Antihypertensive withdrawal for the prevention of cognitive decline

Item does not contain fulltextClinical trials and observational data have variously shown a protective, harmful or neutral effect of antihypertensives on cognitive function. In theory, withdrawal of antihypertensives could improve cerebral perfusion and reduce or delay cognitive decline. However, it is also plausible that withdrawal of antihypertensives may have a detrimental effect on cognition through increased incidence of stroke or other vascular events. To assess the effects of complete withdrawal of at least one antihypertensive medication on incidence of dementia, cognitive function, blood pressure and other safety outcomes in cognitively intact and cognitive impaired adults. We searched ALOIS, the specialised register of the Cochrane Dementia and Cognitive Improvement Group, with additional searches conducted in MEDLINE, Embase, PsycINFO, CINAHL, LILACS, Web of Science Core Collection, ClinicalTrials.gov and the World Health Organization Portal/ICTRP on 12 December 2015. There were no language or date restrictions applied to the electronic searches, and no methodological filters were used to restrict the search. We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) provided they compared withdrawal of antihypertensive medications with continuation of the medications and included an outcome measure assessing cognitive function or a clinical diagnosis of dementia. We included studies with healthy participants, but we also included studies with participants with all grades of severity of existing dementia or cognitive impairment. Two review authors examined titles and abstracts of citations identified by the search for eligibility, retrieving full texts where needed to identify studies for inclusion, with any disagreement resolved by involvement of a third author. Data were extracted independently on primary and secondary outcomes. We used standard methodological procedures expected by Cochrane.The primary outcome measures of interest were changes in global and specific cognitive function and incidence of dementia; secondary outcomes included change in systolic and diastolic blood pressure, mortality, adverse events (including cardiovascular events, hospitalisation and falls) and adherence to withdrawal. The quality of the evidence was evaluated using the GRADE approach. We included two RCTs investigating withdrawal of antihypertensives in 2490 participants. There was substantial clinical heterogeneity between the included studies, therefore we did not combine data for our primary outcome. Overall, the quality of included studies was high and the risk of bias was low. Neither study investigated incident dementia.One study assessed withholding previously prescribed antihypertensive drugs for seven days following acute stroke. Cognition was assessed using telephone Mini-Mental State Examination (t-MMSE) and Telephone Interview for Cognitive Status (TICS-M) at 90 days as a secondary outcome. The t-MMSE score was a mean of 1.0 point higher in participants who withdrew antihypertensive medications compared to participants who continued them (95% confidence interval (CI) 0.35 to 1.65; 1784 participants) and the TICS-M was a mean of 2.10 points higher (95% CI 0.69 to 3.51; 1784 participants). However, in both cases the evidence was of very low quality downgraded due to risk of bias, indirectness and evidence from a single study. The other study was community based and included participants with mild cognitive impairment. Drug withdrawal was for 16 weeks. Cognitive performance was assessed using a composite of at least five out of six cognitive tests. There was no evidence of a difference comparing participants who withdrew antihypertensive medications and participants who continued (mean difference 0.02 points, 95% CI -0.19 to 0.21; 351 participants). This evidence was of low quality and was downgraded due to risk of bias and evidence from single study.In one study, the systolic blood pressure after seven days of withdrawal was 9.5 mmHg higher in the intervention compared to the control group (95% CI 7.43 to 11.57; 2095 participants) and diastolic blood pressure was 5.1 mmHg higher (95% CI 3.86 to 6.34; 2095 participants). This evidence was low quality, downgraded due to indirectness, because the data must be interpreted in the context of the wider study looking at glyceryl trinitrate administration or not, and evidence from a single study. In the other study, systolic blood pressure increased by 7.4 mmHg in the withdrawal group compared to the control group (95% CI 7.08 to 7.72; 356 participants) and diastolic blood pressure increased by 2.6 mmHg (95% CI 2.42 to 2.78; 356 participants). This was moderate quality evidence, downgraded as evidence was from a single study. We combined data for mortality an

Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial

Summary: Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more eff ective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more eff ective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and effi cacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m², l-folinic acid 175 mg, fl uorouracil 400 mg/m² bolus, then 2400 mg/m² by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the fi rst 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratifi cation variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no signifi cant diff erences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confi rmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in signifi cant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [ four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate

Response of glutathione S-transferase Pi (GSTP1) to neoadjuvant therapy in rectal adenocarcinoma

The response of rectal adenocarcinoma to neoadjuvant therapy is variable. Accurate prediction of response would enable selective administration of therapy. The enzyme glutathione S-transferase Pi (GSTP1) has been shown to influence response to therapy in some solid tumours. Few data are available for rectal cancer.The GSTP1 levels in rectal adenocarcinoma and adjacent normal mucosa were quantified before and after exposure to neoadjuvant therapy. Venous blood samples and biopsies of normal rectal mucosa and tumour were prospectively obtained from patients with primary rectal cancer. Patients were stratified by exposure to neoadjuvant therapy or surgery alone. GSTP1 was quantitatively measured using an enzyme-linked immunosorbent assay.Ninety-two patients (54 men; median age 68 years) were recruited. The median GSTP1 level was significantly higher in rectal adenocarcinoma than in matched normal mucosa [6.59 μg/mg vs 4.57 μg/mg; P < 0.001]. The median tumour GSTP1 level was significantly lower in the therapy group compared with unmatched samples from the no-therapy group [4.47 μg/mg vs 7.76 μg/mg; P < 0.001].The GSTP1 level is increased in rectal adenocarcinoma compared with adjacent normal mucosa. It decreases following neoadjuvant therapy. Future studies correlating pre-therapy GSTP1 levels with pathological response would be of interest