Robin Prescott

Prospective Study of Heart Rate Variability and Mortality in Chronic Heart Failure Results of the United Kingdom Heart Failure Evaluation and Assessment of Risk Trial (UK-Heart)

BACKGROUND Patients with chronic heart failure (CHF) have a continuing high mortality. Autonomic dysfunction may play an important role in the pathophysiology of cardiac death in CHF. UK-HEART examined the value of heart rate variability (HRV) measures as independent predictors of death in CHF. METHODS AND RESULTS In a prospective study powered for mortality, we recruited 433 outpatients 62+/-9.6 years old with CHF (NYHA functional class I to III; mean ejection fraction, 0.41+/-0.17). Time-domain HRV indices and conventional prognostic indicators were related to death by multivariate analysis. During 482+/-161 days of follow-up, cardiothoracic ratio, SDNN, left ventricular end-systolic diameter, and serum sodium were significant predictors of all-cause mortality. The risk ratio for a 41.2-ms decrease in SDNN was 1.62 (95% CI, 1.16 to 2.44). The annual mortality rate for the study population in SDNN subgroups was 5.5% for >100 ms, 12.7% for 50 to 100 ms, and 51.4% for <50 ms. SDNN, creatinine, and serum sodium were related to progressive heart failure death. Cardiothoracic ratio, left ventricular end-diastolic diameter, the presence of nonsustained ventricular tachycardia, and serum potassium were related to sudden cardiac death. A reduction in SDNN was the most powerful predictor of the risk of death due to progressive heart failure. CONCLUSIONS CHF is associated with autonomic dysfunction, which can be quantified by measuring HRV. A reduction in SDNN identifies patients at high risk of death and is a better predictor of death due to progressive heart failure than other conventional clinical measurements. High-risk subgroups identified by this measurement are candidates for additional therapy after prescription of an ACE inhibitor.

Barriers to Participation in Randomised Controlled Trials: A Systematic Review

METHOD A systematic review of three bibliographic databases from 1986 to 1996 identified 78 papers reporting barriers to recruitment of clinicians and patients to randomised controlled trials. RESULTS Clinician barriers included: time constraints, lack of staff and training, worry about the impact on the doctor-patient relationship, concern for patients, loss of professional autonomy, difficulty with the consent procedure, lack of rewards and recognition, and an insufficiently interesting question. Patient barriers included: additional demands of the trial, patient preferences, worry caused by uncertainty, and concerns about information and consent. CONCLUSIONS To overcome barriers to clinician recruitment, the trial should address an important research question and the protocol and data collection should be as straightforward as possible. The demands on clinicians and patients should be kept to a minimum. Dedicated research staff may be required to support clinical staff and patients. The recruitment aspects of a randomised controlled trial should be carefully planned and piloted. Further work is needed to quantify the extent of problems associated with clinician and patient participation, and proper evaluation is required of strategies to overcome barriers.

The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease

Objective To determine whether aspirin and antioxidant therapy, combined or alone, are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease. Design Multicentre, randomised, double blind, 2×2 factorial, placebo controlled trial. Setting 16 hospital centres in Scotland, supported by 188 primary care groups. Participants 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease. Interventions Daily, 100 mg aspirin tablet plus antioxidant capsule (n=320), aspirin tablet plus placebo capsule (n=318), placebo tablet plus antioxidant capsule (n=320), or placebo tablet plus placebo capsule (n=318). Main outcome measures Two hierarchical composite primary end points of death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or amputation above the ankle for critical limb ischaemia; and death from coronary heart disease or stroke. Results No evidence was found of any interaction between aspirin and antioxidant. Overall, 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups (18.2% v 18.3%): hazard ratio 0.98 (95% confidence interval 0.76 to 1.26). Forty three deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups (6.7% v 5.5%): 1.23 (0.79 to 1.93). Among the antioxidant groups 117 of 640 (18.3%) primary events occurred compared with 116 of 636 (18.2%) in the no antioxidant groups (1.03, 0.79 to 1.33). Forty two (6.6%) deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 (5.7%) in the no antioxidant groups (1.21, 0.78 to 1.89). Conclusion This trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied. Trial registration Current Controlled Trials ISRCTN53295293.

