The promotion of physical activity is at the top of our national public health agenda. Although regular exercise reduces subsequent cardiovascular morbidity and mortality, the incidence of a cardiovascular event during exercise in patients with cardiac disease is estimated to be 10 times that of otherwise healthy persons. Adequate screening and evaluation are important to identify and counsel persons with underlying cardiovascular disease before they begin exercising at moderate to vigorous levels. This statement provides recommendations for cardiovascular screening of all persons (children, adolescents, and adults) before enrollment or participation in activities at health/fitness facilities. Staff qualifications and emergency policies related to cardiovascular safety are also discussed.
The message from the nation's scientists is clear, unequivocal, and unified: physical inactivity is a risk factor for cardiovascular disease,[7,18] and its prevalence is an important public health issue. New scientific knowledge based on epidemiological observational studies, cohort studies, controlled trials, and basic research has led to an unprecedented focus on physical activity and exercise. The promotion of physical activity is at the top of our national public health agenda, as seen in the publication of the 1996 report of the U.S. Surgeon General on physical activity and health.
The attention now being given to physical activity supports the goals of Healthy People 2000 and should lead to increased levels of regular physical activity throughout the U.S. population, including the nearly one fourth of adult Americans who have some form of cardiovascular disease. Although regular exercise reduces subsequent cardiovascular morbidity and mortality,[7,17,18] the incidence of a cardiovascular event during exercise in patients with cardiac disease is estimated to be 10 times that of otherwise healthy persons. Adequate screening and evaluation are important to identify and counsel persons with underlying cardiovascular disease before they begin exercising at moderate to vigorous levels.
Moderate (or higher) levels of physical activity and exercise are achieved in a number of settings, including more than 15,000 health/fitness facilities across the country. A exact survey of 110 health/fitness facilities in Massachusetts found that efforts to screen new members at enrollment were limited and inconsistent. Nearly 40% of responding facilities stated that they do not routinely use a screening interview or questionnaire to evaluate new members for symptoms or history of cardiovascular disease, and 10% stated that they conducted no initial cardiovascular health history screening at all.
This statement provides recommendations for cardiovascular screening of all persons (children, adolescents, and adults) before enrollment or participation in activities at health/fitness facilities. Staff qualifications and emergency policies related to cardiovascular safety are also discussed. Health/fitness facilities are defined here as organizations that offer health and fitness programs as their primary or secondary service or that promote high-intensity recreational physical activity (e.g., basketball, tennis, racquetball, and swim clubs). Ideally such facilities have a professional staff, but those that provide space and equipment only (e.g., unsupervised hotel exercise rooms) are also included. A health/fitness facility user is defined as a dues-paying member or a guest paying a regular daily fee to use the facility specifically to exercise. These recommendations are intended to assist health/fitness facility staff, healthcare providers, and consumers in the promotion and performance of safe and effective physical activity/exercise.
The writing group based these recommendations on a review of the literature and the consensus of the group. Earlier statements from the American Heart Association (AHA) and the American College of Sports Medicine (ACSM) are highlighted and supplemented. These recommendations were peer reviewed by selected authorities in the field representing the AHA, the ACSM, the American College of Cardiology, the International Health Racquet and Sports Clubs Association (IHRSA), and the Young Men's Christian Association. The recommendations are not mandatory or all-encompassing, nor do they limit provision of individualized care by practitioners exercising independent judgment. With this statement the AHA and the ACSM assume no responsibility toward any individual for whom this statement may be applied in the provision of individualized care. Specific details about exercise testing and training of persons with and without cardiovascular disease and those with other health problems are provided elsewhere.[2,6,8,21] The ACSM has published comprehensive guidelines for operating health/fitness facilities. Although issues in competitive sports are beyond the scope of this statement, the 26th Bethesda Conference on sudden cardiac death in competitive athletes and the AHA provide specific recommendations for the screening and evaluation of athletes for congenital heart disease, systemic hypertension, and other cardiovascular diseases before participation in competitive sports.
Rationale. Regular exercise results in increased exercise capacity and physical fitness, which can lead to many health benefits. Persons who are physically active appear to have lower rates of all-cause mortality, probably because of a decrease in occurrence of chronic illnesses, including coronary heart disease. This benefit may be the result of an improvement in cardiovascular risk factors in addition to enhanced fibrinolysis, improved endothelial function, decreased sympathetic tone, and other as yet undetermined factors. Regular endurance exercise leads to favorable alterations in the cardiovascular, musculoskeletal, and neurohumoral systems. The result is a training effect, which allows an individual to do increasing amounts of work while lowering the heart rate and blood pressure response to submaximal exercise. Such an effect is particularly desirable in patients with coronary artery disease because it allows increased activity with less ischemia.
The Centers for Disease Control and Prevention, the ACSM, and the AHA recommend that every American participate in at least moderate-intensity physical activity for ≥ 30 min on most, if not all, days of the week. Unfortunately, many Americans are sedentary or perform too little physical activity; only 22% of adult Americans engage in regular exercise ≥ 5 times a week. The prevalence of physical inactivity is higher among culturally diverse segments of the U.S. population, low-income groups, the elderly, and women. It is important for healthcare providers to educate the public about the benefits of physical activity and to encourage more leisure-time exercise, particularly for those who are underactive. Consumers should seek information about safe and effective ways to increase physical activity and initiate and maintain a regular program of exercise.
Efforts to promote physical activity will result in an increasing number of persons with and without heart disease joining the more than 20 million persons who already exercise at health/fitness facilities. Current market research indicates that 50% of health/fitness facility members are older than 35 yr, and the fastest-growing segments of users are those older than 55 yr and those aged 35-54 yr. With increased physical activity, more people with symptoms of or known cardiovascular disease will face the cardiovascular stress of physical activity and possible risk of a cardiac event. More than one fourth of all Americans have some form of cardiovascular disease. The prevalence of coronary heart disease for American adults aged 20 yr and older is 7.2% in the general population, 7.5% for non-Hispanic whites, 6.9% for non-Hispanic blacks, and 5.6% for Mexican Americans. The prevalence of myocardial infarction in older Americans aged 65-69 yr is 18.0% and 9.7% for men and women, respectively.
