Jasper J. Brugts

The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials

Objectives To investigate whether statins reduce all cause mortality and major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in men and women, in young and older (>65 years) people, and in people with diabetes mellitus. Design Meta-analysis of randomised trials. Data sources Cochrane controlled trials register, Embase, and Medline. Data abstraction Two independent investigators identified studies on the clinical effects of statins compared with a placebo or control group and with follow-up of at least one year, at least 80% or more participants without established cardiovascular disease, and outcome data on mortality and major cardiovascular disease events. Heterogeneity was assessed using the Q and I2 statistics. Publication bias was assessed by visual examination of funnel plots and the Egger regression test. Results 10 trials enrolled a total of 70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus. Mean follow-up was 4.1 years. Treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to0.81), and major cerebrovascular events (0.81, 0.71 to 0.93). No evidence of an increased risk of cancer was observed. There was no significant heterogeneity of the treatment effect in clinical subgroups. Conclusion In patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.

Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin–angiotensin–aldosterone system inhibitors involving 158 998 patients

Aims Renin–angiotensin–aldosterone system (RAAS) inhibitors are well established for the reduction in cardiovascular morbidity, but their impact on all-cause mortality in hypertensive patients is uncertain. Our objective was to analyse the effects of RAAS inhibitors as a class of drugs, as well as of angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) separately, on all-cause mortality. Methods and results We performed a pooled analysis of 20 cardiovascular morbidity–mortality trials. In each trial at least two-thirds of the patients had to be diagnosed with hypertension, according to the trial-specific definition, and randomized to treatment with an RAAS inhibitor or control treatment. The cohort included 158 998 patients (71 401 RAAS inhibitor; 87 597 control). The incidence of all-cause death was 20.9 and 23.3 per 1000 patient-years in patients randomized to RAAS inhibition and controls, respectively. Overall, RAAS inhibition was associated with a 5% reduction in all-cause mortality (HR: 0.95, 95% CI: 0.91–1.00, P= 0.032), and a 7% reduction in cardiovascular mortality (HR: 0.93, 95% CI: 0.88–0.99, P= 0.018). The observed treatment effect resulted entirely from the class of ACE inhibitors, which were associated with a significant 10% reduction in all-cause mortality (HR: 0.90, 95% CI: 0.84–0.97, P= 0.004), whereas no mortality reduction could be demonstrated with ARB treatment (HR: 0.99, 95% CI: 0.94–1.04, P= 0.683). This difference in treatment effect between ACE inhibitors and ARBs on all-cause mortality was statistically significant (P-value for heterogeneity 0.036). Conclusion In patients with hypertension, treatment with an ACE inhibitor results in a significant further reduction in all-cause mortality. Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result in an important gain in lives saved.

Comparative Tolerability and Harms of Individual Statins A Study-Level Network Meta-Analysis of 246 955 Participants From 135 Randomized, Controlled Trials

Background—Our objective was to estimate the comparative harms of individual statins using both placebo-controlled and active-comparator trials. Methods and Results—We systematically reviewed randomized trials evaluating different statins in participants with and without cardiovascular disease. We performed random-effects pairwise and network meta-analyses to quantify the relative harms of individual statins. We included 55 two-armed placebo-controlled and 80 two- or multiarmed active-comparator trials including 246 955 individuals. According to pairwise meta-analyses, individual statins were not different than control in terms of myalgia, creatine kinase elevation, cancer, and discontinuations because of adverse events. Statins as a class resulted in significantly higher odds of diabetes mellitus (odds ratio, 1.09; 95% confidence interval, 1.02–1.16) and transaminase elevations (odds ratio, 1.51; 95% confidence interval, 1.24–1.84) compared with control. When individual statins were compared in network meta-analyses, there were numerous statistically detectable differences, favoring simvastatin and pravastatin. According to dose-level comparisons, individual statins resulted in higher odds of discontinuations with higher doses of atorvastatin and rosuvastatin. Similarly, higher doses of atorvasatin, fluvastatin, lovastatin, and simvastatin were associated with higher odds of transaminase elevations. Simvastatin at its highest doses was associated with creatine kinase elevations (odds ratio, 4.14; 95% credible interval, 1.08–16.24). Meta-regression analyses adjusting for study-level age at baseline, low-density lipoprotein cholesterol level, and publication year did not explain heterogeneity. There was no detectable inconsistency in the network. Conclusions—As a class, adverse events associated with statin therapy are not common. Statins are not associated with cancer risk but do result in a higher odds of diabetes mellitus. Among individual statins, simvastatin and pravastatin seem safer and more tolerable than other statins.

Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials.

