Effect of atorvastatin on testosterone levels.

BACKGROUND: Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial. OBJECTIVES: Primary objective To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment. Secondary objectives To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work. SELECTION CRITERIA: RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs). We used a fixed-effect meta-analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years. We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD -0.20 nmol/L (95% CI -0.77 to 0.37). In females, atorvastatin may reduce total testosterone by -0.27 nmol/L (95% CI -0.50 to -0.04), FAI by -2.59 nmol/L (95% CI -3.62 to -1.57), androstenedione by -1.37 nmol/L (95% CI -2.26 to -0.49), and DHEAS by -0.63 µmol/l (95% CI -1.12 to -0.15). Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels. AUTHORS' CONCLUSIONS: We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.

Magnesium for skeletal muscle cramps.

BACKGROUND: Skeletal muscle cramps are common and often occur in association with pregnancy, advanced age, exercise or motor neuron disorders (such as amyotrophic lateral sclerosis). Typically, such cramps have no obvious underlying pathology, and so are termed idiopathic. Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this purpose remains unclear. This is an update of a Cochrane Review first published in 2012, and performed to identify and incorporate more recent studies. OBJECTIVES: To assess the effects of magnesium supplementation compared to no treatment, placebo control or other cramp therapies in people with skeletal muscle cramps.   SEARCH METHODS: On 9 September 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, CINAHL Plus, AMED, and SPORTDiscus. We also searched WHO-ICTRP and ClinicalTrials.gov for registered trials that might be ongoing or unpublished, and ISI Web of Science for studies citing the studies included in this review. SELECTION CRITERIA: Randomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp). We considered comparisons of magnesium with no treatment, placebo control, or other therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Two review authors assessed risk of bias. We attempted to contact all study authors when questions arose and obtained participant-level data for four of the included trials, one of which was unpublished. We collected all data on adverse effects from the included RCTs. MAIN RESULTS: We identified 11 trials (nine parallel-group, two cross-over) enrolling a total of 735 individuals, amongst whom 118 cross-over participants additionally served as their own controls. Five trials enrolled women with pregnancy-associated leg cramps (408 participants) and five trials enrolled people with idiopathic cramps (271 participants, with 118 additionally crossed over to control). Another study enrolled 29 people with liver cirrhosis, only some of whom suffered muscle cramps. All trials provided magnesium as an oral supplement, except for one trial which provided magnesium as a series of slow intravenous infusions. Nine trials compared magnesium to placebo, one trial compared magnesium to no treatment, calcium carbonate or vitamin B, and another trial compared magnesium to vitamin E or calcium. We judged the single trial in people with liver cirrhosis and all five trials in participants with pregnancy-associated leg cramps to be at high risk of bias. In contrast, we rated the risk of bias high in only one of five trials in participants with idiopathic rest cramps. For idiopathic cramps, largely in older adults (mean age 61.6 to 69.3 years) presumed to have nocturnal leg cramps (the commonest presentation), differences in measures of cramp frequency when comparing magnesium to placebo were small, not statistically significant, and showed minimal heterogeneity (I² = 0% to 12%). This includes the primary endpoint, percentage change from baseline in the number of cramps per week at four weeks (mean difference (MD) -9.59%, 95% confidence interval (CI) -23.14% to 3.97%; 3 studies, 177 participants; moderate-certainty evidence); and the difference in the number of cramps per week at four weeks (MD -0.18 cramps/week, 95% CI -0.84 to 0.49; 5 studies, 307 participants; moderate-certainty evidence). The percentage of individuals experiencing a 25% or better reduction in cramp rate from baseline was also no different (RR 1.04, 95% CI 0.84 to 1.29; 3 studies, 177 participants; high-certainty evidence). Similarly, no statistically significant difference was found at four weeks in measures of cramp intensity or cramp duration. This includes the number of participants rating their cramps as moderate or severe at four weeks (RR 1.33, 95% CI 0.81 to 2.21; 2 studies, 91 participants; moderate-certainty evidence); and the percentage of participants with the majority of cramp durations of one minute or more at four weeks (RR 1.83, 95% CI 0.74 to 4.53, 1 study, 46 participants; low-certainty evidence). We were unable to perform meta-analysis for trials of pregnancy-associated leg cramps. The single study comparing magnesium to no treatment failed to find statistically significant benefit on a three-point ordinal scale of overall treatment efficacy. Of the three trials comparing magnesium to placebo, one found no benefit on frequency or intensity measures, another found benefit for both, and a third reported inconsistent results for frequency that could not be reconciled. The single study in people with liver cirrhosis was small and had limited reporting of cramps, but found no difference in terms of cramp frequency or cramp intensity. Our analysis of adverse events pooled all studies, regardless of the setting in which cramps occurred. Major adverse events (occurring in 2 out of 72 magnesium recipients and 3 out of 68 placebo recipients), and withdrawals due to adverse events, were not significantly different from placebo. However, in the four studies for which it could be determined, more participants experienced minor adverse events in the magnesium group than in the placebo group (RR 1.51, 95% CI 0.98 to 2.33; 4 studies, 254 participants; low-certainty evidence). Overall, oral magnesium was associated with mostly gastrointestinal adverse events (e.g. diarrhoea), experienced by 11% (10% in control) to 37% (14% in control) of participants. AUTHORS' CONCLUSIONS: It is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this population is needed. We found no RCTs evaluating magnesium for exercise-associated muscle cramps or disease-state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease) other than a single small (inconclusive) study in people with liver cirrhosis, only some of whom suffered cramps.

Time course for blood pressure lowering of beta-blockers with partial agonist activity.

BACKGROUND: Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the day. This review focuses on the subclass of beta-blockers with partial agonist activity (BBPAA). OBJECTIVES: To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24-hour period in adults with essential hypertension. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We sought to include all randomised and non-randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow-up of three weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end-point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24-hour ambulatory BP monitoring (ABPM) device. MAIN RESULTS: Fourteen non-randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta-analysis. Beta-blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes. We analysed and presented data by each hour post-dose. Very low-certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24-hour period, the magnitude of SBP lowering at each hour ranged from -3.68 mmHg to -17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from -2.27 mmHg to -9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from -0.29 beats/min to -10.29 beats/min (4 studies, 71 participants). When comparing between three 8-hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low-certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion. AUTHORS' CONCLUSIONS: There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP-lowering efficacy of BBPAA over a 24-hour period, in adults with essential hypertension. Very low-certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.

