Beta-blockers for preventing aortic dissection in Marfan syndrome.

BACKGROUND: Marfan syndrome is a hereditary disorder affecting the connective tissue and is caused by a mutation of the fibrillin-1 (FBN1) gene. It affects multiple systems of the body, most notably the cardiovascular, ocular, skeletal, dural and pulmonary systems. Aortic root dilatation is the most frequent cardiovascular manifestation and its complications, including aortic regurgitation, dissection and rupture are the main cause of morbidity and mortality. OBJECTIVES: To assess the long-term efficacy and safety of beta-blocker therapy as compared to placebo, no treatment or surveillance only in people with Marfan syndrome. SEARCH METHODS: We searched the following databases on 28 June 2017; CENTRAL, MEDLINE, Embase, Science Citation Index Expanded and the Conference Proceeding Citation Index - Science in the Web of Science Core Collection. We also searched the Online Metabolic and Molecular Bases of Inherited Disease (OMMBID), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 June 2017. We did not impose any restriction on language of publication. SELECTION CRITERIA: All randomised controlled trials (RCTs) of at least one year in duration assessing the effects of beta-blocker monotherapy compared with placebo, no treatment or surveillance only, in people of all ages with a confirmed diagnosis of Marfan syndrome were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for inclusion, extracted data and assessed trial quality. Trial authors were contacted to obtain missing data. Dichotomous outcomes will be reported as relative risk and continuous outcomes as mean differences with 95% confidence intervals. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: One open-label, randomised, single-centre trial including 70 participants with Marfan syndrome (aged 12 to 50 years old) met the inclusion criteria. Participants were randomly assigned to propranolol (N = 32) or no treatment (N = 38) for an average duration of 9.3 years in the control group and 10.7 years in the treatment group. The initial dose of propranolol was 10 mg four times daily and the optimal dose was reached when the heart rate remained below 100 beats per minute during exercise or the systolic time interval increased by 30%. The mean (± standard error (SE)) optimal dose of propranolol was 212 ± 68 mg given in four divided doses daily.Beta-blocker therapy did not reduce the incidence of all-cause mortality (RR 0.24, 95% CI 0.01 to 4.75; participants = 70; low-quality evidence). Mortality attributed to Marfan syndrome was not reported. Non-fatal serious adverse events were also not reported. However, study authors report on pre-defined, non-fatal clinical endpoints, which include aortic dissection, aortic regurgitation, cardiovascular surgery and congestive heart failure. Their analysis showed no difference between the treatment and control groups in these outcomes (RR 0.79, 95% CI 0.37 to 1.69; participants = 70; low-quality evidence).Beta-blocker therapy did not reduce the incidence of aortic dissection (RR 0.59, 95% CI 0.12 to 3.03), aortic regurgitation (RR 1.19, 95% CI 0.18 to 7.96), congestive heart failure (RR 1.19, 95% CI 0.18 to 7.96) or cardiovascular surgery, (RR 0.59, 95% CI 0.12 to 3.03); participants = 70; low-quality evidence.The study reports a reduced rate of aortic dilatation measured by M-mode echocardiography in the treatment group (aortic ratio mean slope: 0.084 (control) vs 0.023 (treatment), P < 0.001). The change in systolic and diastolic blood pressure, total adverse events and withdrawal due to adverse events were not reported in the treatment or control group at study end point.We judged this study to be at high risk of selection (allocation concealment) bias, performance bias, detection bias, attrition bias and selective reporting bias. The overall quality of evidence was low. We do not know whether a statistically significant reduced rate of aortic dilatation translates into clinical benefit in terms of aortic dissection or mortality. AUTHORS' CONCLUSIONS: Based on only one, low-quality RCT comparing long-term propranolol to no treatment in people with Marfan syndrome, we could draw no definitive conclusions for clinical practice. High-quality, randomised trials are needed to evaluate the long-term efficacy of beta-blocker treatment in people with Marfan syndrome. Future trials should report on all clinically relevant end points and adverse events to evaluate benefit versus harm of therapy.

Blood pressure lowering efficacy of renin inhibitors for primary hypertension.

BACKGROUND: Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II. OBJECTIVES: To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension.To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema). SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension. DATA COLLECTION AND ANALYSIS: This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available.Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs. MAIN RESULTS: 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias.Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes.Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue. AUTHORS' CONCLUSIONS: Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.