Background The extent to which individual statins vary in terms of clinical outcomes across all populations, in addition to secondary and primary prevention has not been studied extensively in meta-analyses. Methods We systematically studied 199,721 participants in 92 placebo-controlled and active-comparator trials comparing atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin in participants with, or at risk of developing, cardiovascular disease. We performed pairwise and network meta-analyses for major coronary events and all-cause mortality outcomes, taking into account the dose differences across trials. Systematic review registration: PROSPERO 2011:CRD42011001470. Results There were only a few trials that evaluated fluvastatin. Most frequent comparisons occurred between pravastatin and placebo, atorvastatin and placebo, and rosuvastatin and atorvastatin. No trial directly compared all six statins to each other. Across all populations, statins were significantly more effective than control in reducing all-cause mortality (OR 0.87, 95% credible interval 0.82–0.92) and major coronary events (OR 0.69, 95% CI 0.64–0.75). In terms of reducing major coronary events, atorvastatin (OR 0.66, 95% CI 0.48–0.94) and fluvastatin (OR 0.59, 95% CI 0.36–0.95) were significantly more effective than rosuvastatin at comparable doses. In participants with cardiovascular disease, statins significantly reduced deaths (OR 0.82, 95% CI 0.75–0.90) and major coronary events (OR 0.69, 95% CI 0.62–0.77). Atorvastatin was significantly more effective than pravastatin (OR 0.65, 95% CI 0.43–0.99) and simvastatin (OR 0.68, 95% CI 0.38–0.98) for secondary prevention of major coronary events. In primary prevention, statins significantly reduced deaths (OR 0.91, 95% CI 0.83–0.99) and major coronary events (OR 0.69, 95% CI 0.61–0.79) with no differences among individual statins. Across all populations, atorvastatin (80%), fluvastatin (79%), and simvastatin (62%) had the highest overall probability of being the best treatment in terms of both outcomes. Higher doses of atorvastatin and fluvastatin had the highest number of significant differences in preventing major coronary events compared with other statins. No significant heterogeneity or inconsistency was detected. Conclusions Statins significantly reduce the incidence of all-cause mortality and major coronary events as compared to control in both secondary and primary prevention. This analysis provides evidence for potential differences between individual statins, which are not fully explained by their low-density lipoprotein cholesterol-reducing effects. The observed differences between statins should be investigated in future prospective studies.

The Microcirculation in Health and Critical Disease

The microcirculation is a complex system, which regulates the balance between oxygen demand and supply of parenchymal cells. In addition, the peripheral microcirculation has an important role in regulating the hemodynamics of the human body because it warrants arterial blood pressure as well as venous return to the heart. Novel techniques have made it possible that the microcirculation can be observed directly at the bedside in patients. Currently, research using these new techniques is focusing at the central role of the microcirculation in critical diseases. Experimental studies have demonstrated differences in microvascular alterations between models of septic and hypovolemic shock. In human studies, the microcirculation has most extensively been investigated in septic syndromes and has revealed highly heterogeneous alterations with clear evidence of arteriolar-venular shunting. Until now, the microcirculation in acute heart failure syndromes such as cardiogenic shock has scarcely been investigated. This review concerns the physiologic properties of the microcirculation as well as its role in pathophysiologic states such as sepsis, hypovolemic shock, and acute heart failure.

Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease

AIMS The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic profile to predict the treatment benefit of ACE-inhibitors exist and to optimize therapy with ACE-inhibitors. METHODS AND RESULTS In 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5% of the patients [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5% (HR 1.26; 95% CI 0.97-1.67) with a trend towards a harmful effect. In 1051 patients with cerebrovascular disease from the PROGRESS-trial, treated with perindopril or placebo, an interaction effect of similar direction and magnitude, although not statistically significant, was observed. CONCLUSION The current study is the first to identify genetic determinants of treatment benefit of ACE-inhibitor therapy. We developed a genetic profile which predicts the treatment benefit of ACE-inhibitors and which could be used to optimize therapy.

Impaired sublingual microvascular perfusion during surgery with cardiopulmonary bypass: a pilot study.

OBJECTIVE Complications after cardiac surgery may involve multiple organ failure, which carries a high mortality. Development of multiple organ failure may be related to impaired microcirculatory perfusion as a result of systemic inflammation. Microcirculatory blood flow alterations have been associated with impaired outcome. We investigated whether these alterations occurred before, during, and after coronary artery bypass grafting. METHODS We observed 25 consecutive patients who underwent elective coronary artery bypass grafting with cardiopulmonary bypass. The sublingual microcirculation was investigated using side-stream dark-field imaging. Side-stream dark-field imaging was performed before (baseline), during, and after surgery. Microvascular blood flow was estimated with a semiquantitative microvascular flow index in small, medium, and large microvessels. Changes in microvascular flow were tested with Wilcoxon signed rank test. RESULTS Median microvascular flow index of medium blood vessels decreased after starting cardiopulmonary bypass relative to that after anesthetic induction (2.6, interquartile range 1.6-3.0, vs 3.0, interquartile range 2.8-3.0, P = .02). There was a trend toward decreased microvascular flow index of small and large vessels relative to baseline (P = .08 and P = .05, respectively). Decreases in microvascular flow index occurred irrespective of changes in systemic blood pressure. After each patients return to the intensive care unit, microvascular flow index increased and normalized in all microvessels. CONCLUSION For the first time, sublingual microvascular blood flow alterations have been observed during cardiopulmonary bypass-assisted coronary artery bypass grafting.