Effect of alcohol on blood pressure.

BACKGROUND: Alcohol is consumed by over 2 billion people worldwide. It is a common substance of abuse and its use can lead to more than 200 disorders including hypertension. Alcohol has both acute and chronic effects on blood pressure. This review aimed to quantify the acute effects of different doses of alcohol over time on blood pressure and heart rate in an adult population. OBJECTIVES: Primary objective To determine short-term dose-related effects of alcohol versus placebo on systolic blood pressure and diastolic blood pressure in healthy and hypertensive adults over 18 years of age. Secondary objective To determine short-term dose-related effects of alcohol versus placebo on heart rate in healthy and hypertensive adults over 18 years of age. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2019: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 2), in the Cochrane Library; MEDLINE (from 1946); Embase (from 1974); the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant articles regarding further published and unpublished work. These searches had no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing effects of a single dose of alcohol versus placebo on blood pressure (BP) or heart rate (HR) in adults (≥ 18 years of age). DATA COLLECTION AND ANALYSIS: Two review authors (ST and CT) independently extracted data and assessed the quality of included studies. We also contacted trial authors for missing or unclear information. Mean difference (MD) from placebo with 95% confidence interval (CI) was the outcome measure, and a fixed-effect model was used to combine effect sizes across studies.  MAIN RESULTS: We included 32 RCTs involving 767 participants. Most of the study participants were male (N = 642) and were healthy. The mean age of participants was 33 years, and mean body weight was 78 kilograms. Low-dose alcohol (< 14 g) within six hours (2 RCTs, N = 28) did not affect BP but did increase HR by 5.1 bpm (95% CI 1.9 to 8.2) (moderate-certainty evidence). Medium-dose alcohol (14 to 28 g) within six hours (10 RCTs, N = 149) decreased systolic blood pressure (SBP) by 5.6 mmHg (95% CI -8.3 to -3.0) and diastolic blood pressure (DBP) by 4.0 mmHg (95% CI -6.0 to -2.0) and increased HR by 4.6 bpm (95% CI 3.1 to 6.1) (moderate-certainty evidence for all).  Medium-dose alcohol within 7 to 12 hours (4 RCTs, N = 54) did not affect BP or HR. Medium-dose alcohol > 13 hours after consumption (4 RCTs, N = 66) did not affect BP or HR. High-dose alcohol (> 30 g) within six hours (16 RCTs, N = 418) decreased SBP by 3.5 mmHg (95% CI -6.0 to -1.0), decreased DBP by 1.9 mmHg (95% CI-3.9 to 0.04), and increased HR by 5.8 bpm (95% CI 4.0 to 7.5). The certainty of evidence was moderate for SBP and HR, and was low for DBP. High-dose alcohol within 7 to 12 hours of consumption (3 RCTs, N = 54) decreased SBP by 3.7 mmHg (95% CI -7.0 to -0.5) and DBP by 1.7 mmHg (95% CI -4.6 to 1.8) and increased HR by 6.2 bpm (95% CI 3.0 to 9.3). The certainty of evidence was moderate for SBP and HR, and low for DBP. High-dose alcohol ≥ 13 hours after consumption (4 RCTs, N = 154) increased SBP by 3.7 mmHg (95% CI 2.3 to 5.1), DBP by 2.4 mmHg (95% CI 0.2 to 4.5), and HR by 2.7 bpm (95% CI 0.8 to 4.6) (moderate-certainty evidence for all).  AUTHORS' CONCLUSIONS: High-dose alcohol has a biphasic effect on BP; it decreases BP up to 12 hours after consumption and increases BP > 13 hours after consumption. High-dose alcohol increases HR at all times up to 24 hours. Findings of this review are relevant mainly to healthy males, as only small numbers of women were included in the included trials.

Pharmacotherapy for hypertension in adults 60 years or older.

BACKGROUND: This is the second substantive update of this review. It was originally published in 1998 and was previously updated in 2009. Elevated blood pressure (known as 'hypertension') increases with age - most rapidly over age 60. Systolic hypertension is more strongly associated with cardiovascular disease than is diastolic hypertension, and it occurs more commonly in older people. It is important to know the benefits and harms of antihypertensive treatment for hypertension in this age group, as well as separately for people 60 to 79 years old and people 80 years or older. OBJECTIVES: Primary objective• To quantify the effects of antihypertensive drug treatment as compared with placebo or no treatment on all-cause mortality in people 60 years and older with mild to moderate systolic or diastolic hypertensionSecondary objectives• To quantify the effects of antihypertensive drug treatment as compared with placebo or no treatment on cardiovascular-specific morbidity and mortality in people 60 years and older with mild to moderate systolic or diastolic hypertension• To quantify the rate of withdrawal due to adverse effects of antihypertensive drug treatment as compared with placebo or no treatment in people 60 years and older with mild to moderate systolic or diastolic hypertension SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to 24 November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: Randomised controlled trials of at least one year's duration comparing antihypertensive drug therapy versus placebo or no treatment and providing morbidity and mortality data for adult patients (≥ 60 years old) with hypertension defined as blood pressure greater than 140/90 mmHg. DATA COLLECTION AND ANALYSIS: Outcomes assessed were all-cause mortality; cardiovascular morbidity and mortality; cerebrovascular morbidity and mortality; coronary heart disease morbidity and mortality; and withdrawal due to adverse effects. We modified the definition of cardiovascular mortality and morbidity to exclude transient ischaemic attacks when possible. MAIN RESULTS: This update includes one additional trial (MRC-TMH 1985). Sixteen trials (N = 26,795) in healthy ambulatory adults 60 years or older (mean age 73.4 years) from western industrialised countries with moderate to severe systolic and/or diastolic hypertension (average 182/95 mmHg) met the inclusion criteria. Most of these trials evaluated first-line thiazide diuretic therapy for a mean treatment duration of 3.8 years.Antihypertensive drug treatment reduced all-cause mortality (high-certainty evidence; 11% with control vs 10.0% with treatment; risk ratio (RR) 0.91, 95% confidence interval (CI) 0.85 to 0.97; cardiovascular morbidity and mortality (moderate-certainty evidence; 13.6% with control vs 9.8% with treatment; RR 0.72, 95% CI 0.68 to 0.77; cerebrovascular mortality and morbidity (moderate-certainty evidence; 5.2% with control vs 3.4% with treatment; RR 0.66, 95% CI 0.59 to 0.74; and coronary heart disease mortality and morbidity (moderate-certainty evidence; 4.8% with control vs 3.7% with treatment; RR 0.78, 95% CI 0.69 to 0.88. Withdrawals due to adverse effects were increased with treatment (low-certainty evidence; 5.4% with control vs 15.7% with treatment; RR 2.91, 95% CI 2.56 to 3.30. In the three trials restricted to persons with isolated systolic hypertension, reported benefits were similar.This comprehensive systematic review provides additional evidence that the reduction in mortality observed was due mostly to reduction in the 60- to 79-year-old patient subgroup (high-certainty evidence; RR 0.86, 95% CI 0.79 to 0.95). Although cardiovascular mortality and morbidity was significantly reduced in both subgroups 60 to 79 years old (moderate-certainty evidence; RR 0.71, 95% CI 0.65 to 0.77) and 80 years or older (moderate-certainty evidence; RR 0.75, 95% CI 0.65 to 0.87), the magnitude of absolute risk reduction was probably higher among 60- to 79-year-old patients (3.8% vs 2.9%). The reduction in cardiovascular mortality and morbidity was primarily due to a reduction in cerebrovascular mortality and morbidity. AUTHORS' CONCLUSIONS: Treating healthy adults 60 years or older with moderate to severe systolic and/or diastolic hypertension with antihypertensive drug therapy reduced all-cause mortality, cardiovascular mortality and morbidity, cerebrovascular mortality and morbidity, and coronary heart disease mortality and morbidity. Most evidence of benefit pertains to a primary prevention population using a thiazide as first-line treatment.