CONTROLLED TRIAL OF SOTALOL FOR ONE YEAR AFTER MYOCARDIAL INFARCTION

In a multicentre double-blind randomised study, the effect of sotalol 320 mg once daily was compared with that of placebo in patients surviving an acute myocardial infarction. Treatment was started 5--14 days after infarction in 1456 patients (60% being randomised to sotalol, and 40% to placebo) who represented 45% of those evaluated for entry. Patients were followed for 12 months. The mortality rate was 7.3% (64 patients) in the sotalol group and 8.9% (52 patients) in the placebo group. The mortality was 18% lower in the sotalol than in the placebo group, but this difference was not statistically significant. The rate of definite myocardial reinfarction was 41% lower in the sotalol group than in the placebo group (p less than 0.05). Although the differences in mortality were not significant, this trial supports the evidence that, in the year after myocardial infarction, beta adrenoceptor blocking drugs reduce mortality by 20--25%.

Twelve-year comparison of a bjork-shiley mechanical heart valve with porcine bioprostheses

BACKGROUND Patients undergoing heart-valve replacement may receive a mechanical prosthesis, necessitating lifelong anticoagulant treatment, or a porcine bioprosthesis, which involves no absolute need for anticoagulants. METHODS We carried out a randomized, prospective trial to compare the durability of the Bjork-Shiley mechanical prosthesis (spherical tilting-disk model) and the incidence of valve-related complications with those variables in the Hancock and the Carpentier-Edwards porcine prostheses. The mitral valve was replaced in 261 patients, the aortic valve in 211, and both in 61; the survivors have been followed up for a mean of 12 years. RESULTS We found a trend toward improved actuarial survival after 12 years with the Bjork-Shiley prosthesis, but this trend was not statistically significant (group with Bjork-Shiley valve vs. group with porcine valve [mean +/- SE], 51.5 +/- 3.2 vs. 44.4 +/- 3.2 percent; P = 0.08). There was no significant difference in the actuarial incidence of reoperation after 5 years, but after 12 years significantly more patients with a porcine prosthesis had undergone reoperation (8.5 +/- 2.0 vs. 37.1 +/- 4.1 percent, P less than 0.001). An analysis combining death and reoperation as end points for an actuarial assessment of survival with the original prosthesis intact confirmed that the patients with Bjork-Shiley Shiley prostheses had improved survival (48.6 +/- 3.2 vs. 30.0 +/- 3.0 percent after 12 years, P less than 0.001). Bleeding requiring hospitalization or blood transfusion was significantly more frequent in the patients with Bjork-Shiley prostheses (18.6 +/- 3.2 vs. 7.1 +/- 2.3 percent after 12 years, P less than 0.01). There was no significant difference after 12 years in the actuarial occurrence of embolism (Bjork-Shiley vs. porcine, 21.1 +/- 3.1 vs. 26.4 +/- 3.5 percent) or endocarditis (3.7 +/- 1.4 vs 4.6 +/- 1.6 percent). CONCLUSIONS Survival with an intact valve is better among patients with the Bjork-Shiley spherical tilting-disk prosthesis than among patients with porcine bioprostheses, but use of the Bjork-Shiley valve carries an attendant increased risk of bleeding associated with the need for anticoagulant treatment.

Edinburgh trial of screening for breast cancer : mortality at seven years

Between 1979 and 1981, 45,130 women in Edinburgh aged 45-64 were entered into a randomised trial of breast cancer screening by mammography and clinical examination. The initial attendance rate was 61% but this varied according to age and socioeconomic status and decreased over succeeding years. The cancer detection rate was 6.2 per 1000 women attending at the first visit; the rate fell to around 3 per 1000 in the years when mammography was routinely repeated and to around 1 per 1000 at the intervening visits with clinical examination alone as the screening method. After 7 years of follow-up the mortality reduction achieved was 17% (relative risk = 0.83, 95% CI 0.58-1.18), which was not statistically significant, even when corrected for socioeconomic status. In women aged 50 years and over a mortality reduction of 20% was achieved.

