Studies of mortality risk predictors in hypertensive patients

Hypertension is a leading cause of death and disability worldwide. Despite effective treatment regimens the mortality among hypertensive subjects are much higher than that of normal individuals. Several studies have been carried out to identify prognostic factors that have predictive value for mortality in the general population. New biomarkers that are readily available and cost-effective are important in risk stratification and management of hypertension. While important prognostic information can be learned from routine blood tests that are often conducted in hypertension clinics, the usefulness of these markers in predicting survival are not studied in detail. The thesis aims to explain the relationship between such inexpensive and commonly available markers and survival in a hypertensive population. The thesis is divided into five main results chapters (chapters 3 to 7) based on studies conducted to assess the independent role of blood pressure variability (BPV), haematocrit, serum phosphate, serum electrolytes and indices of liver dysfunction or injury in predicting mortality in hypertensive patients. The study settings (Glasgow Blood Pressure Clinic) provided an opportunity to examine these relationships in a treated hypertensive cohort of more than 15,000, predominantly white population, from the West of Scotland. The hypertension clinic database was linked with the electronic records of General Register Office for Scotland. This electronic linking allowed extraction of primary cause of death data (if patients died during the course of follow-up) according to the International Classification of Diseases, 10th Revision, Version for 2007 (ICD-10), codes. The type of mortality was ascertained (namely; ischaemic heart disease, stroke, cardiovascular, non-cardiovascular and all-cause) from the ICD-10 codes. The independent relationships between predictor variables of interests and mortality were estimated after employing appropriate survival models. The main study findings are summarised below. Blood pressure variability and mortality: Long term average BPV is an independent predictor of mortality. Longitudinal changes in BPV also predict mortality independent of underlying mean BP. While sustained high variability increases mortality, sustained low variability decreases mortality in this hypertensive cohort. The findings indicate that BPV is likely a fundamental physiologic trait and it is a marker of early mortality. Visit-to-visit BPV is an important prognostic indicator of long-term mortality, and physicians should be made aware that long term clinic BPV should not be disregarded as random fluctuation between visits. Haematocrit and mortality: Haematocrit (Hct) is the proportion of blood volume occupied by red blood cells. It is associated with follow-up BP and is an independent predictor of mortality in the hypertensive population. There are distinct differences both in terms of the strength and magnitude of the association of Hct and mortality between men and women that have not previously been known. While Hct is associated with CV mortality in men ('U' shaped, non-linear), it is more closely associated with non-CV mortality in women ('U' shaped, non-linear). In the assessment and management of newly diagnosed hypertensive patients, Hct levels should be taken into consideration as an important risk predictor. Serum phosphate and mortality: Inorganic phosphate is an important mineral that is directly linked to energy metabolism, bone mineralisation, signal transduction, storage and translation of genetic information and maintenance of lipid membrane structure. A positive linear association between serum phosphate and mortality is reported in the present study. Deprivation status, serum calcium and serum alkaline phosphatase levels do not attenuate the mortality risk associated with serum phosphate in men and women. While serum phosphate is associated with CV mortality in men, it is more closely associated with non-CV mortality in women. Serum electrolytes and mortality: Electrolytes, especially sodium, chloride, potassium and bicarbonates, play a vital role in maintaining homeostasis within the human body. While the relationship with all-cause mortality is non-linear across the entire range of serum chloride, there is a linear increase in mortality with decrease in serum chloride level below 100 mEq/L. The relationship between serum chloride and mortality is independent of serum sodium and bicarbonate levels. While serum potassium shows a non-linear "U" shaped relationship with mortality, serum bicarbonate shows a positive linear association. Indices of liver dysfunction or liver injury and mortality: Serum albumin, bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT) and alakaline phosphatase (ALP) are widely used markers of liver function or injury to liver cells. These markers of liver function or injury to liver cells independently predict mortality outcomes in the hypertensive population. While there is a linear association of both GGT and ALP with mortality outcomes, it is a more complex, non-linear and ‘U’ shaped association for AST. Both ALT and bilirubin show inverse linear association with mortality. Age and body mass index significantly influence the relationship between ALT and mortality. Strengths and limitations: The strengths of the studies conducted as part of this thesis include; a large cohort of nearly 15,000 hypertensive adults, a real life clinical setting, 35 years of follow-up with median survival time of 32 years, the ability to link predictor variables with differing causes of mortality outcomes, and adjustment for several potential confounding factors. Exclusion of individuals without predictor variables assessed at baseline and the bias introduced by the missing covariates in the adjusted Cox-proportional hazard models are the major weaknesses. Future recommendations: Although the above mentioned inexpensive markers predict mortality in hypertensive population, the mechanism involved in their association with mortality is not clear. Future studies are required to explain the missing links. Usefulness of inclusion of these markers in predicting mortality should be tested in an independent population