First-line drugs for hypertension.

BACKGROUND: This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical question: What class of drug to use first-line? This review attempted to answer that question. OBJECTIVES: To quantify the mortality and morbidity effects from different first-line antihypertensive drug classes: thiazides (low-dose and high-dose), beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers (ARB), and alpha-blockers, compared to placebo or no treatment.Secondary objectives: when different antihypertensive drug classes are used as the first-line drug, to quantify the blood pressure lowering effect and the rate of withdrawal due to adverse drug effects, compared to placebo or no treatment. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: Randomized trials (RCT) of at least one year duration, comparing one of six major drug classes with a placebo or no treatment, in adult patients with blood pressure over 140/90 mmHg at baseline. The majority (over 70%) of the patients in the treatment group were taking the drug class of interest after one year. We included trials with both hypertensive and normotensive patients in this review if the majority (over 70%) of patients had elevated blood pressure, or the trial separately reported outcome data on patients with elevated blood pressure. DATA COLLECTION AND ANALYSIS: The outcomes assessed were mortality, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. We used a fixed-effect model to to combine dichotomous outcomes across trials and calculate risk ratio (RR) with 95% confidence interval (CI). We presented blood pressure data as mean difference (MD) with 99% CI. MAIN RESULTS: The 2017 updated search failed to identify any new trials. The original review identified 24 trials with 28 active treatment arms, including 58,040 patients. We found no RCTs for ARBs or alpha-blockers. These results are mostly applicable to adult patients with moderate to severe primary hypertension. The mean age of participants was 56 years, and mean duration of follow-up was three to five years.High-quality evidence showed that first-line low-dose thiazides reduced mortality (11.0% with control versus 9.8% with treatment; RR 0.89, 95% CI 0.82 to 0.97); total CVS (12.9% with control versus 9.0% with treatment; RR 0.70, 95% CI 0.64 to 0.76), stroke (6.2% with control versus 4.2% with treatment; RR 0.68, 95% CI 0.60 to 0.77), and coronary heart disease (3.9% with control versus 2.8% with treatment; RR 0.72, 95% CI 0.61 to 0.84).Low- to moderate-quality evidence showed that first-line high-dose thiazides reduced stroke (1.9% with control versus 0.9% with treatment; RR 0.47, 95% CI 0.37 to 0.61) and total CVS (5.1% with control versus 3.7% with treatment; RR 0.72, 95% CI 0.63 to 0.82), but did not reduce mortality (3.1% with control versus 2.8% with treatment; RR 0.90, 95% CI 0.76 to 1.05), or coronary heart disease (2.7% with control versus 2.7% with treatment; RR 1.01, 95% CI 0.85 to 1.20).Low- to moderate-quality evidence showed that first-line beta-blockers did not reduce mortality (6.2% with control versus 6.0% with treatment; RR 0.96, 95% CI 0.86 to 1.07) or coronary heart disease (4.4% with control versus 3.9% with treatment; RR 0.90, 95% CI 0.78 to 1.03), but reduced stroke (3.4% with control versus 2.8% with treatment; RR 0.83, 95% CI 0.72 to 0.97) and total CVS (7.6% with control versus 6.8% with treatment; RR 0.89, 95% CI 0.81 to 0.98).Low- to moderate-quality evidence showed that first-line ACE inhibitors reduced mortality (13.6% with control versus 11.3% with treatment; RR 0.83, 95% CI 0.72 to 0.95), stroke (6.0% with control versus 3.9% with treatment; RR 0.65, 95% CI 0.52 to 0.82), coronary heart disease (13.5% with control versus 11.0% with treatment; RR 0.81, 95% CI 0.70 to 0.94), and total CVS (20.1% with control versus 15.3% with treatment; RR 0.76, 95% CI 0.67 to 0.85).Low-quality evidence showed that first-line calcium channel blockers reduced stroke (3.4% with control versus 1.9% with treatment; RR 0.58, 95% CI 0.41 to 0.84) and total CVS (8.0% with control versus 5.7% with treatment; RR 0.71, 95% CI 0.57 to 0.87), but not coronary heart disease (3.1% with control versus 2.4% with treatment; RR 0.77, 95% CI 0.55 to 1.09), or mortality (6.0% with control versus 5.1% with treatment; RR 0.86, 95% CI 0.68 to 1.09).There was low-quality evidence that withdrawals due to adverse effects were increased with first-line low-dose thiazides (5.0% with control versus 11.3% with treatment; RR 2.38, 95% CI 2.06 to 2.75), high-dose thiazides (2.2% with control versus 9.8% with treatment; RR 4.48, 95% CI 3.83 to 5.24), and beta-blockers (3.1% with control versus 14.4% with treatment; RR 4.59, 95% CI 4.11 to 5.13). No data for these outcomes were available for first-line ACE inhibitors or calcium channel blockers. The blood pressure data were not used to assess the effect of the different classes of drugs as the data were heterogeneous, and the number of drugs used in the trials differed. AUTHORS' CONCLUSIONS: First-line low-dose thiazides reduced all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. First-line ACE inhibitors and calcium channel blockers may be similarly effective, but the evidence was of lower quality. First-line high-dose thiazides and first-line beta-blockers were inferior to first-line low-dose thiazides.