The prevalence of diabetic impotence

SummaryIn a survey of 541 diabetic males, aged 20–59 years, 190 (35%) had erectile impotence. Using linear logistic regression models for analysis the five most significant associations with impotence were age (p<0.001), treatment with either insulin or oral hypoglycaemic agents (p<0.001), retinopathy (p<0.001), symptomatic peripheral neuropathy (p<0.001) and symptomatic autonomic neuropathy (p<0.005). The greatest correlations were found in patients with severe microangiopathy, as demonstrated by proliferative retinopathy and symptomatic autonomic neuropathy. In addition the duration of diabetes and the presence of ischaemic heart disease, nephropathy and poor diabetic control may also be associated with diabetic impotence. It is concluded that diabetic impotence is still a common problem and may have a multifactorial aetiology.

Breast-Conserving Surgery With or Without Radiotherapy: Pooled-Analysis for Risks of Ipsilateral Breast Tumor Recurrence and Mortality

In a recent article in the Journal, Vinh-Hung and Verschraegen (1) provided a valuable pooled analysis of randomized trials of postoperative radiotherapy after breast-conserving surgery. They reported a small increase in breast cancer mortality and a substantial risk of local recurrence from the omission of breast radiotherapy. These important observations should not be interpreted to imply that all patients require breast radiotherapy after breast-conserving surgery and appropriate systemic therapy. We believe, however, that in contrast to younger patients, there are insufficient data to draw this conclusion in older patients. Indeed, the U.S. National Institutes of Health, in its 2000 consensus statement for breast cancer (2), makes no specific recommendation on adjuvant therapy for patients aged 70 years or older because of the paucity of data for this group of patients. Of the 15 randomized trials assessing the role of breast radiotherapy or its omission included in the pooled analysis by VinhHung (1), only three (Uppsala-Orebro, Tokyo, and the Cancer and Leukemia Group B [CALGB]) included patients over age 70. In this older group of patients, there are competing risks of mortality from predominantly vascular comorbidity. In addition, a body of data from both randomized and nonrandomized trials suggests that the risks of local recurrence decrease with age (3). This observation reflects, in part, the increasing proportion of older patients with good prognostic characteristics. Large, adequately powered trials with older patients are needed to assess the role of breast radiotherapy in local recurrence and breast cancer mortality. The dramatic impact of the competing risks of non– breast cancer mortality in the elderly is shown in the CALGB 9343 trial (4), cited in table 1 of Vinh-Hung and Verschraegen (1), which randomly assigned patients with T1, node-negative, ER-positive tumors to breast radiotherapy or no further treatment after breast-conserving therapy and tamoxifen. Of the 39 deaths among the 647 patients in the trial, only one was due to breast cancer. Ongoing trials, such as the Postoperative Radiotherapy In Minimumrisk Elderly (PRIME) trial (5), are addressing issues of local control, morbidity, and quality of life in older, low-risk patients to establish a firm basis for the selection of patients for radiotherapy in this age group. We feel that until the results of randomized trials focused on evaluating breast radiotherapy in the elderly are available, the role of breast radiotherapy in this age group remains uncertain. For many such women, their informed recruitment into appropriately designed, randomized, controlled trials may be the most ethical way of determining treatment.

