Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in ...observational studies. We aimed to confirm these findings in an adequately powered randomized trial.
We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.
There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01–1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.
In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.
Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk.
We performed a 3 × 2 partial ...factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation.
There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval CI, 0.67–1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28–0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27–0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609–2528).
In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424.
To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach.
A two-sample MR analysis included 17 independent genetic variants associated with ...ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (
= 31,200).
Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio OR per SD 0.92 95% CI 0.89-0.95;
= 1.79 × 10
). This result was replicated in the UK Biobank (OR per SD 0.97 0.96-0.99;
= 8.73 × 10
). After standardization, the
GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 0.07-0.51 vs. 0.76 0.60-0.97, respectively;
= 0.007 for difference).
These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice.
Epidemiological studies have reported a relationship between severe hypoglycemia, cognitive dysfunction, and dementia in middle-aged and older people with type 2 diabetes. However, whether severe or ...nonsevere hypoglycemia precedes cognitive dysfunction is unclear. Thus, the aim of this study was to analyze the relationship between hypoglycemia and incident cognitive dysfunction in a group of carefully followed patients using prospectively collected data in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial.
This prospective cohort analysis of data from a randomized controlled trial included individuals with dysglycemia who had additional cardiovascular risk factors and a Mini-Mental State Examination (MMSE) score ≥24 (
= 11,495). Severe and nonsevere hypoglycemic events were collected prospectively during a median follow-up time of 6.2 years. Incident cognitive dysfunction was defined as either reported dementia or an MMSE score of <24. The hazard of at least one episode of severe or nonsevere hypoglycemia for incident cognitive dysfunction (i.e., the dependent variable) from the time of randomization was estimated using a Cox proportional hazards model after adjusting for baseline cardiovascular disease, diabetes status, treatment allocation, and a propensity score for either form of hypoglycemia.
This analysis did not demonstrate an association between severe hypoglycemia and incident cognitive impairment either before (hazard ratio HR 1.16; 95% CI 0.89, 1.52) or after (HR 1.00; 95% CI 0.76, 1.31) adjusting for the severe hypoglycemia propensities. Conversely, nonsevere hypoglycemia was inversely related to incident cognitive impairment both before (HR 0.59; 95% CI 0.52, 0.68) and after (HR 0.58; 95% CI 0.51, 0.67) adjustment.
Hypoglycemia did not increase the risk of incident cognitive dysfunction in 11,495 middle-aged individuals with dysglycemia.
Combination pills containing aspirin, multiple blood pressure (BP) lowering drugs, and a statin have demonstrated safety, substantial risk factor reductions, and improved medication adherence in the ...prevention of cardiovascular disease (CVD). The individual medications in combination pills are already recommended for use together in secondary CVD prevention. Therefore, current information on their pharmacokinetics, impact on the risk factors, and tolerability should be sufficient to persuade regulators and clinicians to use fixed-dose combination pills in high-risk individuals, such as in secondary prevention. Long-term use of these medicines, in a polypill or otherwise, is expected to reduce CVD risk by at least 50-60% in such groups. This risk reduction needs confirmation in prospective randomized trials for populations for whom concomitant use of the medications is not currently recommended (e.g. primary prevention). Given their additive benefits, the combined estimated relative risk reduction (RRR) in CVD from both lifestyle modification and a combination pill is expected to be 70-80%. The first of several barriers to the widespread use of combination therapy in CVD prevention is physician reluctance to use combination pills. This reluctance may originate from the belief that lifestyle modification should take precedence, and that medications should be introduced one drug at a time, instead of regarding combination pills and lifestyle modification as complementary and additive. Second, widespread availability of combination pills is also impeded by the reluctance of large pharmaceutical companies to invest in development of novel co-formulations of generic (or 'mature') drugs. A business model based on 'mass approaches' to drug production, packaging, marketing, and distribution could make the combination pill available at an affordable price, while at the same time providing a viable profit for the manufacturers. A third barrier is regulatory approval for novel multidrug combination pills, as there are few precedents for the approval of combination products with four or more components for CVD. Acceptance of combination therapy in other settings suggests that with concerted efforts by academics, international health agencies, research funding bodies, governments, regulators, and pharmaceutical manufacturers, combination pills for prevention of CVD in those with disease or at high risk (e.g. those with multiple risk factors) can be made available worldwide at affordable prices. It is anticipated that widespread use of combination pills with lifestyle modifications can lead to substantial risk reductions (as much as an 80% estimated RRR) in CVD. Heath care systems need to deploy these strategies widely, effectively, and efficiently. If implemented, these strategies could avoid several millions of fatal and non-fatal CVD events every year worldwide.
Abstract
Aims
The aims of the present study were to describe the proportion of patients eligible for the COMPASS trial within the Reduction of Atherothrombosis for Continued Health (REACH) registry, ...the reasons for ineligibility, and to put in perspective the characteristics and outcomes of trial-eligible patients from the REACH registry compared with those of patients enrolled in the reference aspirin arm of the COMPASS trial.
