Addressing HyperteNsion and Diabetes Through Community-Engaged Systems in Puno, Peru (ANDES Study) (ANDES)

National Heart, Lung, and Blood Institute (NHLBI), Washington University School of Medicine, Johns Hopkins University, Asociacion Benefica Prisma, National Institutes of Health (NIH)

Hypertension (HTN) and has become the largest driver of morbidity and mortality (M&M) worldwide, affecting nearly 1 billion persons, the vast majority living in low- and middle-income countries (LMICs). While clinical research has identified highly-efficacious and inexpensive options to control HTN, rates of awareness, treatment and control of HTN are abysmally low. Implementation strategies that can effectively reach and engage patient populations while feasible within the constraints of frail health systems are urgently needed. In Peru, less than 10% of those with HTN are optimally controlled and thus avoidable M&M continues to increase at unacceptable levels. In the proposed ANDES strategy, we will study a vulnerable, impoverished indigenous Andean population that has a high prevalence of HTN (18.5%) and T2D (7.4%); living at high altitude. The study has two phases: UG3/UH3. The formative UG3 phase (24 months) will draw from two implementation strategies: a) health fairs (HFs) where HTN diagnoses can be rapidly made and linked to care, and b) community health worker (CHW)-based multicomponent intervention to overcome logistical and structural barriers to treatment. The UH3 phase will test the adapted ANDES strategy. ANDES is a two-arm, individually randomized superiority trial with parallel assignment. The overall objective of ANDES is to evaluate the effectiveness of a home-based Health Agent-led intervention in reducing blood pressure and improving diabetes control in patients from under-resourced communities in Puno, Peru. Potential ANDES study participants will be identified, screened, and recruited via 2 different mechanisms: 1) community health fairs and 2) healthcare facility-based enrollment. Health fair planning, will be conducted in collaboration with DIRESA & EsSalud and local healthcare facility leaders. All health fair attendees will be screened for blood pressure measurements and T2D screening (HbA1c). Regarding healthcare facility-based enrollment, healthcare facilities will provide study staff lists of HTN patients. ANDES research study staff will review lists and contact patients (via phone or home visit) to inquire about their willingness for an in-person screening visit at their home. Recruitment will be rolling over 24 months during which 1068 participants in total (534 participants per arm) will be enrolled. To detect a difference in systolic blood pressure of 2.5 mmHg between intervention and control arms with 95% confidence, 90% power and a standard deviation of 12 mmHg, we would need 485 participants per arm. Assuming a conservative lost-to-follow-up of 10% at 12 months, we would need to randomize 1068 participants in total (534 participants per arm). The primary outcome is to determine if ANDES participants randomized to the intervention arm have an average reduction in SBP of at least 2.5 mmHg relative to the usual care arm 12 months after randomization. ANDES participants will initiate one of two care pathways according to the randomization assignment. Participants in the usual care group will be referred to their local healthcare facility for evaluation and/or to receive medical therapy per typical standard of care and at the discretion of the treating physician for the entirety of the ANDES study. Participants in the ANDES intervention group will receive the ANDES implementation package consisting of health agent home visits and a text messaging program for 12 consecutive months. Implementation package delivery will end after month 12, at which time intervention participants will be advised to obtain standard care from their local healthcare facility. Study outcome measures will be obtained in both the usual care and ANDES intervention group at months 6, 12, and 18 post-randomization. All participants will receive a total of four visits for study outcome assessments (at baseline, 6, 12, and 18 months). Intervention participants will additionally receive a total of 18 visits by health agents as part of the intervention package, for a total of 22 visits for those assigned to the intervention group.