Does uric acid qualify as an independent risk factor for cardiovascular mortality? Clin Sci

Abstract UA (uric acid) is the final product of purine metabolism in humans and is implicated in many disease conditions. Sustained hyperuricaemia has putative adverse roles in cardiovascular diseases. Despite strong evidence emerging from large epidemiological studies supporting the hypothesis that UA independently influences cardiovascular disease outcomes and mortality, a causal role is yet to be established. Serum UA is also considered as a useful biomarker for mortality in high-risk patients with acute coronary syndromes, heart failure and hypertension and in patients with Type 2 diabetes mellitus. Post-hoc analyses of clinical trial data suggest beneficial effects of reducing serum UA. However, these findings are inconclusive and are only hypothesis-generating. In the present issue of Clinical Science, Ndrepepa and co-workers have investigated the prognostic role of UA in high-risk Type 2 diabetic patients with established coronary artery disease in predicting 1-year survival and cardiovascular mortality. These results support the independent role of serum UA in predicting survival in Type 2 diabetic patients. However, long-term follow-up studies are required with serial UA measurement to establish the time-dependent association of UA with mortality outcomes

Diastolic blood pressure J-curve phenomenon in a tertiary-care hypertension clinic

Concerns exist regarding the potential increased cardiovascular risk from lowering diastolic blood pressure (DBP) in hypertensive patients. We analyzed 30-year follow-up data of 10 355 hypertensive patients attending the Glasgow Blood Pressure Clinic. The association between blood pressure during the first 5 years of treatment and cause-specific hospital admissions or mortality was analyzed using multivariable adjusted Cox proportional hazard models. The primary outcome was a composite of cardiovascular admissions and deaths. DBP showed a U-shaped association (nadir, 92 mm Hg) for the primary cardiovascular outcome hazard and a reverse J-shaped association with all-cause mortality (nadir, 86 mm Hg) and noncardiovascular mortality (nadir, 92 mm Hg). The hazard ratio for the primary cardiovascular outcome after adjustment for systolic blood pressure was 1.38 (95% CI, 1.18–1.62) for DBP <80 compared with DBP of 80 to 89.9 mm Hg (referrant), and the subdistribution hazard ratio after accounting for competing risk was 1.33 (1.17–1.51) compared with DBP ≥80 mm Hg. Cause-specific nonfatal outcome analyses showed a reverse J-shaped relationship for myocardial infarction, ischemic heart disease, and heart failure admissions but a U-shaped relationship for stroke admissions. Age-stratified analyses showed DBP had no independent effect on stroke admissions among the older patient subgroup (≥60 years of age), but the younger subgroup showed a clear U-shaped relationship. Intensive blood pressure reduction may lead to unintended consequences of higher healthcare utilization because of increased cardiovascular morbidity, and this merits future prospective studies. Low on-treatment DBP is associated with increased risk of noncardiovascular mortality, the reasons for which are unclear

Task sharing with non-physician health-care workers for management of blood pressure in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Task sharing for the management of hypertension could be useful for understaffed and resource-poor health systems. We assessed the effectiveness of task-sharing interventions in improving blood pressure control among adults in low-income and middle-income countries. METHODS: We searched the Cochrane Library, PubMed, Embase, and CINAHL for studies published up to December 2018. We included intervention studies involving a task-sharing strategy for management of blood pressure and other cardiovascular risk factors. We extracted data on population, interventions, blood pressure, and task sharing groups. We did a meta-analysis of randomised controlled trials. FINDINGS: We found 3012 references, of which 54 met the inclusion criteria initially. Another nine studies were included following an updated search. There were 43 trials and 20 before-and-after studies. We included 31 studies in our meta-analysis. Systolic blood pressure was decreased through task sharing in different groups of health-care workers: the mean difference was -5·34 mm Hg (95% CI -9·00 to -1·67, I2=84%) for task sharing with nurses, -8·12 mm Hg (-10·23 to -6·01, I2=57%) for pharmacists, -4·67 mm Hg (-7·09 to -2·24, I2=0%) for dietitians, -3·67 mm Hg (-4·58 to -2·77, I2=24%) for community health workers, and -4·85 mm Hg (-6·12 to -3·57, I2=76%) overall. We found a similar reduction in diastolic blood pressure (overall mean difference -2·92 mm Hg, -3·75 to -2·09, I2=80%). The overall quality of evidence based on GRADE criteria was moderate for systolic blood pressure, but low for diastolic blood pressure. INTERPRETATION: Task-sharing interventions are effective in reducing blood pressure. Long-term studies are needed to understand their potential impact on cardiovascular outcomes and mortality. FUNDING: Wellcome Trust/DBT India Alliance

Association of trans fatty acids with lipids and other cardiovascular risk factors in an Indian industrial population.

