD patients. This patient population consisted of an equal number of adult and geriatric patients. Most physicians (77.69%) preferred prescribing BAIs to patients with asthma and those with COPD.
Approximately 95% of the physicians preferred to prescribe BAIs to even newly diagnosed OAD patients. In Nepal, only FPS (fluticasone and salmeterol) combination is available in the BAI device. However, almost all the physicians (97.80%) believed that they would prefer to shift their existing patients to BAIs irrespective of their existing FPS (via pMDI or DPI) or formoterol and budesonide combination (via pMDI or DPI) treatment.
Most physicians positively perceived BAI usability on various parameters evaluated, as given in the table below (Table 2).

Discussion
Globally, asthma and COPD are associated with significant morbidity and mortality (11). The present  survey was conducted amongst physicians practicing in Nepal to better understand the current trends regarding inhalation devices and to evaluate the perceptions and experiences of the physicians in Nepal regarding breath-actuated inhalation therapy in OADs.
Inhaled medications have been shown to improve disease status, control symptoms, reduce the number and severity of exacerbations, and improve the quality of life. Additionally, the current survey highlighted that selecting the right device is equally important, if not more. Problems with the use of inhalers by patients were noted shortly after the launch of the pMDIs and prevailed to date. Over the last 60 years, numerous errors with pMDIs have been described, with poor hand breath coordination being one of the most commonly reported errors (12). Almost all participating physicians in the current survey also believed the same. The literature reports good adherence levels ranging from 70 to 90% in clinical trials, but this deteriorates in clinical practice and PHC (i.e. 10-40%) (13)(14)(15).
In real-life, cross-sectional, non-interventional studies in Latin America (LASSYC) (14) and a COPD study in Greece (16), only 50% of the patients showed good adherence. Poor adherence to inhaled controller medications is particularly common among patients with asthma and COPD (17). Even though the possible factors influencing non-adherence rates are not yet fully understood, patients from rural and remote areas, regions undergoing financial or social crises, and older patients with multiple morbidities tend to present much higher non-adherence rates. Only a   small subset of the physicians in our survey believed that good patient adherence resulted from the add-on spacer device with a pMDI, given that it required regular washing and additionally led to social stigma and increased cost. In another study, patient-reported non-adherence led to 11.5% more exacerbations and 14.1% more hospitalizations per year (16), along with economic impact (18). Given the above scenario, a patient-reported outcome study in Nepal is needed.
Aside from patient issues, the other factors contributing to patients' poor inhalation techniques include the lack of knowledge of the healthcare professionals regarding the correct inhalation techniques (19,20). In a review of 21 studies looking at misuse of pMDIs, the poor technique was estimated to be prevalent in 14-90% (with an average of 50%) of cases (21). Inhaler technique training delivered to patients by healthcare professionals is important in terms of the nature, frequency, and skill level demonstrated (22). The current survey suggested that only 29% of the physicians demonstrated the inhalation device technique themselves. However, a physician inhaler device education program can improve attitudes toward teaching inhalation techniques and facilitate implementation in clinical practice, as reported in the literature (23). This survey highlighted the physician's perceptions regarding the attributes of inhalers and inhalation techniques. Most participating physicians agreed that "easy to teach, learn and remember" and "no requirement of coordination between breathing and actuating inhaler" are the selection criteria for choosing the right inhaler. Besides, time spent on teaching techniques could be another crucial parameter to check in further studies (24). pMDIs and DPIs, which work on different principles, are widely used to treat asthma and COPD. Although each device has its uniqueness and is specifically suitable for different patients, pMDIs are the most popular and largely prescribed devices worldwide. A previous survey revealed that Nepalese physicians preferred DPIs and pMDIs equally. A known shortcoming is the need to inhale forcefully and consequently generate a sufficient inspiratory flow in DPIs. It suggests that using DPIs correctly could be problematic for patients with severe airflow limitations (8).
On the other hand, pMDIs provide the advantage of portability and reproducible dosing, although they suffer from the drawback of poor technique. Many patients cannot maintain coordination between their breathing rhythm and device actuation and often breathe in too fast, resulting in suboptimal drug deposition in the lungs and peripheral airways, which will, in turn, result in poor disease outcomes (19)(20)(21)(22). This significant gap can be addressed by the novel BAI. BAIs sense an inhalation effort through the actuator and mechanically actuate the dose in synchrony, resolving the issue of patient coordination of actuation with inhalation. Thus, BAIs overcome the drawback associated with lack of coordination and the inability of patients to synchronize actuation with inhalation. BAIs fulfill most of the criteria for desirable features in an inhaler device. In a study to evaluate patients' perceptions (n = 42) of BAIs, 98% found that the BAIs was easy to use (10,25). This is in line with our survey results showing that 95% of physicians had the same perception about BAIs. The current survey data reported that most Nepalese physicians would like to shift their asthma and COPD patients to BAIs since, in their opinion, BAIs can address the challenges patients face on other types of inhaler devices.
The view that breath-actuated devices are easier to teach and use was confirmed in the Sirocco study in which approximately 91% of patients with asthma (n = 6,512) could complete all the procedural steps required to correctly use a breath-actuated device without error after a training session of approximately 4 min (26). In our survey, the physician had similar perceptions of the usability of BAIs, and 96.15% agreed that a breath-actuated device is easier to teach to their OAD patients.
The ease of use of BAIs translates into improved adherence, compliance, and persistence with the prescribed therapy and, thereby, improved disease control (25).
On the other hand, the limitations of BAIs cannot be ignored. These include a limited range of drugs available for use with BAIs, the requirement of shaking the suspension before each use, and the need for priming the device if not used for some time or in cold temperatures (27). However, in the current survey study, almost all the physicians (97.80%) would prefer to shift their existing patients to BAIs irrespective of their existing FPS therapy (via pMDI or DPI) or formoterol and budesonide combination (via pMDI or DPI) treatment. Similarly, a real-world study including 3,811 patients with asthma or COPD demonstrated a significantly lower rate of making at least one critical error with the Autohaler® (a BAI; 11%) compared with other devices (a pMDI, 28%; and the Turbuhaler® DPI, 32%; p < 0.05) (9).

Limitations of the study
There were few limitations associated with this survey. Since in Nepal, the BAI is available only with the Salmeterol/Fluticasone combination, therefore the physicians could only give responses basis their experience on the Salmeterol/Fluticasone. However, in Nepal Salmeterol/fluticasone is available both in pMDI as well as in DPI devices, hence we think, this limitation should not influence the outcomes of the survey as physicians could fully gauge the advantages and disadvantages of all type of devices with the same drug.
Moreover, the survey was conducted only in physicians which was in line with the objective of the survey, still we are missing the perception and experience of patient, which can also be considered as one of the limitations of this study. However, we have already demonstrated device handling and ease of use of BAI in our previously done study 460 participants (28). As more BAIs will be available in Nepal in future, we could plan separate study to get patients perspective also going forward.

Conclusions
In this INTROSPECT survey, physicians in Nepal believed that choosing the right inhalation device is equally important as selecting the right inhalation drug. BAIs could address the key challenges faced with using pMDIs and DPIs in patients with asthma or COPD. BAIs are easier and faster to teach, easy to use, learn and remember inhalation devices. Dose counter in the BAI helps patients to increase adherence to their treatment.