INTRODUCTION Study Rationale Hypertension (HTN) is the major contributor to the global burden of disease and is the leading cause of morbidity and mortality in Peru. Completion of the proposed randomized trial will provide compelling and robust evidence on the acceptability, appropriateness, fidelity, and sustainability of the multicomponent ANDES intervention that is aimed at reducing blood pressure and improving diabetes control in patients from high-risk and under-resourced communities in Puno, Peru. These data are urgently needed to inform policies in low- and middle-income countries on the health gains that can be achieved by multicomponent implementation strategies to reduce hypertension. Background HTN affects ~1.4 billion people worldwide, yet in low-and middle-income countries (LMICs) the vast majority of patients are unaware and untreated, often until the occurrence of devastating complications (e.g., myocardial infarction, stroke). HTN is the leading cause of morbidity and mortality in Peru. Overall age- and sex-standardized prevalence of pre-HTN and HTN among Peruvian adults is 24% and 19%, respectively1. Rates of premature cardiovascular disease (CVD) and stroke mortality are 87 and 27 per 100,000 Peruvians (aged 30-69 yrs), respectively, with greater prevalence in men2. Pre-HTN and HTN are higher in rural- vs. urban-dwelling Puno residents (44 vs 31%, mean age 55 years)3. The PERU MIGRANT study found HTN awareness, treatment, and control rates of 48%, 40%, and 30%, respectively; but only 5% of HTN being treated and controlled4-6. The Puno CRONICAS study cohort found HTN control rates of 19% and 1% among urban vs. rural dwellers, respectively7. Thus, very low HTN control rates in Peru represent an important health care gap. In Peru, indigenous Andean communities (i.e, Aymara and Quechua) represent a population with a high prevalence of HTN and T2D (18.5% and 7.4% respectively for those ≥55 years old); yet access to chronic care is virtually non-existent despite the availability of efficacious and affordable treatment. To address this gap, we propose to develop and test the Addressing HyperteNsion and Diabetes through Community-Engaged Systems in Puno, Peru (ANDES) strategy for HTN/T2D diagnosis, and HTN treatment and control, which will be designed for remote settings where health care has low penetration. Trial Design & Objectives ANDES is a two-arm, individually randomized superiority trial with parallel assignment. The overall objective of ANDES is to evaluate the effectiveness of a home-based Health Agent-led intervention in reducing blood pressure and improving diabetes control in patients from under-resourced communities in Puno, Peru. Health agents are community health workers (CHWs) and/or nurse technicians that act as liaisons between the public health system and community members. METHODS: PARTICIPANTS, INTERVENTIONS, OUTCOMES This study will be conducted in Puno, Peru, a remote region in the Andean 'high plains' that suffers a high burden of HTN/T2D and where access to health care is limited. Puno is the capital of the Puno Region and the Puno Province (2017 census pop: 1,172,697) located in southeastern Peru, at 3,825 meters (13,500 feet) above sea level. The population is primarily indigenous, consisting of Quechua (pop: 537,972) and Aymara (pop: 318,363) Andean people, which together comprise ~72% of the population. Puno city, the urban provincial capital (150,000 residents) borders the shores of Lake Titicaca and northern Bolivia. Rural Puno comprises 14 large districts with each district having up to 20 communities. The public health system in Puno is managed by the Regional Health Administration (Direccion Regional de Salud, or DIRESA), under the Peruvian Ministry of Health (Ministerio de Salud, or MINSA), the governing body that leads, regulates, and promotes national health policy. ANDES Implementation Strategy The "ANDES multicomponent implementation strategy" is an adaptation of the World Health Organization (WHO) HEARTS package26 and consists of the following components: Health agent-managed home care BP monitoring Health coaching Health system navigation Medication delivery assistance Text message-based health coaching Specifically, the ANDES strategy is aligned with four WHO HEARTS technical package components. HEALTH AGENT-managed home care As part of the ANDES implementation strategy, ANDES intervention participants will be provided BP monitoring and health coaching by health agents in their home. Additionally, all participants will be assessed for T2D by having their HbA1c measured after study enrollment. All participants deemed to have T2D will also receive T2D monitoring via HbA1c by a research staff member. Health coaching is defined as "multiple sessions for patient-centered health education and motivation delivered with the goal of facilitating lifestyle modification and/or medication adherence."27 See section 4.2 for a description of BP and HbA1c monitoring. (Note: all participants will also have their BP and HbA1c monitored by a separate team of research fieldworkers at baseline, 6-, 12-, and 18-month follow-up visits. See Section 4.1 for a detailed schedule of activities.) During twice monthly home visits during the first six months and monthly thereafter for the rest of the year, community health agents will meet one-on-one with intervention participants, during which they will complete the following activities: Review personal goals and visit agenda; Conduct health assessments: BP Health Coaching: Assess the participant's HTN health plan and collect