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.

Pharmacotherapy for hypertension in adults aged 18 to 59 years.

BACKGROUND: Hypertension is an important risk factor for adverse cardiovascular events including stroke, myocardial infarction, heart failure and renal failure. The main goal of treatment is to reduce these events. Systematic reviews have shown proven benefit of antihypertensive drug therapy in reducing cardiovascular morbidity and mortality but most of the evidence is in people 60 years of age and older. We wanted to know what the effects of therapy are in people 18 to 59 years of age. OBJECTIVES: To quantify antihypertensive drug effects on all-cause mortality in adults aged 18 to 59 years with mild to moderate primary hypertension. To quantify effects on cardiovascular mortality plus morbidity (including cerebrovascular and coronary heart disease mortality plus morbidity), withdrawal due adverse events and estimate magnitude of systolic blood pressure (SBP) and diastolic blood pressure (DBP) lowering at one year. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to January 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: Randomized trials of at least one year' duration comparing antihypertensive pharmacotherapy with a placebo or no treatment in adults aged 18 to 59 years with mild to moderate primary hypertension defined as SBP 140 mmHg or greater or DBP 90 mmHg or greater at baseline, or both. DATA COLLECTION AND ANALYSIS: The outcomes assessed were all-cause mortality, total cardiovascular (CVS) mortality plus morbidity, withdrawals due to adverse events, and decrease in SBP and DBP. For dichotomous outcomes, we used risk ratio (RR) with 95% confidence interval (CI) and a fixed-effect model to combine outcomes across trials. For continuous outcomes, we used mean difference (MD) with 95% CI and a random-effects model as there was significant heterogeneity. MAIN RESULTS: The population in the seven included studies (17,327 participants) were predominantly healthy adults with mild to moderate primary hypertension. The Medical Research Council Trial of Mild Hypertension contributed 14,541 (84%) of total randomized participants, with mean age of 50 years and mean baseline blood pressure of 160/98 mmHg and a mean duration of follow-up of five years. Treatments used in this study were bendrofluazide 10 mg daily or propranolol 80 mg to 240 mg daily with addition of methyldopa if required. The risk of bias in the studies was high or unclear for a number of domains and led us to downgrade the quality of evidence for all outcomes.Based on five studies, antihypertensive drug therapy as compared to placebo or untreated control may have little or no effect on all-cause mortality (2.4% with control vs 2.3% with treatment; low quality evidence; RR 0.94, 95% CI 0.77 to 1.13). Based on 4 studies, the effects on coronary heart disease were uncertain due to low quality evidence (RR 0.99, 95% CI 0.82 to 1.19). Low quality evidence from six studies showed that drug therapy may reduce total cardiovascular mortality and morbidity from 4.1% to 3.2% over five years (RR 0.78, 95% CI 0.67 to 0.91) due to reduction in cerebrovascular mortality and morbidity (1.3% with control vs 0.6% with treatment; RR 0.46, 95% CI 0.34 to 0.64). Very low quality evidence from three studies showed that withdrawals due to adverse events were higher with drug therapy from 0.7% to 3.0% (RR 4.82, 95% CI 1.67 to 13.92). The effects on blood pressure varied between the studies and we are uncertain as to how much of a difference treatment makes on average. AUTHORS' CONCLUSIONS: Antihypertensive drugs used to treat predominantly healthy adults aged 18 to 59 years with mild to moderate primary hypertension have a small absolute effect to reduce cardiovascular mortality and morbidity primarily due to reduction in cerebrovascular mortality and morbidity. All-cause mortality and coronary heart disease were not reduced. There is lack of good evidence on withdrawal due to adverse events. Future trials in this age group should be at least 10 years in duration and should compare different first-line drug classes and strategies.

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.

Blood pressure-lowering efficacy of loop diuretics for primary hypertension.

BACKGROUND: Antihypertensive drugs from the thiazide diuretic drug class have been shown to reduce mortality and cardiovascular morbidity. Loop diuretics are indicated and used to treat hypertension, but a systematic review of their blood pressure-lowering efficacy or effectiveness in terms of reducing cardiovascular mortality or morbidity from randomized controlled trial (RCT) evidence has not been conducted. OBJECTIVES: To determine the dose-related decrease in systolic or diastolic blood pressure, or both, as well as adverse events leading to participant withdrawal and adverse biochemical effects (serum potassium, uric acid, creatinine, glucose and lipids profile) due to loop diuretics versus placebo control in the treatment of people with primary hypertension. SEARCH METHODS: We searched the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 9), MEDLINE, MEDLINE In-Process, EMBASE, and ClinicalTrials.gov to 27 October 2014. SELECTION CRITERIA: We included double-blind randomized placebo-controlled trials of at least three weeks duration comparing loop diuretic with a placebo in people with primary hypertension defined as blood pressure greater than 140/90 mmHg at baseline. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data. We used weighted mean difference and a fixed effects model to combine continuous outcome data. We analysed the drop outs due to adverse effects using relative risk ratio. MAIN RESULTS: Nine trials evaluated the dose-related blood pressure-lowering efficacy of five drugs within the loop diuretics class (furosemide 40 mg to 60 mg, cicletanine 100 mg to 150 mg, piretanide 3 mg to 6 mg, indacrinone enantiomer -2.5 mg to -10.0/+80 mg, and etozolin 200 mg) in 460 people with baseline blood pressure of 162/103 mmHg for a mean duration of 8.8 weeks. The best estimate of systolic/diastolic blood pressure-lowering efficacy of loop diuretics was -7.9 (-10.4 to -5.4) mmHg/ -4.4 (-5.9 to -2.8) mmHg. Withdrawals due to adverse effects and serum biochemical changes did not show a significant difference.We performed additional searches in 2012 and 2014, which found no additional trials meeting the minimum inclusion criteria. AUTHORS' CONCLUSIONS: Based on the limited number of published RCTs, the systolic/diastolic blood pressure-lowering effect of loop diuretics is -8/-4 mmHg, which is likely an overestimate. We graded the quality of evidence for both systolic and diastolic blood pressure estimates as "low" due to the high risk of bias of included studies and the high likelihood of publication bias. We found no clinically meaningful blood pressure-lowering differences between different drugs within the loop diuretic class. The dose-ranging effects of loop diuretics could not be evaluated. The review did not provide a good estimate of the incidence of harms associated with loop diuretics because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.

Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension.

BACKGROUND: Hypertension is a modifiable cardiovascular risk factor. Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity, the dose-related effect of thiazides in decreasing blood pressure has not been subject to a rigorous systematic review. It is not known whether individual drugs within the thiazide diuretic class differ in their blood pressure-lowering effects and adverse effects. OBJECTIVES: To determine the dose-related decrease in systolic and/or diastolic blood pressure due to thiazide diuretics compared with placebo control in the treatment of patients with primary hypertension. Secondary outcomes included the dose-related adverse events leading to patient withdrawal and adverse biochemical effects on serum potassium, uric acid, creatinine, glucose and lipids. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 1), Ovid MEDLINE (1946 to February 2014), Ovid EMBASE (1974 to February 2014) and ClinicalTrials.gov. SELECTION CRITERIA: We included double-blind, randomized controlled trials (RCTs) comparing fixed-dose thiazide diuretic monotherapy with placebo for a duration of 3 to 12 weeks in the treatment of adult patients with primary hypertension. DATA COLLECTION AND ANALYSIS: Two authors independently screened articles, assessed trial eligibility, extracted data and determined risk of bias. We combined data for continuous variables using a mean difference (MD) and for dichotomous outcomes we calculated the relative risk ratio (RR) with 95% confidence interval (CI). MAIN RESULTS: We included 60 randomized, double-blind trials that evaluated the dose-related trough blood pressure-lowering efficacy of six different thiazide diuretics in 11,282 participants treated for a mean duration of eight weeks. The mean age of the participants was 55 years and baseline blood pressure was 158/99 mmHg. Adequate blood pressure-lowering efficacy data were available for hydrochlorothiazide, chlorthalidone and indapamide. We judged 54 (90%) included trials to have unclear or high risk of bias, which impacted on our confidence in the results for some of our outcomes.In 33 trials with a baseline blood pressure of 155/100 mmHg, hydrochlorothiazide lowered blood pressure based on dose, with doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg/day lowering blood pressure compared to placebo by 4 mmHg (95% CI 2 to 6, moderate-quality evidence)/2 mmHg (95% CI 1 to 4, moderate-quality evidence), 6 mmHg (95% CI 5 to 7, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence), 8 mmHg (95% CI 7 to 9, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence) and 11 mmHg (95% CI 6 to 15, low-quality evidence)/5 mmHg (95% CI 3 to 7, low-quality evidence), respectively.Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available: bendrofluazide, chlorthalidone, cyclopenthiazide, metolazone or indapamide.In seven trials with a baseline blood pressure of 163/88 mmHg, chlorthalidone at doses of 12.5 mg to 75 mg/day reduced average blood pressure compared to placebo by 12.0 mmHg (95% CI 10 to 14, low-quality evidence)/4 mmHg (95% CI 3 to 5, low-quality evidence).In 10 trials with a baseline blood pressure of 161/98 mmHg, indapamide at doses of 1.0 mg to 5.0 mg/day reduced blood pressure compared to placebo by 9 mmHg (95% CI 7 to 10, low-quality evidence)/4 (95% CI 3 to 5, low-quality evidence).We judged the maximal blood pressure-lowering effect of the different thiazides to be similar. Overall, thiazides reduced average blood pressure compared to placebo by 9 mmHg (95% CI 9 to 10, high-quality evidence)/4 mmHg (95% CI 3 to 4, high-quality evidence).Thiazides as a class have a greater effect on systolic than on diastolic blood pressure, therefore thiazides lower pulse pressure by 4 mmHg to 6 mmHg, an amount that is greater than the 3 mmHg seen with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors, and the 2 mmHg seen with non-selective beta-blockers. This is based on an informal indirect comparison of results observed in other Cochrane reviews on ACE inhibitors, ARBs and renin inhibitors compared with placebo, which used similar inclusion/exclusion criteria to the present review.Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides. These effects were dose-related and were least for hydrochlorothiazide. Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides. There is a high risk of bias in the metabolic data. This review does not provide a good assessment of the adverse effects of these drugs because there was a high risk of bias in the reporting of withdrawals due to adverse effects. AUTHORS' CONCLUSIONS: This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect. The mean blood pressure-lowering effect over the dose range 6.25 mg, 12.5 mg, 25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure, thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews, which compared these antihypertensive drug classes with placebo and used similar inclusion/exclusion criteria.Thiazides did not increase withdrawals due to adverse effects in these short-term trials but there is a high risk of bias for that outcome. Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides.

Intravenous immunoglobulin as adjuvant therapy for Wegener's granulomatosis.