Moderately strenuous physical exertion may trigger ischemic cardiac events, particularly among persons not accustomed to regular physical activity and exercise. Siscovick et al. examined the incidence of primary cardiac arrest in men aged 25-75 yr after excluding those with a history of clinically recognized heart disease. Although the risk was significantly increased during high-intensity exercise, the likelihood for primary cardiac arrest during such activity in a clinically healthy population was estimated at 0.55 events/10,000 men per year. Maron et al. studied causes of sudden death in competitive athletes. In persons younger than 35 yr, 48% of deaths were due to hypertrophic cardiomyopathy. Coronary artery anomalies, idiopathic left ventricular hypertrophy, and coronary heart disease each accounted for 10-20% of deaths. In those over 35, coronary artery disease accounted for approximately 80% of all deaths. Overall, the absolute incidence of death during exercise in the general population is low.[25,26,29]Each year approximately 0.75 and 0.13/100,000 young male and female athletesand 6/100,000 middle-aged men die during exertion. No estimates are available for middleaged women or the elderly.
Cardiovascular events other than death during exercise have also been studied. Data from the Framingham heart study indicate that the baseline risk of myocardial infarction in a 50-yr-old man who is a nonsmoker and does not have diabetes is approximately 1% per year, or approximately 1 chance per million per hour. Heavy exertion [≥ 6 METs (metabolic equivalents)] within 1 h of symptomatic onset of acute myocardial infarction has been reported in 4.4-7.1% of patients.[15,31] The adjusted relative risk is significantly greater in persons who do not participate in regular physical activity, with an approximate threefold increase in risk during the morning hours. The relation of physical activity to acute myocardial infarction in the thrombolytic era was examined among 3339 patients in the TIMI II trial, in which moderate or marked physical activity preceded myocardial infarction in 18.7% of patients.
Van Camp et al. reported the incidence of major cardiovascular complications in 167 randomly selected cardiac rehabilitation programs that provided supervised exercise training to 51,000 patients with known cardiovascular disease. The incidence of myocardial infarction was 1 per 294,000 person-hours; the incidence of death was 1 per 784,000 person-hours.
Screening Prospective Members/Users.All facilities offering exercise equipment or services should conduct cardiovascular screening of all new members and/or prospective users. The primary purpose of preparticipation screening is to identify both those not known to be at risk and those known to be at risk for a cardiovascular event during exercise. exact evidence suggests that screening by health/fitness facilities is done only sporadically. In Canada, evidence from the Canadian Home Fitness test and its screening instrument, the Physical Activity Readiness Questionnaire (PAR-Q), suggests that even simple screening questionnaires can effectively identify many persons at high risk and increase the safety of nonsupervised exercise. Current knowledge of the relation between identifiable risk factors, the incidence of cardiovascular disease, and the triggering factors for acute myocardial infarction suggests that screening is both reasonable and prudent.
The cost-effectiveness of preparticipation screening is an important consideration. Exercise testing is comparatively expensive. The incidence of false-positive findings when testing asymptomatic persons and the need to follow up abnormal results can lead to subsequent and more costly procedures. A thorough and mandatory screening process that might prove optimally sensitive in detecting occult cardiovascular disease might be so prohibitive to participation that fewer persons would engage in a fitness program. Such a result would be counterproductive to the goal of maximizing physical activity. Because most of the health benefits of exercise accrue at moderate levels of intensity, in which the risks are probably low, recommendations that would inhibit large numbers of persons from participating in exercise programs are not justified. Preparticipation screening should identify persons at high risk and should be simple and easy to perform. Public health efforts should focus on increasing the use of preparticipation screening.
Two practical tools for preparticipation screening are likely to have an effect on identifying high-risk individuals without inhibiting their participation in exercise programs. The PAR-Q (Table 1) is a self-administered questionnaire that focuses primarily on symptoms that might suggest angina pectoris. Participants are directed to contact their personal physician if they answer "yes" to ≥ 1 questions. The PAR-Q also identifies musculoskeletal problems that should be evaluated before participation because these might involve modification of the exercise program. The questionnaire is designed to be completed when the participant registers at a health/fitness facility. In unsupervised fitness facilities (e.g., hotel fitness centers), the PAR-Q can be self-administered by means of signs prominently displayed at the main entry into the facility. Although less satisfactory than documenting the results of screening, use of signs and similar visual methods are a minimal recommendation for encouraging prospective users to assess their health risks while exercising at any facility.
Another simple, self-administered device that aims to identify high-risk individuals without negatively impacting participation is a questionnaire patterned after one developed by the Wisconsin Affiliate of the American Heart Association (Table 2). The one-page form is slightly more complex than the PAR-Q and uses history, symptoms, and risk factors (including age) to direct prospective members to either participate in an exercise program or contact their physician (or appropriate healthcare provider) before participation. Persons at higher risk are directed to seek facilities providing appropriate levels of staff supervision. The questionnaire can be administered within a few minutes on the same form participants use to join or register at the facility. It identifies potentially high-risk participants, documents the results of screening, educates the consumer, and encourages and fosters appropriate use of the healthcare system. In addition, it can guide staff qualifications and requirements. This instrument is also simple enough to be adapted for use as self-screening signs posted in nonstaffed facilities.
Health appraisal questionnaires should preferably be interpreted by qualified staff (see next section for criteria) who can limit the number of unnecessary referrals for preparticipation medical evaluation, avoiding undue expense and barriers to participation.
In view of the potential legal risk assumed by operators of health/fitness facilities, it is recommended that all facilities providing staff supervision document the results of screening. Screening, particularly for participants for whom a medical evaluation is recommended, requires time, personnel, and financial resources. Individual facilities can determine the most cost-effective way to conduct and document preparticipation screening.
Every effort should be made to educate all prospective new members about the importance of obtaining a health appraisal and-if indicated-medical evaluation/recommendation before beginning exercise testing/training. The potential risks inherent in not obtaining an appraisal should also be emphasized. Without an appraisal, it is impossible to determine whether a person may be at significant risk of severe bodily harm or death by participating in an exercise program. The same is true of persons who undergo a health appraisal, are identified as having symptoms of or known cardiovascular disease, and refuse or neglect to obtain the recommended medical evaluation yet seek admission to a health/fitness facility program. Due to safety concerns, persons with known cardiovascular disease who do not obtain recommended medical evaluations and those who fail to complete the health appraisal questionnaire upon request may be excluded from participation in a health/fitness facility exercise program to the extent permitted by law.
Persons without symptoms or a known history of cardiovascular disease who do not obtain the recommended medical evaluation after completing a health appraisal should be required to sign an assumption of risk or release/waiver. Both of these forms may be legally recognized in the jurisdiction where the facility is located. When appropriate guidelines are followed, it is likely that the potential benefits of physical activity will outweigh the risks. Persons without symptoms or a known history of cardiovascular disease who do not obtain recommended medical evaluations or sign a release/waiver upon request may be excluded from participation in a health/fitness facility exercise program to the extent permitted by law. Persons who do not obtain an evaluation but who sign a release/waiver may be permitted to participate. However, they should be encouraged to participate in only moderate- or lower-intensity physical activities and counseled about warning symptoms and signs of an impending cardiovascular event.
