Prediction of stroke using an algorithm to estimate arterial stiffness.

BACKGROUND: Arterial stiffness is important because it is associated with adverse cardiovascular events including stroke. Methods that are based on pulse wave velocity have significant limitations in estimating arterial stiffness. The purpose of this paper is to present a novel easy to apply non-invasive method to estimate arterial stiffness that is based on pulse pressure. METHODS: Two indices to estimate arterial stiffness, (1) arterial stiffness 1 (AS1) and (2) arterial stiffness 2 (AS2) were developed and applied in two National Institutes of Health funded clinical trials, the Systolic Hypertension in the Elderly Program and the Systolic Blood Pressure Intervention Trial. These indices were developed by fitting individual survival models for selected predictor variables to the response, i.e. time to stroke, by selecting the coefficients that were statistically significant at the 0.05 α level after adjusting the variable weights. The indices were derived as the weighted linear combination of the coefficients. RESULTS: AS1 and AS2 performed well in two goodness of fit criteria i.e. overall model p-value and concordance correlation. Comparison of Cox models using indices AS1 and AS2 and chronological age indicated that AS1 and AS2 independently predicted the occurrence of stroke at five years better than chronological age. Nearly identical effects were observed when the analyses were limited to Black participants in SPRINT with a concordance correlation of 0.80 and log rank test p-value of 0.007. CONCLUSION: These indices that are derived from pulse pressure predict the occurrence of stroke better than either pulse pressure or chronological age alone and may be used in designing new randomized clinical trials, and possibly incorporated in hypertension and stroke guidelines.

Monotherapy treatment with chlorthalidone or amlodipine in the systolic blood pressure intervention trial (SPRINT).

This post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) examined the performance of chlorthalidone (C) versus amlodipine (A) monotherapies. ANOVA was used to analyze the differences in systolic blood pressure (SBP) response between C and A. Logistic regression was used to examine monotherapy failure (adding a second antihypertensive agent or switching to a different antihypertensive agent) rates. Four hundred ninety-one participants were treated with C monotherapy (n = 210, mean dose = 22 mg/day) or A monotherapy (n = 281, mean dose = 7 mg/day). There was a significant difference in mean SBP reduction between the C and A monotherapies at the third visit (higher reduction with A, adjusted p = .018). Unadjusted analysis showed a higher failure with C in the standard treatment group. Although the average SBP at failure was higher and above the 140 mm Hg cutoff that indicated monotherapy failure with A (142.60) compared with C (138.40), more participants on C failed despite having SBP below the 140 cutoff. This was probably due to decisions made by the investigative teams to change the antihypertensive regimen, because, in their opinion, the clinical picture required it. After adjusting for baseline characteristics, C had higher failure than A only in the standard treatment group (1.64 odds ratio [OR], 95% CI 1.06-2.56, p = .028). A sub-analysis including participants who had never used antihypertensive treatment before randomization had similar results (2.57 OR, 95% CI 1.34-5.02, p = .004). Overall, in SPRINT chlorthalidone was associated with higher monotherapy failure than amlodipine in the standard treatment group because of decisions of the investigative teams.

Limitations of Randomized Clinical Trials.

Randomized clinical trials are essential for determining the efficacy of interventions, but have limitations. The types of limitations discussed in this review may be grouped in 11 categories including incorrect statistical inference, low internal or external validity, misinterpretation of the difference between frequentist and Bayesian statistical approaches, publication bias, that healthy persons with a given condition participate in clinical trials although they are not representative of the population as a whole, the rather short duration (3 to 5 years) that does not give correct estimates of the lifetime effects of the interventions or the legacy effect when participants who receive active therapy derive residual benefit after the end of the study when all participants receive active medication and the tension between the generalizability of the evidence versus the reliability of the findings of different types of clinical trials and the difficulty in applying the findings of randomized clinical trials to individual patients. These limitations are described and illustrated by examples and figures from the literature. In conclusion, this review will be useful to clinical trialists, clinical trial participants and regulatory agents.

Use of advanced statistical techniques to predict all-cause mortality in the Systolic Blood Pressure Intervention Trial.