Methods and results
The COMPASS selection and exclusion criteria were applied to REACH patients with either coronary artery disease (CAD) or peripheral artery disease (PAD). We used the COMPASS primary composite outcome of cardiovascular (CV) death, myocardial infarction (MI), or stroke. In REACH, 31 873 patients had CAD or PAD and detailed information allowing evaluation of eligibility. Among these, 9518 (29.9%) patients had exclusion criteria and an additional 5480 patients (17.2%) did not fulfil the inclusion criteria and thus were not eligible. The ‘COMPASS-Eligible’ population therefore comprised 52.9% of the evaluable REACH patients (n = 16 875). The main reasons for exclusion were high-bleeding risk (51.8%), anticoagulant use (44.8%), requirement for dual antiplatelet therapy within 1 year of an ACS or PCI with stent, (25.9%), history of ischaemic stroke <1 year (12.4%), and severe renal failure (2.2%). Eligibility was highest among patients with PAD alone (68.4%). COMPASS-Eligible patients from REACH experienced higher annualized primary outcome event rates than patients actually enrolled in the reference aspirin arm of COMPASS (4.2% vs. 2.9% per year, P < 0.001).
Conclusion
COMPASS-Eligible patients represent a substantial fraction of stable CAD/PAD patients encountered in routine clinical practice in the large international REACH registry suggesting good external applicability. COMPASS-Eligible patients experienced a higher rate of the primary outcome compared with COMPASS participants in the aspirin alone treatment arm.
Physical activity (PA) has been shown to reduce the impact of FTO variation and obesity genetic risk scores (GRS) on BMI. We examined this interaction using a quantitative measure of PA and two ...adiposity indexes in a longitudinal multi-ethnic study. We analyzed the impact of PA on the association between 14 obesity predisposing variants (analyzed independently and as a GRS) and baseline/follow-up obesity measures in the multi-ethnic prospective cohort EpiDREAM (17423 participants from six ethnic groups). PA was analyzed using basic (low-moderate-high) and quantitative measures (metabolic equivalents (METS)), while BMI and the body adiposity index (BAI) were used to measure obesity. Increased PA was associated with decreased BMI/BAI at baseline/follow-up. FTO rs1421085, CDKAL1 rs2206734, TNNl3K rs1514176, GIPR rs11671664 and the GRS were associated with obesity measures at baseline and/or follow-up. Risk alleles of three SNPs displayed nominal associations with increased (NTRK2 rs1211166, BDNF rs1401635) or decreased (NPC1 rs1805081) basic PA score independently of BMI/BAI. Both basic and quantitative PA measures attenuated the association between FTO rs1421085 risk allele and BMI/BAI at baseline and follow-up. Our results show that physical activity can blunt the genetic effect of FTO rs1421085 on adiposity by 36-75% in a longitudinal multi-ethnic cohort.
In low-resource settings, access to basic rehabilitation could be supplemented by community-level interventions provided by community health workers, health volunteers, or family caregivers. Yet, it ...is unclear whether basic physical rehabilitation interventions delivered to adults by non-professional alternative resources in the community, under task-shifting or task-sharing approaches, are effective as those delivered by skilled rehabilitation professionals. We aim to synthesize evidence on the effectiveness of community-level rehabilitation interventions delivered by non-professional community-level workers or informal caregivers to improve health outcomes for persons with physical impairments or disabilities.
We performed a systematic review with a PROSPERO registration. Eight databases were searched for (PubMed, CINAHL, Global Health, PDQ Evidence, Scopus, ProQuest, CENTRAL, and Web of Science), supplemented by snowballing and key-informant recommendations, with no time restrictions, applied. Controlled and non-controlled experiments were included if reporting the effects of interventions on mobility, activities of daily living (ADLs), quality of life, or social participation outcomes. Two independent investigators performed the eligibility decisions, data extraction, risk of bias, and assessed the quality of the evidence using the GRADE approach.
Ten studies (five randomized controlled trials RCTs) involving 2149 participants were included. Most common targeted stroke survivors (n = 8); family caregivers were most frequently used to deliver the intervention (n = 4); and the intervention was usually provided in homes (n = 7), with training initiated in the hospital (n = 4). Of the four RCTs delivered by family caregivers, one demonstrated a statistically significant improvement in mobility (effect size: 0.3; confidence interval CI 121.81-122.19; p = 0.04) and another one in ADLs (effect size: 0.4; CI 25.92-35.08; p = 0.03). Of the five non-RCT studies by community health workers or volunteers, one demonstrated a statistically significant improvement in mobility (effect size: 0.3; CI 10.143-16.857; p < 0.05), while two demonstrated improved statistically significant improvement in ADLs (effect size: 0.2; CI 180.202-184.789 p = 0.001; 0.4; CI - 7.643-18.643; p = 0.026). However, the quality of evidence, based on GRADE criteria, was rated as low to very low.
While task-sharing is a possible strategy to meet basic rehabilitation needs in low-resource settings, the current evidence on the effectiveness of delivering rehabilitation interventions by non-professional community-level workers and informal caregivers is inconclusive. We can use the data and experiences from existing studies to better design studies and improve the implementation of interventions. Trial registration PROSPERO registration number: CRD42022319130.
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