The major objectives of preparticipation cardiovascular screening are to identify persons with known cardiovascular disease, symptoms of cardiovascular disease, and/or risk factors for disease development who should receive a medical evaluation/recommendation before starting an exercise program or undergoing exercise testing. Screening also identifies persons with known cardiovascular disease who should not participate in an exercise program or who should participate at least initially in a medically supervised program, as well as persons with other special needs.[8,19]
Screening also serves another purpose. One of the trends in cardiac rehabilitation is to "mainstream" low-risk, clinically stable patients to community facilities rather than specialized, often costly cardiac programs. Facility directors should expect that an increasing percentage of their participants will have health histories that warrant supervision of exercise programs by professional staff.
When a medical evaluation/recommendation is advised or required, written and active communication with the individual's personal physician (or healthcare provider) is strongly recommended. The sample letter and medical release form in Table 3A and B, can be used or modified for such purposes.
Characteristics of Participants. Intensity of physical activity is measured through endurance- or strength-type exercise as defined in Table 4. Health appraisal questionnaires should be used before exercise testing and/or training to initially classify participants by risk for triage and preliminary decision making (Table 5), namely, apparently healthy persons (Class A-1), persons at increased risk (Classes A-2 and A-3), and persons with known cardiovascular disease (Classes B, C, and D). Apparently healthy persons of all ages and asymptomatic persons at increased risk (Classes A-1 through A-3) may participate in moderateintensity exercise without first undergoing a medical examination or a medically supervised, symptom-limited exercise test. Apparently healthy younger persons (Class A-1) may also participate in vigorous exercise without first undergoing a medical examination and a medically supervised exercise test. It is suggested that persons classified as Class A-2 and particularly Class A-3 undergo a medical examination and possibly a maximal exercise test before engaging in vigorous exercise. All other persons (Classes B and C) should undergo a medical examination and perform a maximal exercise test before participation in moderate or vigorous exercise unless exercise is contraindicated (i.e., Class D). Data from a medical evaluation performed within 1 yr are acceptable unless clinical status has changed. Medically supervised exercise tests should be conducted in accordance with previously published guidelines.
Using Screening Results for Risk Stratification. With completion of the initial health appraisal and, if indicated, medical consultation and supervised exercise test, participants can be further classified for exercise training on the basis of individual characteristics detailed below. The following classifications have been modified using existing AHA and ACSM guidelines and are recommended (Table 5):
Class A: Apparently Healthy. There is no evidence of increased cardiovascular risk for exercise. This classification includes 1) "apparently healthy" younger persons (Class A-1) and 2) irrespective of age, persons who are "apparently healthy" or at "increased risk" (Classes A-2 and A-3) and who have a normal diagnostic maximal exercise test. Submaximal exercise tests are sometimes performed at health/fitness facilities where permitted by law for nondiagnostic purposes, including physical fitness assessment, exercise prescription, and monitoring of progress. Such testing is also useful for educating participants about exercise and for motivating them. Nondiagnostic exercise testing should be conducted only for persons in Class A and only by appropriately qualified, well-trained personnel (see section on staffing below) who are knowledgeable about indications and contraindications for exercise testing, indications for test termination, and test interpretation. All health/fitness facilities, including those where exercise testing is performed, should have an emergency plan (see section on emergency policies and procedures below) to ensure that emergencies are handled safely, efficiently, and effectively. No restrictions other than provision of basic guidelines are required for exercise training. No special supervision is required during exercise training.
Class B: Presence of known, Stable Cardiovascular Disease with Low Risk for Vigorous Exercise but Slightly Greater than for Apparently Healthy Persons. This classification includes clinically stable persons with 1) coronary artery disease (myocardial infarction, coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, angina pectoris, abnormal exercise test, or abnormal coronary angiogram); 2) valvular heart disease; 3) congenital heart disease (risk stratification for patients with congenital heart disease should be guided by the 26th Bethesda Conference recommendations); 4) cardiomyopathy (includes stable patients with heart failure with characteristics as outlined below but not exact myocarditis or hypertrophic cardiomyopathy); and 5) exercise test abnormalities that do not meet the criteria outlined in Class C below. The clinical characteristics of such persons are 1) New York Heart Association (NYHA) Class I or II (Table 6); 2) exercise capacity > 6 METs; 3) no evidence of heart failure; 4) free of ischemia or angina at rest or on the exercise test ≤ 6 METs; 5) appropriate rise in systolic blood pressure during exercise; 6) absence of nonsustained or sustained ventricular tachycardia; and 7) ability to satisfactorily self-monitor intensity of activity. For these persons, activity should be individualized with exercise prescription by qualified personnel. Medical supervision is recommended during prescription sessions and nonmedical supervision by appropriately qualified staff for other exercise sessions until the participant understands how to monitor his or her own activity. Subsequent exercise training may be performed without special supervision.
Class C: Those at Moderate to High Risk for Cardiac Complications during Exercise and/or who are Unable to Self-regulate Activity or Understand the Recommended Activity Level. This classification includes persons with 1) coronary artery disease with the clinical characteristics outlined below; 2) acquired valvular heart disease; 3) congenital heart disease (risk stratification for patients with congenital heart disease should be guided by the 26th Bethesda Conference recommendations); 4) cardiomyopathy (includes stable patients with heart failure with characteristics as outlined below but not exact myocarditis or hypertrophic cardiomyopathy); 5) exercise test abnormalities not directly related to ischemia; 6) a previous episode of ventricular fibrillation or cardiac arrest that did not occur in the presence of an acute ischemic event or cardiac procedure; 7) complex ventricular arrhythmias that are uncontrolled at mild to moderate work intensity with medication; 8) threevessel or left main coronary artery disease; and 9) ejection fraction < 30%. One or more of the following clinical characteristics are also present: 1) two or more previous myocardial infarctions; 2) NYHA Class III or greater; 3) exercise capacity < 6 METs; 4) ischemic horizontal or down-sloping ST depression ≥ 1 mm or angina at a workload ≤ 6 METs; 5) a fall in systolic blood pressure with exercise; 6) a medical problem that the physician believes may be potentially life-threatening; 7) a previous episode of primary cardiac arrest; and 8) ventricular tachycardia at a workload < 6 METs. Physical activity should be individualized, and exercise should be prescribed by appropriately qualified medical personnel. Medical supervision, monitoring for adverse signs and symptoms, electrocardiographic monitoring of heart rate and rhythm, and blood pressure monitoring are recommended during exercise sessions until safety is established. Subsequent exercise training should be supervised by appropriately qualified personnel.