BACKGROUND: The Systolic Blood Pressure Intervention Trial (SPRINT) was conducted in patients with hypertension and additional risk for cardiovascular disease who were randomized to the intensive blood pressure group targeting systolic blood pressure (SBP) less than 120 mm Hg and to the standard group where the target was less than 140 mm Hg. Analyses were done in the matched group of participants with the same gender, same age (±2 years) and same SBP (±3 mm Hg) at three months of treatment regardless of initial randomization to intensive or standard group (shaded area in Figure 1). METHODS AND RESULTS: During 3.26 years of follow-up, intensive group participants had 14.8 mm Hg lower SBP and received on average one more (2.8 vs. 1.8) blood pressure lowering medications. This was associated with lower all-cause mortality in the intensive treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90, p = 0.003). The effect on SBP was achieved at 3 months and remained unchanged thereafter. This paper addresses two questions with respect to all-cause mortality in SPRINT in the matched set. 1) What is the effect of receiving more than one drug on all-cause mortality. Conditional logistic regression for all-cause mortality with respect to number of drugs indicated that during the 3.26 years of follow-up persons who received more than one drug were more likely to die (coefficient = 0.5039, OR = 1.6552, p = 0.0322) than patients who received one drug. 2) Was there a U curve relationship between on treatment SBP and all-cause mortality? A U curve fitting a quadratic equation (parabola) of SBP and all-cause death was observed. This was seen in the patients randomized to the standard target group in unadjusted analyses as well as in analyses adjusted for demographics or all covariates (p < 0.001 for all). The U curves in the combined group and the intensive treatment group were less pronounced. CONCLUSION: SPRINT participants who were matched for gender, age, and SBP at 3 months, and received more than one drug had higher all-cause mortality during the 3.26 years of follow-up. Those who were randomized to standard treatment target had a U curve relationship between SBP at three months and all-cause mortality. The U curves in the combined group and the intensive treatment group were less pronounced.

Effect of cholesterol lowering with statins or proprotein convertase subtilisin/kexin type 9 antibodies on cataracts: A meta-analysis.

BACKGROUND: It is not known whether statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies are associated with cataract and whether very low achieved low-density lipoprotein cholesterol (LDL-C) lowering may cause cataract. OBJECTIVE: To examine two questions: whether statins and/or PCSK9 antibodies cause or prevent cataracts and whether very low LDL-C is associated with increased risk of cataract. METHODS: Systematic searches of PubMed, ClinicalTrials.gov, Web of Science, The Cochrane Library, and an Federal Drug Administration report were used to perform random effects meta-analyses on the relationship of statins and/or PCSK9 antibodies with cataract. These meta-analyses were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: Prespecified analyses indicated no significant effect of statins or PCSK9 antibodies (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.83-1.17, P = .8889) or differences between the effects of statins (OR 0.89, 95% CI 0.66-1.19, P = .4349) and PCSK9 antibodies (OR 1.04, 95% CI 0.85-1.28, P = .7042) on the development of cataract. Also, there was no significant effect of LDL-C lowering to different levels with respect to cataract (OR 1.06, 95% CI 0.92-1.22, P = .4317). Meta-regression of the log OR for cataract vs LDL-C during treatment did not show a statistically significant relationship (P for slope = .3972). CONCLUSION: There was no significant effect of cholesterol lowering with statins or PCSK9 antibodies or differences between these two medication classes in causing or preventing cataracts. However, it is difficult to make definitive statements regarding PCSK9 antibodies because there is no long-term experience with these agents. Very low LDL-C was not associated with higher risk of cataract.

Statins and Cataracts--a visual insight.

Cataract is the leading cause of visual impairment, other than uncorrected refractive errors, and the number one cause of preventable blindness worldwide. Common adverse events of statins include statin-related muscle toxicity, elevation of transaminases, diabetes, and possible association with cancer. Publications on the relationship of cataract to statins have reported inconsistent findings. A meta-analysis indicated a 19 % decrease in cataract among statin users. The pleiotropic effects of statins including effects on inflammation and oxidation may mediate a decrease in the rate of cataract formation. On the other hand, bidirectional effects of statins on oxidation and inhibition of appropriate lens epithelial cell development may promote cataractogenesis. Younger age and longer duration of statin therapy was associated with greater benefit while a benefit was not observed among older persons. A definitive way to settle the issue of the relationship of statins to cataract is to perform a randomized clinical trial or include cataract as an end point in epidemiologic studies. An increased risk of cataract may be balanced by the marked benefits of statins for those at high risk for cardiovascular events, while a decreased risk may help increase adherence to statin therapy.

The effect of statins on erectile dysfunction: a meta-analysis of randomized trials.

INTRODUCTION: Erectile dysfunction (ED) is common in older men, especially those with comorbidities such as diabetes and atherosclerotic disease, conditions where statins are frequently prescribed. AIM: To examine the effect of statin therapy on ED using the five-item version of the International Inventory of Erectile Function (IIEF). METHODS: We performed a random-effects meta-analysis of studies identified by a systematic search of MEDLINE, Web of Knowledge, the Cochrane Database, and ClinicalTrials.gov. Examination of the 186 retrieved citations resulted in the selection of 11 randomized trials for inclusion in the meta-analysis. MAIN OUTCOME MEASURES: Change in the IIEF score. RESULTS: IIEF increased by 3.4 points (95% CI 1.7-5.0, P = 0.0001) with statins compared to control. This effect remained statistically significant after multiple sensitivity analyses, including analysis for publication bias, a cumulative meta-analysis, and 11 repeated analyses with each study omitted sequentially. The increase in IIEF with statins was approximately one-third to one-half of that previously reported with phosphodiesterase-5 inhibitors and larger than the effect of lifestyle modification. Metaregression showed an increase in benefit with decreasing lipophilicity. The average age of participants and the degree of LDL cholesterol lowering did not alter the effect on IIEF. CONCLUSION: Statins cause a clinically relevant improvement of erectile function as measured by the five-item version of the IIEF.