14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening

BACKGROUND The Edinburgh randomised trial of breast-cancer screening recruited women aged 45-64 years from 1978 to 1981 (cohort 1), and those aged 45-49 years during 1982-85 (cohorts 2 and 3). Results based on 14 years of follow-up and 270,000 woman-years of observation are reported. METHODS Breast-cancer mortality rates in the intervention group (28,628 women offered screening) were compared with those in the control group (26,026) with adjustment for socioeconomic status (SES) of general medical practices. Rate ratios were derived by means of logistic regression for the total trial population and for women first offered screening while younger than 50 years. Analyses were by intention to treat. FINDINGS Initial unadjusted results showed a difference of just 13% in breast-cancer mortality rates between the intervention and control groups (156 deaths [5.18 per 10,000] vs 167 [6.04 per 10,000]; rate ratio 0.87 [95% CI 0.70-1.06]), but the results were influenced by differences in SES by trial group. After adjustment for SES, the rate ratio was 0.79 (95% CI 0.60-1.02). When deaths after diagnosis more than 3 years after the end of the study were censored the rate ratio became 0.71 (0.53-0.95). There was no evidence of heterogeneity by age at entry and no evidence that younger entrants had smaller or delayed benefit (rate ratio 0.70 [0.41-1.20]). No breast-cancer mortality benefit was observed for women whose breast cancers were diagnosed when they were younger than 50 years. Other-cause mortality rates did not differ by trial group when adjusted for SES. INTERPRETATION Our findings confirm results from randomised trials in Sweden and the USA that screening for breast cancer lowers breast-cancer mortality. Similar results are reported by the UK geographical comparison, UK Trial of Early Detection of Breast Cancer. The results for younger women suggest benefit from introduction of screening before 50 years of age.

Does the storage time of transfused red blood cells influence regional or global indexes of tissue oxygenation in anemic critically ill patients

ObjectiveTo determine whether transfusion of red cells either ≤5 days or ≥20 days from donation alters tonometric indexes of gastric mucosal oxygenation or global oxygenation parameters in euvolemic anemic critically ill patients without ongoing hemorrhage. The a priori hypothesis was that stored red cells worsen gastric oxygenation. DesignProspective, double-blind, randomized study. SettingA 12-bed general medical/surgical intensive care unit in a Scottish teaching hospital. PatientsVentilated euvolemic anemic (mean ± sd hemoglobin, 85.8 ± 8.4 g/L) critically ill patients with significant organ failure, but no evidence of hemorrhage. InterventionsAfter baseline measurements, patients were randomized to receive two units of leukodepleted red cells that were either ≤5 days (ten patients) or ≥20 days (12 patients) after donation according to a standardized protocol. Measurements and Main ResultsChanges in gastric to arterial Pco2 gap (Pg-Paco2 gap), gastric intramucosal pH, arterial pH, arterial base excess, and arterial lactate concentrations were measured during baseline (2.5 hrs), during transfusion (3 hrs), and for 5 hrs after transfusion. Mean age of red cells stored ≤5 days was 2 days (first and third quartile, 2, 2.25; range, 2–3); red cells stored ≥20 days had a mean age of 28 days (first and third quartile, 27, 31; range, 22–32). Hemoglobin concentration increased by 15.0 g/L and 16.6 g/L, respectively, in the fresh and stored groups (p = .62). There were no significant differences between the groups either using treatment-by-time analysis or comparing the pre- and posttransfusion periods either for Pg-Paco2 gap (mean difference, 0.03 kPa; 95% confidence limits, −1.66, 1.72) or gastric intramucosal pH (mean difference, 0.015 pH units; 95% confidence limits, −0.054, 0.084). The mean change within each group from the pre- to posttransfusion period for Pg-Paco2 gap and gastric intramucosal pH, respectively, was 0.56 kPa (95% confidence limits, −0.68, 1.79) and −0.018 pH units (95% confidence limits, −0.069, 0.032) for “fresh” red cells and 0.52 kPa (95% confidence limits, −0.6, 1.64) and −0.033 pH units (95% confidence limits, −0.080, 0.129) for “stored” red cells. There was no statistically or clinically significant improvement in any other oxygenation index during the measurement period for either group compared to baseline values. ConclusionsTransfusion of stored leukodepleted red cells to euvolemic, anemic, critically ill patients has no clinically significant adverse effects on gastric tonometry or global indexes of tissue oxygenation. These findings do not support the use of fresh red cells in critically ill patients.