BACKGROUND: Wegener's granulomatosis (WG) is a necrotizing small-vessel vasculitis that can affect any organ in the body but mainly affects the upper and lower respiratory tract, the kidneys, joints, skin and eyes. The current mainstay of remission induction therapy is systemic corticosteroids in combination with oral daily cyclophosphamide (CYC) which induces remission in 75% to 100% of cases. Although standard therapy is effective in inducing partial or complete remission, 50% of complete remissions are followed by at least one relapse. This is an update of a review first published in 2009. OBJECTIVES: To determine if intravenous immunoglobulin (IVIg) adjuvant therapy provides a therapeutic advantage over and above treatment with systemic corticosteroids in combination with immunosuppressants for the treatment of WG. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched November 2012) and CENTRAL (2012, Issue 11). Trial databases were searched by the TSC for details of ongoing and unpublished studies. No date or language restrictions were applied. SELECTION CRITERIA: Randomized controlled trials (RCTs), or quasi RCTs, or randomized cross-over trials. Participants had to be adults with a confirmed diagnosis of WG. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. Relative risk was used to analyze dichotomous variables, and mean difference (MD) was used to analyze continuous variables. MAIN RESULTS: We included one RCT with 34 participants who were randomly assigned to receive IVIg or placebo once daily in addition to azathioprine and prednisolone for remission maintenance. There were no significant differences between adjuvant IVIg and adjuvant placebo in mortality, serious adverse events, time to relapse, open-label rescue therapy, and infection rates. The fall in disease activity score, derived from patient-reported symptoms, was slightly greater in the IVIg group than in the placebo group at one month (MD 2.30; 95% Confidence interval (CI) 1.12 to 3.48, P < 0.01) and three months (MD 1.80; 95% CI 0.35 to 3.25, P = 0.01). There was a significant increase in total adverse events in the IVIg group (relative risk (RR) 3.50; 95% CI 1.44 to 8.48, P < 0.01). AUTHORS' CONCLUSIONS: There is insufficient evidence from one RCT that IVIg adjuvant therapy provides a therapeutic advantage compared with the combination of steroids and immunosuppressants for patients with WG. Given the high cost of IVIg (one dose at 2 g/kg for a 70 kg patient = $8,400), it should be limited to treat WG in the context of a well conducted RCT powered to detect patient-relevant outcomes.

Magnesium for skeletal muscle cramps.

BACKGROUND: Skeletal muscle cramps are common and often presented to physicians in association with pregnancy, advanced age, exercise or disorders of the motor neuron (such as amyotrophic lateral sclerosis). Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this indication has never been evaluated by systematic review. OBJECTIVES: To assess the effects of magnesium supplementation compared to no treatment, placebo control or other cramp therapies in people with skeletal muscle cramps.   SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (11 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 3), MEDLINE (January 1966 to September 2011), EMBASE (January 1980 to September 2011), LILACS (January 1982 to September 2011), CINAHL Plus (January 1937 to September 2011), AMED (January 1985 to October 2011) and SPORTDiscus (January 1975 to September 2011). SELECTION CRITERIA: Randomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp). We considered comparisons of magnesium with no treatment, placebo control, or other therapy. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion and extracted data. Two authors assessed risk of bias. We attempted to contact all study authors and obtained patient level data for three of the included trials, one of which was unpublished. All data on adverse effects were collected from the included RCTs. MAIN RESULTS: We identified seven trials (five parallel, two cross-over) enrolling a total of 406 individuals amongst whom 118 cross-over participants additionally served as their own controls. Three trials enrolled women with pregnancy-associated leg cramps (N = 202) and four trials enrolled idiopathic cramp sufferers (N = 322 including cross-over controls). Magnesium was compared to placebo in six trials and to no treatment in one trial.For idiopathic cramps (largely older adults presumed to have nocturnal leg cramps), differences in measures of cramp frequency, magnesium versus placebo, were small, not statistically significant, and without heterogeneity (I(2) = 0%). This includes the primary endpoint, percentage change from baseline in the number of cramps per week at four weeks (-3.93%, 95% confidence interval (CI) -21.12% to 13.26%, moderate quality evidence) and the difference in the number of cramps per week at four weeks (0.01 cramps/week, 95% CI -0.52 to 0.55, moderate quality evidence). The percentage of individuals experiencing a 25% or better reduction in cramp rate from baseline was also no different, being 8% lower in the magnesium group (95% CI -28% to 12%, moderate quality evidence). Similarly, no statistically significant difference was found at four weeks in measures of cramp intensity (moderate quality evidence) or cramp duration (low quality evidence).Meta-analysis was not possible for trials of pregnancy-associated leg cramps. The single study comparing magnesium to no treatment failed to find statistically significant benefit on a three-point ordinal scale of overall treatment efficacy. The two trials comparing magnesium to placebo differed in that one trial found no benefit on frequency or intensity measures while the other found benefit for both.Withdrawals due to adverse events were not significantly different than placebo. While we could not determine the number of subjects with minor adverse events, studies of oral magnesium generally described potential side effects as similar in frequency to placebo. AUTHORS' CONCLUSIONS: It is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this patient population is needed. We found no randomized controlled trials evaluating magnesium for exercise-associated muscle cramps or disease state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease).

Blood pressure lowering efficacy of loop diuretics for primary hypertension.

BACKGROUND: Antihypertensive drugs from the thiazide diuretic drug class have been shown to reduce mortality and cardiovascular morbidity. Loop diuretics are indicated and used as antihypertensive drugs but a systematic review of their blood pressure lowering efficacy or effectiveness in terms of reducing cardiovascular mortality or morbidity from randomized controlled trial evidence has not been conducted. OBJECTIVES: To determine the dose related decrease in systolic and/or diastolic blood pressure as well as adverse events leading to patient withdrawal and adverse biochemical effects (serum potassium, uric acid, creatinine, glucose and lipids profile) due to loop diuretics versus placebo control in the treatment of patients with primary hypertension. SEARCH METHODS: Medline (1946-February 2012), EMBASE (1974-February 2012), CENTRAL (issue 2, 2012) and bibliographic citations were searched. SELECTION CRITERIA: Double blind randomized placebo controlled trials of at least 3 weeks duration comparing loop diuretic with a placebo in patients with primary hypertension defined as BP >140/90 mmHg at baseline were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. Weighted mean difference and a fixed effects model were used to combine continuous outcome data. The drop outs due to adverse effects was analysed using relative risk ratio. MAIN RESULTS: Nine trials evaluated the dose-related blood pressure lowering efficacy of five drugs within the loop diuretics class (furosemide 40 to 60mg, cicletanine 100 to 150 mg, piretanide 3 to 6 mg, indacrinone enantiomer -2.5 to -10.0/+80 mg and etozolin 200 mg) in 460 patients with baseline blood pressure of 162/103 mmHg for a mean duration of 8.8 weeks. The best estimate of systolic/diastolic blood pressure lowering efficacy of loop diuretics was -7.9 (-10.5, -5.4) mmHg/ -4.4 (-5.6, -2.8) mmHg . Withdrawals due to adverse effects and serum biochemical changes did not show a significant difference.The 2012 updated search resulted in no additional new trials meeting the minimum inclusion criteria. AUTHORS' CONCLUSIONS: Based on the limited number of published RCTs, the systolic/diastolic blood pressure lowering effect of loop diuretics is modest (-8/-4 mmHg) and is likely an overestimate due to the high risk of bias in the included studies. There are no clinically meaningful BP lowering differences between different drugs within the loop diuretic class. The dose ranging effects of loop diuretics could not be evaluated. The review did not provide a good estimate of the incidence of harms associated with loop diuretics because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.