Prevention of cataracts by statins: a meta-analysis.

BACKGROUND: Current data indicate a persisting concern about possible cataractogenecity of statins. OBJECTIVE: To perform a meta-analysis of studies pertaining to statins and cataract. METHODS: We identified 363 records by a systematic search of the MedLine, Web of Knowledge, Cochrane database, and ClinicalTrials.gov. After exclusion of duplicates, studies without cataract as an outcome, reviews, and animal or basic science studies, we analyzed 14 studies. Two end points were examined: clinical cataract (requiring extraction or reported by the patient) and lens opacities discovered by slit-lamp examination. RESULTS: Using random effects meta-analysis, a statistically significant decrease in cataracts with statins was observed among studies examining clinical cataract (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.71-0.93, P = .0022). Absolute risk reduction was 1.4% ± 0.015%, 95% CI 1.1%-1.7%, P < .0001, corresponding to 71, 95% CI 59-91, number needed to treat. The effect was larger for the harder end point of cataract extraction (OR 0.66, 95% CI 0.61-0.71, P < .0001). Metaregression indicated an increase in benefit with longer duration of statin use with OR varying from 0.54 for a treatment duration of 14 years to 0.95 for a treatment duration of 6 months. Older age was associated with lower benefit (OR 1.03 for persons in their 70s to OR 0.49 for persons in their 40s), and there were no differences by gender. Several sensitivity analyses confirmed the results. Limitations of this analysis include the combination of randomized and observational studies and imprecise ascertainment of exposure and incomplete adjustment for confounders in several observational studies. CONCLUSION: This meta-analysis indicates a clinically relevant protective effect of statins in preventing cataracts. The effect is more pronounced in younger patients and with longer duration of follow-up, while there is no difference by gender.

Meta-analysis of statin effects in women versus men.

OBJECTIVES: The aim of this study was to evaluate the effect of statins in decreasing cardiovascular events in women and men. BACKGROUND: Published data reviews have suggested that statins might not be as effective in women as in men in decreasing cardiovascular events. METHODS: Published data searches and contacts with investigators identified 18 randomized clinical trials of statins with sex-specific outcomes (N = 141,235, 40,275 women, 21,468 cardiovascular events). Odds ratios (ORs) and 95% confidence intervals (CIs) for cardiovascular events were calculated for women and men separately with random effects meta-analyses. RESULTS: The cardiovascular event rate was lower among those randomized to statin intervention than in those randomized to control (low-dose statin in 4 studies, placebo in 11 studies, usual care in 3 studies) and similar in women and men (OR: 0.81, 95% CI: 0.75 to 0.89; p < 0.0001, and OR: 0.77, 95% CI: 0.71 to 0.83, p < 0.0001, respectively). The benefit of statins was statistically significant in both sexes, regardless of the type of control, baseline risk, or type of endpoint and in both primary and secondary prevention. All-cause mortality was also lower with statin therapy both in women and men without significant interaction by sex (p for interaction = 0.4457). CONCLUSIONS: Statin therapy is associated with significant decreases in cardiovascular events and in all-cause mortality in women and men. Statin therapy should be used in appropriate patients without regard to sex.

Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid-lowering therapy.

BACKGROUND: Long-term follow-up of clinical trials with lipid-lowering medications has suggested a continuation of event reduction after study completion. OBJECTIVE: To evaluate the persistence of the benefit of lipid-lowering therapy in decreasing mortality after the end of clinical trials, when all patients were advised to take the same open-label lipid-lowering therapy. METHODS: Through searches of MEDLINE, the Cochrane Library, the Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov until June 2010 we identified randomized clinical trials of lipid-lowering agents with a second report describing results after the end of the trial. RESULTS: Among the 459 trials reviewed, only 8 including 44,255 patients and 8144 deaths qualified for the meta-analysis. All-cause and cardiovascular mortality were lower in the active intervention group during the first phase (0.84, 95% confidence interval [CI] 0.76-0.93; P = .0006 and 0.72, 95% CI 0.63-0.82, P < .0001, respectively) when 71 ± 23% of the patients randomized to receive active therapy actually received it compared with 13 ± 5% of patients who received active therapy although they were randomized to placebo (P = .0001). The lower mortality among those initially randomized to active therapy persisted during the second phase (odds ratio 0.90, 95% CI 0.84-0.97, P = .0035, and 0.82 95% CI 0.73-0.93, P = .0014), when patients in both randomized groups received active therapy in the same proportions (5 ± 2% for both groups). Numerous sensitivity analyses support the conclusions of the paper. CONCLUSION: The decrease in mortality with lipid-lowering therapy in clinical trials persists after discontinuation of randomized therapy when patients in the treatment and placebo groups receive active therapy.