Interventions for deliberately altering blood pressure in acute stroke.

It is unclear whether blood pressure should be altered actively during the acute phase of stroke. This is an update of a Cochrane review first published in 1997, and previously updated in 2001. To assess the effect of altering blood pressure in people with acute stroke, and the effect of different vasoactive drugs on blood pressure in acute stroke. We searched the Cochrane Stroke Group Trials Register (last searched July 2007), the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2 2008), MEDLINE, EMBASE and other databases, reference lists of relevant publications and contacted researchers in the field. Randomised controlled trials of interventions that aimed to alter blood pressure in patients within one week of acute ischaemic or haemorrhagic stroke. Two review authors independently applied the inclusion criteria, assessed trial quality and extracted data. Twelve trials involving 1153 participants were included (603 participants were assigned active therapy and 550 participants received placebo/control). The trials tested angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARA), calcium channel blockers (CCBs), clonidine, glyceryl trinitrate (GTN), thiazide diuretic and mixed antihypertensive therapy. One trial tested phenylephrine. At 24 hours after randomisation ACEIs reduced systolic blood pressure (SBP, mean difference, MD -6 mmHg, 95% confidence interval, CI -22 to 10) and diastolic blood pressure (DBP, MD -5 mmHg, 95% CI -18 to 7), ARA reduced SBP (MD -3, 95% CI -7 to 2) and DBP (MD -3, 95% CI -6 to 0.4), iv CCBs reduced SBP (MD -32 mmHg, 95% CI -65 to 1) and DBP (MD -13 mmHg, 95% CI -31 to 6), oral CCBs reduced SBP (MD -13 mmHg, 95% , CI -43 to 17) and DBP (MD -6 mmHg, 95% CI -14 to 2), GTN reduced SBP (MD -10 mmHg, 95% CI -18 to -3) and DBP (MD -1 mmHg, 95% CI -5 to 3) while phenylephrine, non-significantly increased SBP (MD 21 mmHg, 95% CI -13 to 55) and DBP (MD 1 mmHg, 95% CI -15 to 16). Functional outcome and death were not altered by any of the drugs. There is insufficient evidence to evaluate the effect of altering blood pressure on outcome during the acute phase of stroke. In patients with acute stroke, CCBs, ACEI, ARA and GTN each lower blood pressure while phenylephrine probably increases blood pressure.

It is unclear whether blood pressure should be managed after acute stroke and if so whether it is best to reduce or increase blood pressure. The objective of this review was to assess the effect of lowering or elevating blood pressure in people with acute stroke, and the effect of different vasoactive drugs on blood pressure in acute stroke. We searched the Cochrane Library (1999 Issue 1) using the CDSR and the CCTR databases, MEDLINE (from 1966), EMBASE (from 1980), BIDS ISI (Science Citation Index from 1981), and existing review articles. We contacted researchers in the field and pharmaceutical companies. Randomised trials of interventions that would be expected, on pharmacological grounds, to alter blood pressure in patients within two weeks of the onset of acute ischaemic or haemorrhagic stroke. Two reviewers independently applied the trial inclusion criteria, assessed trial quality, and extracted the data. Sixty five trials were identified involving in excess of 11,500 patients; a further 5 trials are ongoing. Data were obtained for 32 trials (5,368 patients). Significant imbalances in baseline blood pressure were present across trials of intravenous calcium channel blockers and prostacyclin. Major imbalances in baseline blood pressure between treatment and control groups have made the interpretation of these results