Angiotensin receptor blockers for heart failure.

BACKGROUND: Chronic heart failure (HF) is a prevalent world-wide. Angiotensin receptor blockers (ARBs) are widely prescribed for chronic HF although their role is controversial. OBJECTIVES: To assess the benefit and harm of ARBs compared with ACE inhibitors (ACEIs) or placebo on mortality, morbidity and withdrawals due to adverse effects in patients with symptomatic HF and left ventricular systolic dysfunction or preserved systolic function. SEARCH METHODS: Clinical trials were identified by searching CENTRAL, HTA, and DARE , (The Cochrane Library 2010 Issue 3), as well as MEDLINE (2002 to July 2010), and EMBASE (2002 to July 2010). Reference lists of retrieved articles and systematic reviews were checked for additional studies not identified by the electronic searches. SELECTION CRITERIA: Double blind randomised controlled trials in men and women of all ages who have symptomatic (NYHA Class II to IV) HF and: 1) left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) ≤40%; or 2) preserved ejection fraction, defined as LVEF >40%. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data from included studies. MAIN RESULTS: Twenty two studies evaluated the effects of ARBs in 17,900 patients with a LVEF ≤40% (mean 2.2 years). ARBs did not reduce total mortality (RR 0.87 [95% CI 0.76, 1.00]) or total morbidity as measured by total hospitalisations (RR 0.94 [95% CI 0.88, 1.01]) compared with placebo.Total mortality (RR 1.05 [95% CI 0.91, 1.22]), total hospitalisations (RR 1.00 [95% CI 0.92, 1.08]), MI (RR 1.00 [95% CI 0.62, 1.63]), and stroke (RR 1.63 [0.77, 3.44]) did not differ between ARBs and ACEIs but withdrawals due to adverse effects were lower with ARBs (RR 0.63 [95% CI 0.52, 0.76]). Combinations of ARBs plus ACEIs increased the risk of withdrawals due to adverse effects (RR 1.34 [95% CI 1.19, 1.51]) but did not reduce total mortality or total hospital admissions versus ACEI alone.Two placebo-controlled studies evaluated ARBs in 7151 patients with a LVEF >40% (mean 3.7 years). ARBs did not reduce total mortality (RR 1.02 [95% CI 0.93, 1.12]) or total morbidity as measured by total hospitalisations (RR 1.00 [95% CI 0.97, 1.05]) compared with placebo. Withdrawals due to adverse effects were higher with ARBs versus placebo when all patients were pooled irrespective of LVEF (RR 1.06 [95% CI 1.01, 1.12]). AUTHORS' CONCLUSIONS: In patients with symptomatic HF and systolic dysfunction or with preserved ejection fraction, ARBs compared to placebo or ACEIs do not reduce total mortality or morbidity. ARBs are better tolerated than ACEIs but do not appear to be as safe and well tolerated as placebo in terms of withdrawals due to adverse effects. Adding an ARB in combination with an ACEI does not reduce total mortality or total hospital admission but increases withdrawals due to adverse effects compared with ACEI alone.

Human albumin for intradialytic hypotension in haemodialysis patients.

BACKGROUND: Intradialytic hypotension (IDH) occurs in 20% to 55% of haemodialysis sessions and is more frequent among patients on long-term haemodialysis. Symptomatic IDH is generally defined as a decrease in systolic blood pressure (BP) of at least 10 mm Hg or a systolic BP less than 100 mm Hg, with symptoms such as cramps, nausea, vomiting, and dizziness. IDH is managed acutely by volume expansion through the intravenous administration of fluids. OBJECTIVES: To compare the benefits and harms of volume expansion with human albumin, alone or in combination with crystalloid or non-protein colloids, for treating IDH in haemodialysis patients. SEARCH STRATEGY: The Cochrane Renal Group's Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 9) MEDLINE (1966 to Oct 2009), and EMBASE (1980 to Oct 2009) were searched. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs as well as randomised crossover studies were to be included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. Relative risk (RR) was to be used to analyse dichotomous variables and mean difference (MD) used to analyse continuous variables. MAIN RESULTS: One double blind randomised crossover trial met the inclusion criteria and compared 5% albumin to normal saline in patients with a previous history of IDH. Results from 45 assessable participants did not lead to rejection of the null hypothesis of no difference between 5% albumin and normal saline in the primary outcome measure of percentage target ultrafiltration achieved, nor in 11/12 secondary outcomes. Additional (unblinded) saline was given less often when 5% albumin was used compared with saline (16% versus 36%, P = 0.04). However, the volume of additional fluid administered was similar in both groups. There were no significant differences in the nursing time required to treat IDH and the time to restore BP. AUTHORS' CONCLUSIONS: No randomised or controlled trial was identified comparing albumin to crystalloids (other than normal saline) or non-protein colloids, or a combination of both, in the treatment of symptomatic hypotension during dialysis. One double blind crossover RCT in 45 assessable patients showed that 5% albumin is not superior to normal saline for the treatment of symptomatic hypotension in maintenance haemodialysis patients with a previous history of IDH. Given the cost and relative rarity of albumin use compared to saline, saline should be first line of therapy for treatment of IDH in stable dialysis patients.

Pharmacotherapy for hypertension in the elderly.