Class D: Unstable Conditions with Activity Restriction. This classification includes those with 1) unstable ischemia; 2) heart failure that is not compensated; 3) uncontrolled arrhythmias; 4) severe and symptomatic aortic stenosis; 5) hypertrophic cardiomyopathy or cardiomyopathy from exact myocarditis; 6) severe pulmonary hypertension; or 7) other conditions that could be aggravated by exercise (for example, resting systolic blood pressure > 200 mm Hg or resting diastolic blood pressure > 110 mm Hg; active or suspected myocarditis or pericarditis; suspected or known dissecting aneurysm; thrombophlebitis and exact systemic or pulmonary embolus). In this population no physical activity is recommended for conditioning purposes. Risk stratification for patients with congenital heart disease should be guided by the 26th Bethesda Conference recommendations.
These classifications are presented as a means of beginning exercise with the lowest possible risk. They do not consider accompanying morbidities (for example, insulindependent diabetes mellitus, morbid obesity, severe pulmonary disease, complicated pregnancy, or debilitating neurological or orthopedic conditions) that may constitute a contraindication to exercise or necessitate closer supervision during exercise training.
Using Screening Results for Exercise Prescription. For individuals considered to be in Class A, exercise training intensity (Table 4) may be prescribed using the rating of perceived exertion alone and/or specific target heart rates. A suggested rating of perceived exertion for such persons is 12-16 (moderate to hard) on the Borg scale of 6-20 and/or an intensity level that corresponds to 50-90% of maximum heart rate or 45-85% of maximum oxygen uptake or heart rate reserve. Heart rate reserve is defined as maximum heart rate minus resting heart rate. For persons taking medications that affect heart rate (e.g., β-adrenergic blockers), these heart rate methods do not apply unless guided by an exercise tolerance test.
In the absence of atrial fibrillation, frequent atrial or ventricular ectopy, a fixed-rate pacemaker, or similar conditions, exercise intensity should be prescribed for persons with cardiovascular disease (Class B or C) using target heart rates and perceived exertion ratings in accordance with previously published guidelines.[2,8] For these persons, target heart rates should be prescribed using data obtained during exercise testing performed while the participant is taking his or her usual cardioactive medications. In the absence of myocardial ischemia or other significant exercise test abnormalities, a target range of 50-90% of peak heart rate or 45-85% of peak measured oxygen uptake or heart rate reserve is recommended. This intensity level corresponds to 12-16 (moderate to hard) on the Borg scale. In the presence of myocardial ischemia (i.e., ischemic ST-segment depression > 1 mm, chest discomfort believed to be angina pectoris, or other symptoms believed to be an anginal equivalent), significant arrhythmia, or other significant exercise test abnormalities (e.g., a fall in systolic blood pressure from baseline, systolic blood pressure > 240 mm Hg, or diastolic blood pressure > 110 mm Hg), the target training intensity is derived from the heart rate associated with the abnormality. If this occurs at a high level of exercise, the above target heart rate recommendations are applicable, provided that the upper limit of the range is at least 10 beats per minute (bpm) below the level at which the abnormality appears. Other-wise, the recommended upper limit of training heart rate is 10 bpm less than that associated with the abnormality.
Health/fitness facility personnel involved in management or delivery of exercise programs must meet academic and professional standards and have the required experience as established by the ACSM.[2,19] Such personnel include the general manager/executive director, medical liaison, fitness director, and exercise leader. In general, health/fitness facility personnel should have the formal training and experience needed to ensure that clients are provided with safe, effective programs and services. The levels of education and experience needed to ensure effectiveness and safety vary with the health status of the client population. The kinds of personnel who should be employed at health/fitness faciliies serving various types of clients are summarized in Table 5.
The general manager/executive director is responsible for the overall management of the facility and should have competencies in business as well as design and delivery of exercise programs.
The medical liaison reviews medical emergency plans, witnesses and critiques medical emergency drills, and reviews medical incident reports. In level 2 and 3 facilities (Table 5), the medical liaison may be a licensed physician, a registered nurse trained in advanced cardiac life support, or an emergency medical technician. In level 4 and 5 facilities (Table 5), the medical liaison must be a licensed physician.
The fitness director manages the facility's exercise and activity programs and is responsible for program design and the training and supervision of staff. He or she must have a degree in exercise science, another health-related field, or equivalent experience, and knowledge of exercise physiology, exercise programming, and operation of exercise facilities. The fitness director must hold professional certification at an advanced level by a nationally recognized health/fitness organization. In level 3 facilities this certification should be comparable to ACSM health fitness instructor certification. In level 4 and 5 facilities the fitness director should be certified at a level that correlates with ACSM exercise specialist certification. The exercise specialist typically holds a master's degree in exercise science or a related field and has extensive experience in exercise testing and leadership in clinical populations. He or she must be trained in cardiopulmonary resuscitation (CPR) and should have at least 1 yr of supervisory experience in the fitness industry.
The exercise leader works directly with program participants and provides instruction and leadership in specific modes of exercise. He or she also helps program participants master the behavioral skills needed to adhere to exercise programs. In level 1, 2, and 3 facilities the exercise leader as a minimum must have a high school diploma or equivalent and entry-level or higher professional certification from a nationally recognized health/fitness organization (comparable to ACSM exercise leader certification). In level 4 facilities, the exercise leader should have education and experience corresponding to that required by ACSM health fitness instructor certification. In level 5 facilities, the exercise leader should be either an exercise specialist or a health fitness instructor directly supervised by an exercise specialist. In all cases the exercise leader must be trained in CPR and should have prior supervised internship or work experience in the health/fitness industry.
Some health/fitness facilities provide services in allied health fields such as nutrition, stress management, and physical therapy. Personnel providing such services should meet current accepted professional standards in those fields and should be certified as recommended by relevant professional organizations and licensed by or registered with the state as required by law.
All health/fitness facilities must have written emergency policies and procedures that are reviewed and practiced regularly. Such plans will correspond to the type of facility and risk level of its membership outlined in Table 5. All fitness center staff who directly supervise program participants should be trained in basic life support. Health/fitness facilities must develop appropriate emergency response plans and must train their staff in appropriate procedures to provide during a life-threatening emergency. When an incident occurs, each staff member must perform the necessary emergency support steps in accordance with established procedures. It is important for everyone to know the emergency plan. Emergency drills should be practiced once every 3 months or more often with changes in staff; retraining and rehearsal are especially important. When new staff are hired, new team arrangements may be necessary. Because life-threatening cardiovascular emergencies are rare, constant vigilance by staff and familiarity with the plan and how to follow it are important.