medication adherence data and health services access data Provide health education and counseling: Provide educational materials, medical appointment log, weekly pill organizer and calendar Review behavioral strategies to lower BP (e.g., diet and particularly salt consumption, physical activity, weight management, stress management, sleep, and alcohol use28) Review barriers to improving BP as well as strategies to overcome them. Provide healthcare system navigation support: Work with patients to set up, prepare for, and attend doctor's appointments. Empower the patient to advocate for their own health care and emphasize their roles and responsibilities as a member of their healthcare team. Provide medication delivery assistance A complete visit will be determined by the ability of a health agent to cover appropriate issues from the list above. We have developed a checklist as a guide for the health agents to follow. This guide will also be used to evaluate fidelity to the multicomponent strategy. Text messages As part of the multi-component strategy developed by ANDES for HTN detection and management, a text messaging system was developed directed to patients, their families, and health agents. Text messages provide reminders, education, and orientation for stakeholders to encourage healthy behaviors, thus improving chronic disease management and health outcomes29. The ANDES texting component is directed to patients, their families, and health agents. In all cases, messages have been tailored to fit with the characteristics of the population, taking into consideration local foods, belief systems, and traditions. The main objective of patient messages is to promote healthy behaviors such as reducing salt consumption, increasing physical activity, and increasing consumption of fruits and vegetables. Messaging will also encourage medical adherence by sending reminders to refill their medication and attend their medical appointments. Text messages directed to families are meant to educate them in regards to hypertension management and enforce healthy habits in the household of the ANDES hypertensive patient. We believe families are strong allies when trying to improve hypertensive patients' health. Finally, the main objective of messages directed to health agents is to communicate weekly reminders regarding topics of discussion with their patients. Messages will also motivate and provide positive reinforcement to health agents for their dedication to the patients and support of the intervention. Recruitment Potential ANDES study participants will be identified, screened, and recruited via 2 different mechanisms: 1) community health fairs and 2) healthcare facility-based enrollment. Health Fairs. Health fairs are 1-day events offering HTN/T2D screening in Puno, Peru. Health fair planning, including the selection of the date, times, and location of health fairs will be conducted in collaboration with DIRESA & EsSalud and local healthcare facility leaders. Outreach campaigns and advertisements (e.g., local radio announcements, posters, fliers) will encourage all adult community members (18+ years) to attend health fair events. All health fair attendees will be asked to complete a Screening Case Report Form (CRF), which includes blood pressure measurements and T2D screening (HbA1c). (See below for Screening CRF details.) Healthcare facility-based enrollment. Participating healthcare facilities will provide study staff lists of HTN patients. ANDES research study staff will review lists and contact patients (via phone or home visit) to inquire about their willingness for an in-person screening visit at their home. During the screening visit, study staff will confirm if the contact information is correct (i.e., if they have to correct patient phone number or address) and administer the Screening CRF and associated health assessments, as done at health fairs (See Section 3.5.2 for details). The Screening CRF is used to determine the eligibility of participants captured by health fairs and facility-based enrollment. The Screening CRF confirms each inclusion and exclusion criteria via the following methods: Participant age is verified by government document. They must be at least 18 years old. The following criteria are verified by participant report: place of residence within the study area, no plans to move during study period, willingness and availability to attend baseline visit, not currently or planning to become pregnant, and no other member of their household already a participant in ANDES. Ambulatory status is based on patient report and observation by ANDES staff. HTN status is based on patient report and the following criteria: If the participant reports a HTN diagnosis and DOES have a current prescription, they will move directly to the Informed Consent Process if interested in the study. If the participant reports a HTN diagnosis but DOES NOT have a current prescription, one of the following scenarios will occur: i. If their blood pressure is ≥ 140/90 mmHg (measured by study staff), they will be referred to a healthcare facility to be re-evaluated. If they are diagnosed with hypertension and/or provided a prescription, they will then proceed to the Informed Consent Process. ii. If their blood pressure is < 140/90 mmHg, they will not proceed to Informed Consent Process. They will be thanked for their time and be offered counseling on hypertension and health habits. - If the participant has a blood pressure ≥ 140/90 mmHg and DOES NOT report a past diagnosis or current prescription, they will be referred to a