difficult. Intravenous calcium channel blockers (CCBs) and oral CCBs significantly lowered late blood pressure as compared to controls. (systolic/diastolic BP): iv CCBs -8.2/-6.7 mm Hg (95% CI -12.6 to -3.8)/ (95% CI -9.2 to -4.3); oral CCBs -3.2/-2.1 mm Hg (95% CI -5.0 to -1.3)/ (95% CI -3.0 to -1.0). Beta blockers significantly lowered late diastolic blood pressure but not significantly late systolic blood pressure; -5.0/-4.5 mm Hg (95% CI -10.2 to 0.4)/(95% CI -7.8 to -1.15). Angiotensin converting enzyme inhibitors and prostacyclin non-significantly reduced late BP as compared to the controls by -5.4/-3.0 mm Hg (95% CI -16.5 to 5.8)/(95% CI -11.1 to 5.0) and -7.4/-3.9 mmHg (95% CI -15.6 to 0.2)/(95% CI -8.1 to 0.4) respectively. Magnesium, naftidrofuryl and piracetam had no significant effect on blood pressure. Oral CCBs and beta blockers each significantly reduced late heart rate (beats per minute (bpm)): CCBs -2.8 bpm (95%CI -3.9 to -1.7); beta blockers -9.3 bpm (95% CI -12.0 to -6.6). Prostacyclin significantly increased late heart rate by +5.6 bpm (95% CI 0.8 to 10.4). None of the drug classes significantly altered outcome apart from beta blockers and streptokinase which increased early case fatality (odds ratio 1.77, 95%CI, 1.05 to 3.00) and 2.27 (95% CI 1.4 to 3.67). There is not enough evidence reliably to evaluate the effect of altering blood pressure on outcome after acute stroke. CCBs, beta blockers, and probably ACE-inhibitors, prostacyclin and nitric oxide, each lowered BP during the acute phase of stroke. In contrast, magnesium, naftidrofuryl and piracetam had little or no effect on BP.

It is unclear whether hypertension should be treated after acute stroke, and some have hypothesised that blood pressure should be increased to improve cerebral perfusion. The objective of this review was to assess the effect of lowering or elevating blood pressure in people with acute stroke, and the effect of different vasoactive drugs on blood pressure in acute stroke. We searched the Cochrane Stroke Group trials register, the Ottawa Stroke Trials Registry (1994), Medline (from 1965), Embase (from 1981), ISI, and existing review articles. We contacted researchers in the field and pharmaceutical companies. Randomised trials of interventions that aimed to alter blood pressure in patients within two weeks of acute ischaemic or haemorrhagic stroke. Two reviewers independently applied the inclusion criteria and assessed trial quality. Two reviewers extracted the data. Three trials involving 133 people were included. The trials tested the following vasodilators: nimodipine (66 people), nicardipine (five people), captopril (three people) and clonidine (two people). Oral calcium channel blockers (nimodipine, nicardipine) reduced systolic blood pressure (weighted mean difference 10.9mmHg, 95% confidence interval 2.0 to 19.7), diastolic blood pressure (weighted mean difference 9.5mmHg, 95% confidence interval 4.0 to 15.1) and heart rate (weighted mean difference 4.7 beats per minute, 95% confidence interval 0.2 to 9.2) at 48 hours. The greatest fall in blood pressure over the first 24 hours was shown in patients given the highest dose of nimodipine. The relationship between change in blood pressure and clinical outcome was not clear. There was not enough information to assess the effect of drugs other than calcium channel blockers. No studies of interventions to raise blood pressure were found. There is not enough evidence to evaluate the effect of altering blood pressure after acute stroke. Although oral calcium channel blockers appear to reduce blood pressure following acute stroke, the balance of benefit and risk remains unclear.