It is essential to acknowledge that emergency equipment alone does not save lives. Equipment alone may offer a false sense of security if it is not backed up with appropriate staffing. The training and preparedness of an astute professional staff who can readily handle emergencies is paramount. This issue is particularly important if persons with certain medical conditions are recruited and encouraged to exercise in a specific health/fitness facility. Such a facility has the responsibility to offer appropriate coverage by personnel as outlined above and in Table 5. Acquisition of equipment for evaluation and resuscitation will depend on the risk level of participants, personnel, and medical coverage. All facilities must have a telephone that is readily accessible and available when emergency assistance is needed. It would be useful for all supervised facilities to have a sphygmomanometer and stethoscope readily available. Level 4 and 5 facilities that recruit members with known cardiovascular disease must have such equipment available, and level 5 (supervised cardiac rehabilitation) facilities should be fully equipped according to the recommendations of the AHA and the American Association of Cardiovascular and Pulmonary Rehabilitation. Such equipment includes a defibrillator, oxygen, and fully stocked crash cart. Delineation of specific equipment standards in such facilities is beyond the scope of these guidelines; such information is detailed in the documents above.[1,21] Appropriately trained staff who are medically and legally empowered must be available to operate such devices during a facility's operational hours.
The emergency plan must address transportation of victims to a hospital emergency room and must include telephone access to 911 or the local emergency unit access system. Health/fitness facility personnel should be familiar with emergency transport teams in the area so that access and location of the center are clearly identified. Staff should greet the emergency response team at the entrance of the facility so that they can be promptly guided to the site of the emergency. A staff member should remain with the victim at all times. Prompt emergency transport is optimized by free and ready access to the victim within the health/fitness facility and assistance by designated staff.
In selecting a health/fitness facility, an individual should first consider his or her health status. Persons with a history of cardiovascular disease should seek facilities that provide or require a thorough medical evaluation of prospective members/users. Personnel should include nurses, exercise specialists, health/fitness instructors, and/or exercise leaders licensed or certified by the appropriate agencies, organizations, or authorities. They should be trained to recommend and supervise exercise in patients with cardiovascular and other chronic diseases. Persons at high risk for development of cardiovascular disease should seek facilities that require appropriate medical evaluation of clients and employ exercise leaders who are certified as competent to design and deliver exercise programs for high-risk persons. Table 5 summarizes personnel and safety recommendations for health/fitness facilities (levels 1 through 5) serving clients in various health categories (Classes A through C).
Persons seeking health/fitness facilities should select one that meets professional and industry standards. Facilities should be clean, well-maintained, and spacious enough to ensure the comfort and safety of program participants. Indoor facilities should be climate controlled, and changing rooms and showers should be provided. Flooring in areas where exercise is to be carried out should be designed to minimize risk of injury. Exercise equipment should be well-maintained. The variety, amount, and availability of exercise equipment should match individual needs and preferences, including time of day and preferred mode of exercise. For example, if aerobic dance is the preferred mode of exercise, individuals should seek a fitness center that offers this program at a convenient time and that provides an exercise leader who is competent in this activity and able to teach men and women of various age and fitness levels.
The programs and services of a health/fitness center should optimize participation. The location of the center should minimize time spent traveling to it. The social environment should be attractive and the staff competent in helping members/users master the behavioral skills needed to adopt and maintain a physically active lifestyle.
The purpose of this study was to assess whether maximal oxygen uptake (V.O2max) could be predicted from submaximal ratings of perceived exertion (RPE) elicited during the multistage fitness test (MFT). Eleven female volunteers completed three maximal exercise tests in random order; the MFT, a simulated MFT on a motorised treadmill and a graded exercise test to volitional exhaustion (GXT), also on a motorised treadmill. RPE values were recorded at the end of each 1 min stage in all three tests. Oxygen consumption (VO2) was recorded continuously during the treadmill tests. Measured V.O2max values from the GXT and simulated MFT were not significantly different (48.2 and 47.5 ml/kg/min, respectively), but they were significantly higher than V.O2max values predicted by the MFT (41.2 ml/kg/min, p<0.05). Regression of submaximal RPE values (7–17) elicited from the MFT and VO2 values predicted by the MFT were extrapolated to RPE 20 to predict V.O2max. The RPE-predicted V.O2max from the MFT (47.5 ml/kg/min) was similar to measured V.O2max. The findings suggest that submaximal RPE values can be used to provide acceptable estimates of V.O2max which are more accurate than the published table values for the MFT. Furthermore, the use of RPE measures in conjunction with the MFT enhances the accuracy of V.O2max prediction by the MFT.
This study was part of a large randomised controlled multicentre trial of sick-listed patients referred to the neck and back outpatient clinics at St. Olav's Hospital and Oslo University Hospital, Ullevål between August 2009 and August 2011. The primary outcome, RTW, was reported in Spine. The patients were randomised in blocks to a work-focused or control intervention using a website hosted by the medical faculty. The allocation was concealed in the data files for the researchers analysing the outcome until all analyses were run. An independent statistician generated the block size stratified by centre. The block size was concealed for all involved in the study. The first block was 20 and subsequent blocks 10.
All patients included in the study had signed an informed consent. The study was conducted in accordance with the Helsinki Declaration and the Norwegian guidelines authorised by the Data Protection for Research at Oslo University Hospital (1207–091208). The study was evaluated by the Regional Committees for Medical and Health Research Ethics in South-East Norway (S09024b 2009/1000) and registered at clinicaltrials.gov (NCT00840697).
All patients referred for diagnostic consideration or multidisciplinary treatment of neck and/or back pain were screened for eligibility at their first consultation at the outpatient clinic. The inclusion criteria were: neck and/or back pain, age 18–60 years, employed or self-employed, and duration of sick leave between 4 weeks and 12 months. Patients in need of surgical treatment were excluded from the study. Additional exclusion criteria were: cauda equina syndrome; symptomatic spinal deformity; osteoporosis with fracture; inflammatory rheumatic disease; pregnancy; legal labour dispute; insufficient Norwegian language skills; cardiac, pulmonary, or metabolic disease with functional restrictions; and DSM-V-diagnosed mental disorders.