OBJECTIVE: Trans-fat, an invariable component of industrial fat is considered as one of the major dietary factors associated with CVD. Although the use of trans-fat is completely banned in some of the high-income countries where the CVD epidemic is declining, it is widely used in LMIC. We aimed to investigate the association of trans fatty acid in serum with risk markers of CVD in an industrial population in India. Participants were randomly selected from a study conducted in an industrial setting among employees and their family members. Information related to their demographic profile, anthropometric measurements, oil intake were recorded. Fasting samples were collected and stored at - 80 °C for analysis. Their lipid profile and hs CRP were measured and fatty acids analyzed using gas chromatography (GC) with flame ionization detector (FID). RESULTS: Complete data was available for 176 participants. Among trans fatty acids, mono trans fatty acid was significant predictor of serum triglycerides [Unadjusted β (95% CI) 22.9 (2.6, 43.2); Adjusted β (95% CI) 20.4 (3.5, 37.3)]. None of the other trans fatty acids either individually or in group correlated with any of the biochemical markers studied

Voices of care: unveiling patient journeys in primary care for hypertension and diabetes management in Kerala, India

BackgroundDiabetes and hypertension are leading public health problems, particularly affecting low- and middle-income countries, with considerable variations in the care continuum between different age, socio-economic, and rural and urban groups. In this qualitative study, examining the factors affecting access to healthcare in Kerala, we aim to explore the healthcare-seeking pathways of people living with diabetes and hypertension.MethodsWe conducted 20 semi-structured interviews and one focus group discussion (FGD) on a purposive sample of people living with diabetes and hypertension. Participants were recruited at four primary care facilities in Malappuram district of Kerala. Interviews were transcribed and analyzed deductively and inductively using thematic analysis underpinned by Levesque et al.’s framework.ResultsThe patient journey in managing diabetes and hypertension is complex, involving multiple entry and exit points within the healthcare system. Patients did not perceive Primary Health Centres (PHCs) as their initial points of access to healthcare, despite recognizing their value for specific services. Numerous social, cultural, economic, and health system determinants underpinned access to healthcare. These included limited patient knowledge of their condition, self-medication practices, lack of trust/support, high out-of-pocket expenditure, unavailability of medicines, physical distance to health facilities, and attitude of healthcare providers.ConclusionThe study underscores the need to improve access to timely diagnosis, treatment, and ongoing care for diabetes and hypertension at the lower level of the healthcare system. Currently, primary healthcare services do not align with the “felt needs” of the community. Practical recommendations to address the social, cultural, economic, and health system determinants include enabling and empowering people with diabetes and hypertension and their families to engage in self-management, improving existing health information systems, ensuring the availability of diagnostics and first-line drug therapy for diabetes and hypertension, and encouraging the use of single-pill combination (SPC) medications to reduce pill burden. Ensuring equitable access to drugs may improve hypertension and diabetes control in most disadvantaged groups. Furthermore, a more comprehensive approach to healthcare policy that recognizes the interconnectedness of non-communicable diseases (NCDs) and their social determinants is essential

Task-sharing interventions for cardiovascular risk reduction and lipid outcomes in low- and middle-income countries: A systematic review and meta-analysis.

BACKGROUND: One of the potential strategies to improve health care delivery in understaffed low- and middle-income countries (LMICs) is task sharing, where specific tasks are transferred from more qualified health care cadre to a lesser trained cadre. Dyslipidemia is a major risk factor for cardiovascular disease but often it is not managed appropriately. OBJECTIVE: We conducted a systematic review with the objective to identify and evaluate the effect of task sharing interventions on dyslipidemia in LMICs. METHODS: Published studies (randomized controlled trials and observational studies) were identified via electronic databases such as PubMed, Embase, Cochrane Library, PsycINFO, and CINAHL. We searched the databases from inception to September 2016 and updated till 30 June 2017, using search terms related to task shifting, and cardiovascular disease prevention in LMICs. All eligible studies were summarized narratively, and potential studies were grouped for meta-analysis. RESULTS: Although our search yielded 2938 records initially and another 1628 in the updated search, only 15 studies met the eligibility criteria. Most of the studies targeted lifestyle modification and care coordination by involving nurses or allied health workers. Eight randomized controlled trials were included in the meta-analysis. Task sharing intervention were effective in lowering low-density lipoprotein cholesterol (-6.90 mg/dL; 95% CI -11.81 to -1.99) and total cholesterol (-9.44 mg/dL; 95% CI -17.94 to -0.93) levels with modest effect size. However, there were no major differences in high-density lipoprotein cholesterol (-0.29 mg/dL; 95% CI -0.88 to 1.47) and triglycerides (-14.31 mg/dL; 95% CI -33.32 to 4.69). The overall quality of evidence based on Grading of Recommendations Assessment, Development and Evaluation was either "low" or "very low". CONCLUSION: Available data are not adequate to make recommendations on the role of task sharing strategies for the management of dyslipidemia in LMICs. However, the studies conducted in LMICs demonstrate the potential use of this strategy especially in terms of reduction in low-density lipoprotein cholesterol and total cholesterol levels. Our review calls for the need of well-designed and large-scale studies to demonstrate the effect of task-sharing strategy on lipid management in LMICs