Treatment of blood pressure in acute stroke is controversial, whether attempts are made to reduce or to increase blood pressure. Few clinical studies are available to guide clinicians. A Cochrane review1 on deliberately altering blood pressure within 2 weeks of stroke onset found 5 small trials, involving 218 patients randomized to nimodipine, nicardipine, captopril, clonidine, glyceryl trinitrate, or perindopril versus placebo or control treatment. The limited number of data made it impossible to assess the relationship between blood pressure and clinical outcome. Ahmed et al2 made a post hoc analysis on the effect of intravenous nimodipine in acute ischemic stroke within 24 hours. They found that a reduction of diastolic blood pressure of about 15 mm Hg was associated with poor outcome, whereas a spontaneous fall in the placebo group of about 8 …

It is unclear whether blood pressure (BP) should be altered actively during the acute phase of stroke. To assess the effect of lowering or elevating BP in people with acute stroke, and the effect of different vasoactive drugs on BP in acute stroke. We searched the Cochrane Stroke Group Trials Register (last searched June 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2009), MEDLINE (1966 to October 2009), EMBASE (1980 to October 2009), and Science Citation Index (1981 to October 2009). Randomised trials of interventions that would be expected, on pharmacological grounds, to alter BP in patients within one week of the onset of acute stroke. Two review authors independently applied the trial inclusion criteria, assessed trial quality, and extracted data. We identified 131 trials involving in excess of 18,000 patients; a further 13 trials are ongoing. We obtained data for 43 trials (7649 patients). Among BP-lowering trials, beta receptor antagonists lowered BP (early systolic BP (SBP) mean difference (MD) -6.1 mmHg, 95% CI -11.4 to -0.9; late SBP MD -4.9 mmHg, 95% CI -10.2 to 0.4; late diastolic BP (DBP) MD -4.5 mmHg, 95% CI -7.8 to -1.2). Oral calcium channel blockers (CCB) lowered BP (late SBP MD -3.2 mmHg, 95% CI -5.4 to -1.1; early DBP MD -2.5, 95% CI -5.6 to 0.7; late DBP MD -2.1, 95% CI -3.5 to -0.7). Nitric oxide donors lowered BP (early SBP MD -10.3 mmHg, 95% CI -17.6 to -3.0). Prostacyclin lowered BP (late SBP MD, -7.7 mmHg, 95% CI -15.6 to 0.2; late DBP MD -3.9 mmHg, 95% CI -8.1 to 0.4). Among BP-increasing trials, diaspirin cross-linked haemoglobin (DCLHb) increased BP (early SBP MD 15.3 mmHg, 95% CI 4.0 to 26.6; late SBP MD 15.9 mmHg, 95% CI 1.8 to 30.0). None of the drug classes significantly altered outcome apart from DCLHb which increased combined death or dependency (odds ratio (OR) 5.41, 95% CI 1.87 to 15.64). There is not enough evidence to evaluate reliably the effect of altering BP on outcome after acute stroke. However, treatment with DCLHb was associated with poor clinical outcomes. Beta receptor antagonists, CCBs, nitric oxide, and prostacyclin each lowered BP during the acute phase of stroke. In contrast, DCLHb increased BP.

In this issue of the journal, Elewa et al. [1] present interesting data about the potential neurovascular protection of lowering blood pressure during reperfusion after experimental cerebral ischaemia in rats. Following 3 h of middle cerebral artery occlusion, either enalapril or dihydralazine caused a marked decrease in blood pressure and infarct size, although this did not influence neurological outcome. From the same group, Fagan et al. [2] have previously shown that candesartan causes a similar reduction in blood pressure and infarct size in a similar rat model, but additionally confers an improved neurological outcome. There is no consensus on how to treat patients with elevated blood pressure after ischaemic stroke and the issue has been much debated [3,4]. The majority of stroke patients experience a transient rise in blood pressure, regardless of whether the patient is normotensive or hypertensive before the insult. In ischaemic stroke, an underperfused but viable zone, the ischaemic penumbra, surrounds the infarcted area in the brain. It has been argued that the penumbra is dependent on elevated blood pressure to survive, and that a spontaneous or induced fall in blood pressure could result in a larger infarction area. On the other hand, there is evidence that severely elevated blood pressure after stroke results in ischaemic oedema and possibly increasing risk of cerebral haemorrhage. A Cochrane review on the subject has been unable to point towards any difference in either disability or survival whether blood pressure in acute stroke was lowered by drugs or left to settle spontaneously. The studies included in this analysis were rather small, and