BACKGROUND: Elevated blood pressure (known as hypertension) increases with age, and most rapidly over age 60. Systolic hypertension is more strongly associated with cardiovascular disease than diastolic hypertension, and occurs more commonly in older people. It is important to know the benefits and harms of antihypertensive treatment of hypertension in this age group. OBJECTIVES: To quantify antihypertensive drug effect on overall mortality, cardiovascular mortality and morbidity and withdrawal due to adverse effects in people 60 years and older with mild to moderate systolic or diastolic hypertension. SEARCH STRATEGY: Updated search of electronic database of EMBASE, CENTRAL, MEDLINE until Dec 2008; previous search of two Japanese databases (1973-1995) and WHO-ISH Collaboration register (August 1997); references from reviews, trials and previously published meta-analyses; and experts. SELECTION CRITERIA: Randomized controlled trials of at least one year duration in hypertensive elders (at least 60 years old) comparing antihypertensive drug therapy with placebo or no treatment and providing morbidity and mortality data. DATA COLLECTION AND ANALYSIS: Outcomes assessed were total mortality (including cardiovascular, coronary heart disease and cerebrovascular mortality); total cardiovascular morbidity and mortality (representing combined coronary heart disease and cerebrovascular morbidity and mortality); and withdrawal due to adverse events. MAIN RESULTS: Fifteen trials (24,055 subjects >/= 60 years) with moderate to severe hypertension were identified. These trials mostly evaluated first-line thiazide diuretic therapy for a mean duration of treatment of 4.5 years. Treatment reduced total mortality, RR 0.90 (0.84, 0.97); event rates per 1000 participants reduced from 116 to 104. Treatment also reduced total cardiovascular morbidity and mortality, RR 0.72 (0.68, 0.77); event rates per 1000 participants reduced from 149 to 106. In the three trials restricted to persons with isolated systolic hypertension the benefit was similar. In very elderly patients >/= 80 years the reduction in total cardiovascular mortality and morbidity was similar RR 0.75 [0.65, 0.87] however, there was no reduction in total mortality, RR 1.01 [0.90, 1.13]. Withdrawals due to adverse effects were increased with treatment, RR 1.71 [1.45, 2.00]. AUTHORS' CONCLUSIONS: Treating healthy persons (60 years or older) with moderate to severe systolic and/or diastolic hypertension reduces all cause mortality and cardiovascular morbidity and mortality. The decrease in all cause mortality was limited to persons 60 to 80 years of age.

Blood pressure lowering efficacy of loop diuretics for primary hypertension.

BACKGROUND: Antihypertensive drugs from the thiazide diuretic drug class have been shown to reduce mortality and cardiovascular morbidity. Loop diuretics are indicated and used as antihypertensive drugs but a systematic review of their blood pressure lowering efficacy or effectiveness in terms of reducing cardiovascular mortality or morbidity from randomized controlled trial evidence has not been conducted. OBJECTIVES: To determine the dose related decrease in systolic and/or diastolic blood pressure as well as adverse events leading to patient withdrawal and adverse biochemical effects (serum potassium, uric acid, creatinine, glucose and lipids profile) due to loop diuretics versus placebo control in the treatment of patients with primary hypertension. SEARCH STRATEGY: Medline (Jan.1966-March-2009), EMBASE (Jan.1988-March-2009), CENTRAL (issue 1, 2009) and bibliographic citations were searched. SELECTION CRITERIA: Double blind randomized placebo controlled trials of at least 3 weeks duration comparing loop diuretic with a placebo or no treatment in patients with primary hypertension defined as BP >140/90 mmHg at baseline were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. Weighted mean difference and a fixed effects model were used to combine continuous outcome data. The drop outs due to adverse effects was analysed using relative risk ratio. MAIN RESULTS: Nine trials evaluated the dose-related blood pressure lowering efficacy of five drugs within the loop diuretics class (furosemide 40 to 60mg, cicletanine 100 to 150 mg, piretanide 3 to 6 mg, indacrinone enantiomer -2.5 to -10.0/+80 mg and etozolin 200 mg) in 460 patients with baseline blood pressure of 162/103 mmHg for a mean duration of 8.8 weeks. The best estimate of SBP/DBP lowering efficacy of loop diuretics was -7.9 (-10.5, -5.4) mmHg/ -4.4 (-5.6, -2.8) mmHg . Withdrawals due to adverse effects and serum biochemical changes did not show a significant difference. AUTHORS' CONCLUSIONS: Based on the limited number of published RCTs, the SBP/DBP lowering effect of loop diuretics is modest -8/-4 mmHg and is likely an overestimate due to the high risk of bias in the included studies. There is no clinically meaningful BP lowering differences between different drugs within the loop diuretic class. The dose ranging effects of loop diuretics could not be evaluated.The review did not provide a good estimate of the incidence of harms associated because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.

Methyldopa for primary hypertension.

BACKGROUND: Hypertension is associated with an increased risk of stroke, myocardial infarction and congestive heart failure. Methyldopa is a centrally acting antihypertensive agent, which was commonly used in the 1970's and 80's for blood pressure control. Its use at present has largely been replaced by antihypertensive drug classes with less side effects, but it is still used in developing countries due to its low cost. A review of its relative effectiveness compared to placebo on surrogate and clinical outcomes is justified. OBJECTIVES: To quantify the effect of methyldopa compared to placebo in randomized controlled trials (RCTs) on all cause mortality, cardiovascular mortality, serious adverse events, myocardial infarctions, strokes, withdrawals due to adverse effects and blood pressure in patients with primary hypertension. SEARCH STRATEGY: We searched the following databases: Cochrane Central Register of Controlled Trials (1960-June 2009), MEDLINE (2005-June 2009), and EMBASE (2007-June 2009). Bibliographic citations from retrieved studies were also reviewed. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs studying patients with primary hypertension. We excluded studies of patients with secondary hypertension or gestational hypertension. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality using the risk of bias tool. Data synthesis and analysis was performed using RevMan 5. Data for blood pressure were combined using the generic inverse variance method. MAIN RESULTS: Twelve trials (N=595) met the inclusion criteria for this review. None of these studies evaluated the effects of methyldopa compared to placebo on mortality and morbidity outcomes. Data for withdrawals due to adverse effects were not reported in a way that permitted meaningful meta-analysis. Data from six of the twelve trials (N=231) were combined to evaluate the blood pressure lowering effects of methyldopa compared to placebo. This meta-analysis shows that methyldopa at doses ranging from 500-2250 mg daily lowers systolic and diastolic blood pressure by a mean of 13 (95%CI 6-20) / 8 (95% CI 4-13) mmHg. Overall, the risk of bias was considered moderate. AUTHORS' CONCLUSIONS: Methyldopa lowers blood pressure to varying degrees compared to placebo for patients with primary hypertension. Its effect on clinical outcomes, however, remains uncertain.