Quality Improvement for Cardiovascular Disease Care in Low- and Middle-Income Countries: A Systematic Review

Background The majority of global cardiovascular disease (CVD) burden falls on people living in low- and middle-income countries (LMICs). In order to reduce preventable CVD mortality and morbidity, LMIC health systems and health care providers need to improve the delivery and quality of CVD care. Objectives As part of the Disease Control Priorities Three (DCP3) Study efforts addressing quality improvement, we reviewed and summarized currently available evidence on interventions to improve quality of clinic-based CVD prevention and management in LMICs. Methods We conducted a narrative review of published comparative clinical trials that evaluated efficacy or effectiveness of clinic-based CVD prevention and management quality improvement interventions in LMICs. Conditions selected a priori included hypertension, diabetes, hyperlipidemia, coronary artery disease, stroke, rheumatic heart disease, and congestive heart failure. MEDLINE and EMBASE electronic databases were systematically searched. Studies were categorized as occurring at the system or patient/provider level and as treating the acute or chronic phase of CVD. Results From 847 articles identified in the electronic search, 49 met full inclusion criteria and were selected for review. Selected studies were performed in 19 different LMICs. There were 10 studies of system level quality improvement interventions, 38 studies of patient/provider interventions, and one study that fit both criteria. At the patient/provider level, regardless of the specific intervention, intensified, team-based care generally led to improved medication adherence and hypertension control. At the system level, studies provided evidence that introduction of universal health insurance coverage improved hypertension and diabetes control. Studies of system and patient/provider level acute coronary syndrome quality improvement interventions yielded inconclusive results. The duration of most studies was less than 12 months. Conclusions The results of this review suggest that CVD care quality improvement can be successfully implemented in LMICs. Most studies focused on chronic CVD conditions; more acute CVD care quality improvement studies are needed. Longer term interventions and follow-up will be needed in order to assess the sustainability of quality improvement efforts in LMICs

Effect of workplace physical activity interventions on the cardio-metabolic health of working adults: systematic review and meta-analysis.

BACKGROUND: Adults in urban areas spend almost 77% of their waking time being inactive at workplaces, which leaves little time for physical activity. The aim of this systematic review and meta-analysis was to synthesize evidence for the effect of workplace physical activity interventions on the cardio-metabolic health markers (body weight, waist circumference, body mass index (BMI), blood pressure, lipids and blood glucose) among working adults. METHODS: All experimental studies up to March 2018, reporting cardio-metabolic worksite intervention outcomes among adult employees were identified from PUBMED, EMBASE, COCHRANE CENTRAL, CINAHL and PsycINFO. The Cochrane Risk of Bias tool was used to assess bias in studies. All studies were assessed qualitatively and meta-analysis was done where possible. Forest plots were generated for pooled estimates of each study outcome. RESULTS: A total of 33 studies met the eligibility criteria and 24 were included in the meta-analysis. Multi-component workplace interventions significantly reduced body weight (16 studies; mean diff: - 2.61 kg, 95% CI: - 3.89 to - 1.33) BMI (19 studies, mean diff: - 0.42 kg/m2, 95% CI: - 0.69 to - 0.15) and waist circumference (13 studies; mean diff: - 1.92 cm, 95% CI: - 3.25 to - 0.60). Reduction in blood pressure, lipids and blood glucose was not statistically significant. CONCLUSIONS: Workplace interventions significantly reduced body weight, BMI and waist circumference. Non-significant results for biochemical markers could be due to them being secondary outcomes in most studies. Intervention acceptability and adherence, follow-up duration and exploring non-RCT designs are factors that need attention in future research. Prospero registration number: CRD42018094436