Low-dose nitroglycerin improves microcirculation in hospitalized patients with acute heart failure

Impaired tissue perfusion is often observed in patients with acute heart failure. We tested whether low‐dose nitroglycerin (NTG) improves microcirculatory perfusion in patients admitted for acute heart failure.

Dose-comparative effects of different statins on serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized controlled trials

Aims The extent to which individual statins vary in terms of their impact on serum lipid levels has been studied mainly on the basis of placebo-controlled trials. Our objective was to review and quantify the dose-comparative effects of different statins on serum lipid levels using both placebo- and active-comparator trials. Methods We systematically reviewed randomized trials evaluating different statins in participants with, or at risk of developing, cardiovascular disease. We performed random-effects Bayesian network meta-analyses to quantify the the relative potency of individual statins across all possible dose combinations using both direct and indirect evidence. Dose-comparative effects were determined by estimating the mean change from baseline in serum lipids as compared to control treatment. (systematic review registration: PROSPERO 2011:CRD42011001470). Results We included 181 placebo-controlled and active-comparator trials including 256,827 individuals. There were 83 two-armed placebo-controlled trials and the remaining 98 were two- or multi-armed active-comparator trials. All statins reduced serum LDL and total cholesterol levels: higher doses resulted in higher reductions in pretreatment LDL and total cholesterol concentrations. In absolute terms, all statins significantly reduced LDL cholesterol levels as compared to control treatment from average baseline levels of approximately 150 mg/dl, except for fluvastatin at ≤20 mg/day and lovastatin at ≤10 mg/day. Atorvastatin, rosuvastatin, and simvastatin were broadly equivalent in terms of their LDL cholesterol-lowering effects. Dose-comparative effects of indivudual statins were not different between those with and without coronary heart disease at baseline. According to meta-regression analyses, LDL cholesterol-lowering effects of individual statins were not impacted by differences across trials in terms of baseline mean age and proportion of women as trial participants. Pretreatment LDL cholesterol concentrations had a marginally statistically significant effect on LDL cholesterol change from baseline. Mean differences from baseline in HDL cholesterol as compared to control treatment was not significant for any statin-dose combination. Conclusions The findings of this comprehensive review provide supporting evidence for the dose–response relationship of statins in reducing LDL and total cholesterol. The LDL cholesterol-reducing effects of some statins appear less pronounced than the findings of previous meta-analyses, which is particularly the case for the high-dose formulations of atorvastatin and rosuvastatin. The most consistent evidence for a combined reduction in both LDL and total cholesterol was achieved with atorvastatin at >40 mg/day, rosuvastatin at >10 mg/day, and simvastatin at >40 mg/day, which appear equivalent in terms of their LDL and total cholesterol-reducing effects.

The Effects of Intra-Aortic Balloon Pump Support on Macrocirculation and Tissue Microcirculation in Patients with Cardiogenic Shock

Objectives: It was the aim of this study to evaluate the effects of intra-aortic balloon pump (IABP) counterpulsation on sublingual microcirculation as a model for tissue perfusion. Methods: In 13 patients with cardiogenic shock treated with IABP, the IABP assist ratio was reduced from 1:1 to 1:8 for 15 min. Using sidestream dark field imaging, 117 movie files of the sublingual microcirculation were obtained and quantified at different IABP assist ratios at 3 time points: 1:1 (T0), 1:8 (T1) and 1:1 (T2), respectively. Data are presented as the median and interquartile range. Results: The median age of the patients was 59 years (range 56–73), and 62% were males. Discontinuation of IABP decreased the mean arterial pressure [75 mm Hg (71–84) at T0 vs. 69 mm Hg (64–79) at T1; p < 0.001], cardiac index [2.9 l/min/m2 (1.6–3.3) at T0 vs. 2.4 l/min/m2 (1.5–2.8) at T1; p = 0.005] and cardiac power index [0.46 W/m2 (0.29–0.59) at T0 vs. 0.36 W/m2 (0.24–0.50) at T1; p = 0.006]. However, these modest changes in macrohemodynamics did not significantly influence sublingual perfused capillary density and capillary red blood cell velocity (p = 0.28 and 0.73, respectively). Conclusion: A temporary, modest decrease in microcirculatory driving force, induced by lowering the IABP assist ratio, does not impair sublingual microcirculatory perfusion as measured by a novel 2-dimensional imaging technique.