healthcare facility to be evaluated. If they receive a diagnosis of HTN and/or are provided a prescription, they will then proceed to the Informed Consent Process. Recruitment will be rolling over 24 months during which 1068 participants in total (534 participants per arm) will be enrolled. See Sample Size Consideration for details (Section 5.1). Informed consent will be obtained from all study participants using standard procedures. ANDES is a randomized, two-arm intervention individually randomized trial with parallel assignment. Healthcare centers were selected based on activities conducted during formative research. We will consider each healthcare center as a stratum and will create stratum-stratified permuted blocks to balance the intervention across the different types of healthcare centers. ANDES will use rolling enrollment with 45 participants per month who meet inclusion/exclusion criteria. All participants will be followed longitudinally for 18 months. To maintain balance of treatment assignments, the sample will be stratified by healthcare center. Following enrollment and a baseline assessment (Visit 0), ANDES participants will initiate one of two care pathways according to the randomization assignment. Participants in the usual care group will be referred to their local healthcare facility for evaluation and/or to receive medical therapy per typical standard of care and at the discretion of the treating physician for the entirety of the ANDES study. Participants in the ANDES intervention group will receive the ANDES implementation package consisting of health agent home visits and a text messaging program for 12 consecutive months. Implementation package delivery will end after month 12, at which time intervention participants will be advised to obtain standard care from their local healthcare facility. Study outcome measures will be obtained in both the usual care and ANDES intervention group at months 6, 12, and 18 post-randomization. All participants will receive a total of four visits for study outcome assessments (at baseline, 6, 12, and 18 months). Intervention participants will additionally receive a total of 18 visits by health agents as part of the intervention package, for a total of 22 visits for those assigned to the intervention group. No financial incentives will be offered; participants can withdraw from the study at any time without loss of healthcare benefits they would otherwise be eligible to receive (i.e., usual care). Nonetheless, based on our experience with prior studies in Peru, and specifically in the Puno area, we anticipate limited attrition (≤ 10%). Health Screening The following health assessments will be conducted by fieldworkers hired and trained by the ANDES study team. Blood pressure measurements: A member of our research team will measure resting blood pressure in the right arm in triplicate (with at least 1 minute between measurements) using an automatic oscillometric sphygmomanometer (Omron, model HEM-907XL) at the participant's home using procedures detailed in the "Blood Pressure Measurement - Standard Operating Procedures" document. Briefly, the participant will refrain from exercise, consumption/use of tobacco products, alcohol or caffeinated beverages, or cooking using biomass in the 30 minutes prior, and confirm that they do not have a full bladder. Clothing will be removed to expose the right upper-arm and an appropriately sized cuff will be positioned as outlined in the "Standard Operating Procedure: Blood Pressure and Glucose" document. Before starting the measurement, the participant will be instructed to sit on a chair in a quiet room for five minutes with legs uncrossed, back supported by the chair, and arm supported on a table at the level of the heart (mid-sternum). Heart rate will also be recorded. The participant will refrain from talking or from engaging in other activities such as reading or using their cell phone in the five minutes prior to and during the blood pressure measurements. We will take the average of all three measurements for SBP and DBP as the final measurement. Uncontrolled hypertension is defined as an average SBP ≥140 mm Hg and/or DBP ≥90 mm Hg. Participants in the intervention group will have their blood pressure assessed by community health agents twice monthly for the first six months, and monthly thereafter for the rest of the year. Blood pressure assessment will follow the same procedure as described above. Diabetes assessment. The presence of type 2 diabetes will be determined by use of an FDA-approved laboratory based HbA1c testing (Roche cobas c311 analyzer) as a secondary aim to assess whether the multicomponent intervention has any effect on diabetes control. A measurement will be taken from each participant at the time of the baseline, 6-, 12-, and 18-month visits. A trained member of our research staff will perform a minimally invasive finger stick to collect up to 30 µl of whole blood; the sample will then be taken for testing at a central health facility laboratory. Alternatively, patients will have the opportunity to go to the central health facility to have the test performed independently of the home visit. All samples will be destroyed after testing. T2D diagnosis will be defined as ongoing treatment with a hypoglycemic drug or insulin, or a HbA1c ≥7%. If the patient has a diagnosis of T2D, documentation will be obtained from the healthcare facility. Anthropometry: We will assess height with a stadiometer (seca 213, seca, Hamburg, Germany) and waist size with a circumference tape (seca circumference tape 