Both work-focused and control interventions took place at the neck and back clinics of the respective hospitals, but separate teams was used for the different interventions to avoid contamination. All participants received a standard clinical examination by a physician before inclusion in the study. In this consultation relevant imaging was evaluated and patients were informed about findings and were also informed that the origin of pain is often difficult to visualise via imaging. Patients were also reassured that daily activities, physical exercise, or work would not hurt or damage their necks or backs. Emphasis was placed on removing fear avoidance, restoring activity level, and enhancing self-care and coping.
At the time of this study, the neck and back clinic at St. Olav's hospital used a comprehensive multi-disciplinary intervention based on the model described by Brox et al., whereas the neck and back clinic at Oslo University Hospital used a brief model based on the model by Indahl et al.. Both programmes were used as control interventions (Table 1). The brief intervention at Oslo University hospital consisted of the diagnostic clarification at the first visit and a session with a physiotherapist. The physiotherapist advised patients in activities and encouraged the patients to exercise. The physiotherapists also focused on reducing fear avoidance. One clarifying session with the medical specialist was also offered within 2 weeks.
The multidisciplinary intervention at St. Olav's hospital was administered by a team of medical specialists, physiotherapists and a social worker. The treatment had components of both cognitive behavioural therapy and exercise. The main focus was on reassurance, removing fear avoidance and physical conditioning.
The work-focused intervention was also a multidisciplinary intervention, and had duration of 5–6 days (Table 1). However, additional focus was placed on the RTW process and on reducing FAB of work. Patients received individual appointments with a caseworker during the first days of treatment. Work histories, family lives, and obstacles to RTW were discussed. The caseworkers contacted participants' employers by phone in most cases (unless the patient refused) to inform them of the programme and to inquire about possible temporary modifications at work. The patients created a RTW schedule together with the caseworker and the multi-disciplinary team. The patients and caseworkers also discussed relevant issues for a meeting with the employer. Additionally, the caseworkers offered the patients assistance at this meeting if requested. If sick-leave compensation was an issue, the caseworkers contacted municipal social services. The medical records and RTW schedules were sent to participants and their general practitioner, who managed the patients' sick-leave certificates.
The participants completed a comprehensive questionnaire before randomisation and at 4 and 12-months follow-up. Compliance to the treatment was assessed by the multidisciplinary team, and was defined as attending at least 50% of the treatment sessions offered.
Demographic Factors. Gender and age was recorded from patient medical records. Education was classified into four categories: up to 10 years primary school; vocational high school or general academic secondary school; college or university <4 years; and college or university ≥4 years. The two last categories were collapsed for logistic regression analyses. Occupation was manually classified using the International Standard Classification of Occupations (ISCO-88) and reported using four categories: low-skilled blue collar worker, high-skilled blue collar worker, low-skilled white collar worker, and high-skilled white collar worker.
Concurrent Treatment. Patients were asked if they had received treatment outside the hospital the last 4 months at the 4-month follow-up, and the last 8 months at 12-month follow-up. They answered 8 dichotomous questions (yes/no) about exercise by physiotherapist, other treatment by physiotherapist, manual therapy, psychomotor physiotherapy, treatment by chiropractor, alternative medicine, other rehabilitation programs or other therapy. If at least one question was answered "yes", they were considered to have had concurrent treatment.
Hospital Anxiety and Depression Scale (HADS). The level of psychological distress was assessed at baseline using the validated Norwegian version of the Hospital anxiety and depression scale (HADS). HADS has one subscale for depression (HADS-D) and another for anxiety (HADS-A). Both subscales consist of 7 items scored from 0 to 3, adding up to a sum score falling within a range of 0 to 21. High scores indicate high level of symptoms. Cases with more than one missing value in a subscale were excluded. In the case of a single missing value, the missing value was replaced with the individual mean.
Pain. Pain was measured with an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain). Patients were asked to rate pain at rest and during activity for back/neck pain and leg/arm pain. The highest score of the four scales was used in the analysis. Changes in scores between baseline and the 12-month follow-up were computed by subtracting the scores at 12 months from the baseline scores. In some of the analyses, these scores were dichotomised using a cut-off point of 2 for the change between baseline and 12-month follow-up.[39,40]
Disability. Neck and back pain-related disability was measured by the Norwegian version of the Oswestry Disability Index (ODI) for back pain patients and Neck Disability Index (NDI) for neck pain patients.[41,42] Both questionnaires are composed of 10 items ranging from 0 to 5. The summed score is presented as a percentage, where 0% represents no disability and 100% represents maximum disability. In the analyses, the higher of the two scores was used if the patient had completed both questionnaires. One or two missing values were replaced with the individual mean. Scores with more than two missing values were excluded from the analysis.
Change in the ODI/NDI was calculated. In analyses with dichotomised scores, a cut-off point of 12 for the change between baseline and 12-month follow-up were applied.[39,43]
Fear Avoidance. The Fear Avoidance Belief Questionnaire (FABQ) has two subscales. The physical activity subscale (FABQ-P) has four items with a possible score from 0 to 24. The work subscale (FABQ-W) has seven items with a possible score of 0 to 42. High scores indicate a high degree of fear avoidance. The minimal detectable change in the FABQ score was 9 for the physical activity subscale and 12 for the work subscale in a previous study of the Norwegian version. These values were used as the cut-off in analyses with dichotomised scores.
Return to Work. Return to work was defined as the first five-week period after randomisation that the patient did not receive sickness benefits, work assessment allowance (AAP), or disability pension from the Norwegian Labour and Welfare Administration (NAV). The five-week duration was chosen as Norwegian holidays last five weeks. Information on social compensation benefits was taken from national databases. Patients receiving partial disability pension before inclusion were considered RTW when they returned to their partly disabled status.
The sample size calculation was based on the primary outcome, RTW, and is reported elsewhere.
Comparisons of differences in baseline variables between patients who completed 12 month follow-up and patients lost to follow-up, and between the work-focused and control group were tested with t-tests for continuous variables and chi-square tests for categorical variables. Change in pain and disability from baseline to follow-up were tested using paired-sample t-tests. Differences in change scores between the work-focused and control intervention regarding pain and disability were analysed with independent samples t-tests. These analyses were carried out both with an intention to treat analyses and with available cases only (patients attending 12-month follow-up). In the intention to treat analyses multiple imputing was used to replace missing values at 12 months. Patients with missing baseline scores were not included in the analyses. The variables pain at baseline, disability at baseline, age, and return to work within one year were used to impute the missing pain scores at 12 months. The variables age, gender, education, smoking, occupation, disability at baseline, pain at baseline, and return to work within one year were used to impute disability scores at 12 months in participants with missing data at one-year follow-up. Changes in FABQ-P and FABQ-W from baseline to 4-month follow-up were calculated. Only patients with complete FABQ scores at both baseline and 4-months were included in these analyses. Subsequently, logistic regression analyses were applied to evaluate if reduction in FABQ- P and FABQ-W during the interventions influenced pain, disability and RTW within 12-month follow-up. Pain, disability and FABQ scores were dichotomised into improved and not improved in these analyses.
First, univariate logistic regression analyses, including baseline demographic variables and improvement in FABQ-P and FABQ-W from baseline to 4-month follow-up, were calculated as independent variables. Improvements in pain (≥2 points on NRS), disability (≥12 points on NDI/ODI) and RTW within 12 months were calculated as dependent variables. Subsequently, three multiple logistic regression models were built. Age, gender and intervention group were controlled for in all models and in addition we included variables with p < 0.2 from the univariate analyses. Multiple regressions controlling for baseline values of FABQ were also conducted. Correlations between independent variables were tested with Spearman's rho, and none of the variables were correlated above 0.7. Goodness of fit was tested using the Hosmer-Lemeshow test.
A two-sided significance level of p < 0.05 was used for all analyses.
All statistical analyses were performed using SPSS Statistics, version 20 (IBM corp®, Armonk NY, USA).
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Reproxalap Statistically Superior to Vehicle for Both Primary Endpoints of Ocular Redness (P=0.0004) and Schirmer Test (P=0.0005)
Schirmer Test ≥10mm Responder Analysis Multiplicity-Controlled Secondary Endpoint Achieved (P=0.0361)
Secondary Endpoints Achieved for All Symptoms Assessed: Dryness (P=0.0068), Discomfort (P<0.0001), Grittiness (P=0.0001), Stinging (P=0.0001), Burning (P<0.0001), and Itching (P=0.0003)
Company to Host Conference Call at 8:00 a.m. ET Today
LEXINGTON, Mass., July 12, 2022--(BUSINESS WIRE)--Aldeyra Therapeutics, Inc. (Nasdaq: ALDX) (Aldeyra) today announced the achievement of the primary endpoints in a sequence-randomized, double-masked, vehicle-controlled crossover clinical trial of 0.25% reproxalap ophthalmic solution, an investigational new drug candidate, for the treatment of dry eye disease. Reproxalap was statistically superior to vehicle for each of the two prespecified primary endpoints, ocular redness in a dry eye chamber (P=0.0004) and Schirmer test (P=0.0005), a measure of tear production, after a single day of dosing. The secondary endpoint of Schirmer test ≥10 mm responder analysis, which was multiplicity-controlled, was also achieved (P=0.0361).
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Aldeyra Therapeutics, Inc. (Nasdaq: ALDX) on July 12, 2022, announced the achievement of the primary endpoints in a crossover clinical trial of 0.25% reproxalap ophthalmic solution, an investigational new drug candidate, for the treatment of dry eye disease. Reproxalap was statistically superior to vehicle for each of the two prespecified primary endpoints, ocular redness in a dry eye chamber and Schirmer test, a measure of tear production, after a single day of dosing. (Graphic: Aldeyra Therapeutics)
"Statistical significance in favor of reproxalap over vehicle for all three dry eye disease signs that we intend to submit to a New Drug Application, in addition to observed rapid symptomatic improvement, favorably positions reproxalap, if approved for sale, as a potentially differentiated therapeutic option for the treatment of dry eye disease," stated Todd C. Brady, M.D., Ph.D., President and Chief Executive Officer of Aldeyra.
Relative to vehicle, statistically significant reduction in ocular redness was observed following treatment with reproxalap as soon as 10 minutes after dry eye chamber entry, which was the first time point assessed, and over the majority of chamber assessment time points, including the final time point 90 minutes after chamber entry. Schirmer test, which was assessed approximately 10 minutes before and after the fourth dose of reproxalap or vehicle, was statistically significant in favor of reproxalap at both time points, indicating the potential activity of prior dosing as well as additional activity of the fourth dose over a single day of drug administration. The Schirmer test ≥10 mm responder analysis has been reported to correlate with symptomatic improvement in dry eye disease,1 and achievement of the responder endpoint is consistent with the symptomatic improvement observed in the crossover clinical trial: reproxalap was statistically lower than vehicle for the secondary endpoints of ocular dryness (P=0.0068), discomfort (P<0.0001), grittiness (P=0.0001), stinging (P=0.0001), burning (P<0.0001), and itching (P=0.0003) symptoms.
No safety signals were observed in the trial, and reproxalap was well tolerated; there were no treatment-emergent moderate or serious adverse events. Three patients discontinued due to adverse events, two during vehicle administration and one during reproxalap administration. Reproxalap has now been studied in over 1,800 patients. The most common reported adverse event in clinical trials is mild and transient instillation site discomfort.
Pending discussion with the U.S. Food and Drug Administration (FDA), Aldeyra intends to submit the crossover clinical trial, which was designed to be adequate and well-controlled, as part of a dry eye disease New Drug Application (NDA) for reproxalap, including data on ocular redness, Schirmer test, and the Schirmer test ≥10 mm responder analysis. A pre-NDA meeting with the FDA has been scheduled for the third quarter of 2022. The NDA submission is expected to include a comprehensive set of data from acute and chronic clinical trials, as well as a combination of challenge and field-based assessments and parallel-group and crossover clinical trial designs.
"With another set of positive clinical results showing improvement in both the signs and symptoms of dry eye disease, I believe that reproxalap is an eagerly anticipated advancement for our patients suffering from dry eye disease because available therapies are often inadequate," stated John P. Berdahl, M.D., a specialist in diseases of the anterior segment at Vance Thompson Vision and Professor of Ophthalmology at the Sanford School of Medicine.
Conference Call Information
Aldeyra will host a conference call to discuss this announcement at 8:00 a.m. ET today, July 12, 2022. The dial-in numbers are (844) 200-6205 for domestic callers and (646) 904-5544 for international callers. The access code is 853619. A live webcast of the conference call will also be available on the "Investors & Media" section of the Aldeyra website at https://ir.aldeyra.com. Presentation slides, which contain material information and should be reviewed in conjunction with this press release, will be available on the investor relations page prior to the start of the conference call and webcast.
After the live webcast, the event will remain archived on the Aldeyra website for 90 days.