203, Hamburg, Germany) at baseline. We will assess weight using a digital balance (seca 803, seca, Hamburg, Germany) at baseline, 6, 12 and 18 months. These measurements will be conducted by our research staff. All anthropometric measurements will be measured in triplicate and mean value will be used as the final anthropometric measurement. We will follow standard procedures for the assessment of anthropometry. Oxyhemoglobin saturation: We will assess oxyhemoglobin saturation using the Rad 5v (Masimo, Irvine CA) pulse oximeter. These measurements will be conducted by our research staff. Participants will be at rest for 2 minutes before oxyhemoglobin saturation. We will record values of oxygen saturation at 60, 90 and 120 seconds. The mean value will be used as the final oxyhemoglobin saturation. Participants in the usual care group will not receive the same benefits as those in the intervention group, which include delivery medications, assistance with appointment and intensive health coaching. To offset this difference, we will offer the following clinical exams will be offered to all trial participants as an additional benefit to address their overall non-communicable disease risk: Lung function: Spirometry will be offer to all participants at baseline, 6, 12 and 18 months. These measurements will be conducted by our research staff. Spirometry will be conducted by trained staff before and after inhaled bronchodilation (400 mcg of salbutamol using a spacer) following standard American Thoracic Society/European Respiratory Society guidelines. We will use the EasyOne Air handheld spirometer (ndd, Zurich, Switzerland), a device that has been validated and used in several large population-based studies in low-income settings by our group. We will adapt a standardized grading system for quality control, review, and interpretation. All lung function tests will be read by a pulmonologist on the research team as part of the quality control/quality assurance procedures. We will record pre- and post-bronchodilator Peak Expiratory Flow (PEF), Forced Expiratory Volume in One Second (FEV1), and Forced Vital Capacity (FVC). If a spirometry measurement does not meet quality standards of acceptability or reproducibility, we will attempt to repeat the procedure on a different day for a maximum of 3 tests in total. Participants with any spirometry abnormalities will be referred to the nearest health center. Ambulatory blood pressure: We will offer ambulatory blood pressure measurement at 6, 12, and 18 months. These measurements will be conducted by our research staff. We will measure 24-hour BP by fitting participants with a CE/ISO approved 24-hour ambulatory blood pressure monitor [Contec Medical Systems Co., Ltd, Qinhuangdao, China] oscillometric device with an appropriate cuff for mid-upper arm circumference (small, 20-24 cm; medium, 24-32 cm; large, 32-38 cm). The 24-hour ambulatory blood pressure monitors will be fitted on a regular working day (i.e., a day during which participants would be undertaking their regular daily activities). Blood pressure will be automatically measured at 30 minute intervals over the 24 hour period. Personal exposure to PM2.5: We will offer air quality assessment at baseline, 6, 12, and 18 months. These measurements will be conducted by our research staff. We will collect 24-our personal exposures of PM2.5 using the UPAS device (Access Sensor Technologies, Fort Collins, CO). The UPAS is a small, lightweight wearable device that is easy to use and has built-in technology for gravimetric (filter-based) sampling. Long battery life and GPS tracking help ensure that data is collected and that the participant is wearing the device over the specified time interval, and the device can quickly be deployed between locations without having to return to a lab environment between tests for calibration. Study Staff Training Health agents will receive training on all study procedures and counseling techniques, including educational and motivational counseling techniques, BP measurement, finger stick, medication management, and behavioral change related to hypertension. The training program has been designed by the ANDES team and is based on materials from the Pan-American Health Organization's HEARTS technical package. These materials are validated for use in Spanish, as the health agents are all Spanish speakers and will be coaching most of their patients in Spanish as well. Health agents are instructed and assessed on how to properly take clinical measures under supervision of licensed professionals and study staff. Upon completion of this training, the ANDES team will issue the health agent a certificate indicating that they are able to perform clinical measures and healthy lifestyle coaching on behalf of the ANDES Study. Fieldworkers hired by the research team will be trained on all study procedures relevant to the collection of study outcome data, including BP measurement, finger stick, spirometry, ambulatory blood pressure, personal exposure to PM2.5, and CRF administration. These fieldworkers will be responsible for collecting outcome measures to be used in analysis. They will be instructed to remain blinded to each participant's group. Sample Size To detect a difference in systolic blood pressure of 2.5 mmHg between intervention and control arms with 95% confidence, 90% power and a standard deviation of 12 mmHg, we would need 485 participants per arm. Assuming a conservative lost-to-follow-up of 10% at 12 months, we would need to randomize 1068 participants in total (534 participants per arm).