Reproxalap is an investigational first-in-class small-molecule modulator of RASP (reactive aldehyde species), which are elevated in ocular and systemic inflammatory disease. Reproxalap’s unique mechanism of action has been supported by the demonstration of statistically significant and clinically relevant activity in multiple physiologically distinct late-phase clinical indications.
About Dry Eye Disease
Dry eye disease is a common inflammatory disease estimated to affect 39 million or more adults in the United States.2 The disease is characterized by insufficient moisture and lubrication in the anterior surface of the eye, leading to dryness, inflammation, pain, discomfort, irritation, diminished quality of life, and in severe cases, permanent vision impairment. Among many physicians and patients, existing therapy for dry eye disease is generally regarded as inadequate and often requires weeks or months to demonstrate activity. In patients with dry eye disease, RASP may contribute to ocular inflammation, diminished tear production, ocular redness, and changes in tear lipid composition.3 By diminishing RASP levels, Aldeyra’s lead RASP modulator reproxalap represents a novel and differentiated approach for the treatment of the symptoms and signs of dry eye disease.
Aldeyra develops innovative therapies designed to treat immune-mediated diseases. Our approach is to discover pharmaceuticals that modulate immunological systems, instead of directly inhibiting or activating single protein targets, with the goal of optimizing multiple pathways at once while minimizing toxicity. Two of our lead product candidates, reproxalap and ADX-629, target pre-cytokine, systems-based mediators of inflammation known as RASP (reactive aldehyde species). Reproxalap is in late-stage clinical trials in patients with dry eye disease and allergic conjunctivitis. ADX-629, an orally administered RASP modulator, is in Phase 2 clinical testing for the treatment of systemic immune-mediated diseases. Our pipeline also includes ADX-2191 (intravitreal methotrexate 0.8%), in development for the prevention of proliferative vitreoretinopathy and the treatment of retinitis pigmentosa and primary vitreoretinal lymphoma. For more information, visit https://www.aldeyra.com/ and follow us on LinkedIn, Facebook, and Twitter.
Safe Harbor Statement
This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the timing and submission of a potential NDA; the anticipated timing of enrollment and results from Aldeyra’s clinical trials; expectations regarding the results of the upcoming Type B Pre-NDA meeting, including the FDA’s acceptance of Aldeyra’s post-hoc review of data, the FDA’s agreement with Aldeyra’s methods of analyzing data and Aldeyra’s intention to submit the crossover clinical trial as part of its NDA; and Aldeyra’s projected cash runway. Aldeyra intends such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. In some cases, you can identify forward-looking statements by terms such as, but not limited to, "may," "might," "will," "objective," "intend," "should," "could," "can," "would," "expect," "believe," "anticipate," "project," "on track," "scheduled," "target," "design," "estimate," "predict," "potential," "aim," "plan" or the negative of these terms, and similar expressions intended to identify forward-looking statements. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions, and uncertainties. Aldeyra is at an early stage of development and may not ever have any products that generate significant revenue. All of Aldeyra's development timelines may be subject to adjustment depending on recruitment rate, regulatory review, preclinical and clinical results, and other factors that could delay the initiation, enrollment or completion of clinical trials. Important factors that could cause genuine results to differ materially from those reflected in Aldeyra's forward-looking statements include, among others, the timing of enrollment, commencement and completion of Aldeyra's clinical trials, the timing and success of preclinical studies and clinical trials conducted by Aldeyra and its development partners; updated or refined data based on Aldeyra's continuing or post-hoc review and quality control analysis of clinical data, Aldeyra's ability to design clinical trials with protocols, data analysis methodologies, and endpoints acceptable to applicable regulatory authorities; delay in or failure to obtain regulatory approval of Aldeyra's product candidates; the ability to maintain regulatory approval of Aldeyra's product candidates, and the labeling for any approved products; the risk that prior results, such as signals of safety, activity, or durability of effect, observed from preclinical or clinical trials, will not be replicated or will not continue in ongoing or future studies or clinical trials involving Aldeyra's product candidates in clinical trials focused on the same or on different indications; the risk that the results from earlier clinical trials, portions of clinical trials, or pooled clinical data may not accurately predict results of subsequent trials or the remainder of a clinical trial; the scope, progress, expansion, and costs of developing and commercializing Aldeyra's product candidates; uncertainty as to Aldeyra’s ability to commercialize (alone or with others) and obtain reimbursement for Aldeyra's product candidates following regulatory approval, if any; the size and growth of the potential markets and pricing for Aldeyra's product candidates and the ability to serve those markets; Aldeyra's expectations regarding Aldeyra's expenses and revenue, the sufficiency or use of Aldeyra's cash resources and needs for additional financing; political, economic, legal, social, and health risks, including the COVID-19 pandemic and subsequent public health measures, and war or other military actions, that may affect Aldeyra’s business or the global economy; the rate and degree of market acceptance of any of Aldeyra's product candidates; Aldeyra's expectations regarding competition; Aldeyra's anticipated growth strategies; Aldeyra's ability to attract or retain key personnel; Aldeyra’s limited sales and marketing infrastructure; Aldeyra's ability to establish and maintain development partnerships; Aldeyra’s ability to successfully integrate acquisitions into its business; Aldeyra's expectations regarding federal, state, and foreign regulatory requirements; regulatory developments in the United States and foreign countries; Aldeyra's ability to obtain and maintain intellectual property protection for its product candidates; the anticipated trends and challenges in Aldeyra's business and the market in which it operates; and other factors that are described in the "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of Aldeyra's Annual Report on Form 10-K for the year ended December 31, 2021, and Aldeyra’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2022, which are on file with the Securities and Exchange Commission (SEC) and available on the SEC's website at https://www.sec.gov/. Additional factors may be set forth in those sections of Aldeyra's Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, expected to be filed with the SEC in the third quarter of 2022.
In addition to the risks described above and in Aldeyra's other filings with the SEC, other unknown or unpredictable factors also could affect Aldeyra's results. No forward-looking statements can be guaranteed and genuine results may differ materially from such statements. The information in this release is provided only as of the date of this release, and Aldeyra undertakes no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law.
1 Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000;118(5):615-21.
2 Company estimates and Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health-related quality of life. Am J Ophthalmol. 2014;157(4):799-806.
3 Choi W, Lian C, Ying L, Kim GE, You IC, Park SH, Yoon KC. Expression of Lipid Peroxidation Markers in the Tear Film and Ocular Surface of Patients with Non-Sjogren Syndrome: Potential Biomarkers for Dry Eye Disease. Curr Eye Res. 2016 Sep;41(9):1143-9. doi: 10.3109/02713683.2015.1098707. Epub 2016 Jan 5. PMID: 26731289.
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