Participants in the ANDES intervention group will receive the ANDES implementation package consisting of health agent home visits and a text messaging program for 12 consecutive months. Implementation package delivery will end after month 12, at which time intervention participants will be advised to obtain standard care from their local healthcare facility. ANDES is an adaptation of the World Health Organization (WHO) HEARTS package and consists of the following components: A. Health agent-managed home care BP monitoring Health coaching Health system navigation Medication delivery assistance B. Text message-based health coaching Specifically, the ANDES strategy is aligned with four WHO HEARTS technical package components.

Participants in the usual care group will be referred to their local healthcare facility for evaluation and/or to receive medical therapy per typical standard of care and at the discretion of the treating physician for the entirety of the ANDES study.

ANDES intervention group will receive the ANDES implementation package consisting of health agent home visits and a text messaging program for 12 consecutive months

To determine if ANDES participants randomized to the intervention arm have an average reduction in SBP of at least 2.5 mmHg relative to the usual care arm 12 months after randomization.

To measure if the proportion of ANDES participants randomized to the intervention strategy with blood pressure ≥140/90 mmHg is reduced compared to the proportion among participants randomized to the usual care strategy at 12 months.

Within a subgroup of ANDES participants with HTN and T2D, to determine if the proportion of participants randomized to the intervention strategy with a HbA1c ≥7% is reduced when compared to participants randomized to the usual care strategy at 12 months.

To determine if the proportion of ANDES participants who have maintained a lower systolic blood pressure is greater among those randomized to the intervention arm than those randomized to the usual care arm at 18 months.

To determine if the proportion of ANDES participants with blood pressure ≥140/90 mmHg is reduced among those randomized to the intervention arm compared to those randomized to the usual care arm at 18 months.

Within a subgroup of ANDES participants with HTN and T2D, to determine if the proportion of participants with a HbA1c ≥7% is reduced among those randomized to the intervention arm compared to those randomized to the usual care arm at 18 months.

Percent of patients retained in care at participating health establishments at 12 months. Percent of total possible visits by health agents that were 1) attempted and 2) conducted. Percent of visits in which a health agent completed the health coaching checklists, including the provision of the following: Motivational support for lifestyle modification Education on medication adherence Blood pressure monitoring Home delivery of medications

Implementation outcome: Acceptability: Measure of stakeholder acceptance or satisfaction with various aspects of the implementation strategy

Percent of patients reporting satisfaction with implementation strategy components (e.g., patient satisfaction with health agent services) Percent of health agent supervisors reporting satisfaction with implementation strategy components (e.g., health agent delivery of care)

Implementation outcome: Adoption: Absolute number or proportion of health facilities or individuals willing to initiate the ANDES strategy

Percent of patients who: Visit a healthcare facility after being referred for care Take medications as prescribed Implement recommended lifestyle/behavioral changes

Percent of patients who: Complete >1 clinical encounter (healthcare facility or health agent) Are offered BP behavioral or clinical hypertension control interventions Meet pre-defined medication adherence threshold

Out-of-pocket costs (opportunity costs, time, transportation, caring for sick relatives instead of working, etc.) associated with controlled and uncontrolled HTN/T2D; Cost savings due to avoided healthcare utilization, assuming that the intervention improves control of HTN/T2D and thus reduces the probability of referral to more complex levels of care.

Inclusion Criteria: Diagnosis of HTN, defined as one or more of the following: Physician-prescribed use of antihypertensive medications; and/or, Physician diagnosed hypertension defined as a hypertensive Hypertensive blood pressure measurement (SBP≥140 mmHg and/or DBP≥90 mmHg) documented or measured on two or more separate occasions. Willing and available for the first baseline health agent home visit. Exclusion Criteria: Less than 18 years old;. Has a SBP less than 140 mmHg and DBP less than 90 mmHg and is not currently taking medication; Unwilling, unable, or or not cognitively capable of providing informed consent; Pregnant or plan to become pregnant in the next 18 months; Plan to move out of the study area in the next 18 months; Are not ambulatory; Currently receives home visits for HTN control; Life expectancy less than 6 months.

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