most used a calcium antagonist in the active treatment arm [5]. The studies by the Fagan group provide an important contribution to the debate on whether blood pressure lowering with or without angiotensin receptor blockers (ARBs) confers neuroprotection in acute stroke. This topic is reviewed briefly below. Stroke prevention beyond blood pressure lowering with angiotensin receptor blockers? The LIFE study showed that patients with hypertension and left ventricular hypertrophy treated with the ARB losartan had a lower incidence of stroke compared to a similar patient group treated with the β-blocker atenolol [6]. A meta-analysis from 2005 has convincingly shown that β-blockers convey only approximately one-half of the protection against stroke afforded by other groups of antihypertensives [7]. This may have influenced the outcome of the LIFE-study. The VALUE study did not reveal any beneficial effect of the ARB valsartan versus the calcium antagonist, amlodipine, beyond blood pressure lowering on stroke and acute myocardial infarction in patients with hypertension and high cardiovascular risk. Indeed, there was a slightly worse outcome in the valsartan arm, which had higher blood pressure [8]. In a recent analysis of VALUE patients on monotherapy with valsartan or amlodipine, blood pressure and outcome were identical in the two arms [9]. The MOSES study compared the ARB, eprosartan, with the calcium antagonist, nitrendipine [10]. The endpoints were cardiovascular and cerebrovascular events. Here, both arms achieved the same blood pressure and there was an improved outcome for stroke in the eprosartan arm of the study. The LIFE and MOSES trials indicate a specific beneficial effect on stroke for treatment with ARBs whereas the VALUE study does not support this. In most studies, apart from the beneficial effect of the lower blood pressure, angiotensin-converting enzyme (ACE) inhibitors do not give better protection against stroke compared to other antihypertensive medication. By contrast, there appears to be a slightly increased incidence of stroke in the trial arms treated with ACE inhibitors [11]. In the PROGESS study, combination therapy with indapamide and the ACE inhibitor, perindopril, prevented stroke recurrence, whereas monotherapy with perindopril had no such effect [12]. As an exception from this pattern, in the HOPE study, the ACE inhibitor ramipril caused a marked reduction in stroke [13]. The Fournier hypothesis Albert Fournier has suggested that antihypertensive medication that increases the concentration of angiotensin II (diuretics, calcium antagonists and ARBs) has a greater protective effect against stroke than agents that lower the concentration of angiotensin II (β-blockers and ACE inhibitors). This hypothesis is based on a critical review of the results of a number of controlled clinical hypertension trials and is supported by many experimental stroke studies in rodents [14]. Fournier et al. [14] explain the protection against stroke observed in the ACE inhibitor arm in the HOPE study as being mediated by prevention of heart disease in high-risk patients. The antihypertensive effect of ARBs is primarily mediated via the subtype 1 receptors. It is possible that the subtype 2 receptor is concomitantly activated by the increased amount of angiotensin II being around. Fournier et al. [14] have thus hypothesized that the neuroprotective effect of the ARB is mediated via the subtype 2 receptor. A test of this hypothesis requires a large clinical trial, unlikely to be undertaken, in which an ACE inhibitor and an ARB are compared head to head. Experimental studies of angiotensin receptor blockers in acute ischemic stroke The studies conducted by the Fagan group are the most recent of several where acute ischemic stroke with or without reperfusion in rodents has been carried out to investigate whether there is a beneficial effect of the ARBs. One study showed that treatment with candesartan in spontaneously hypertensive rats for 14 days prior to a cerebral insult both lowered blood pressure and decreased the size of the cerebral infarction [15]. Groth et al. [16] found that the size of the infarction and the neurological deficit was smaller when treated with candesartan administered subcutaneously for 5 days prior to a cerebral insult. A single dose of candesartan given 4 h before the cerebral insult did not have any effect [16]. Brdon et al. [17] recently found that a relatively small dose of candesartan exerted neuroprotection in acute ischaemic stroke with reperfusion in the rat when given 3 h but not 24 h after the insult [17]. A larger dose of candesartan did not reduce infarct volume, and the authors suggest that the neuroprotective effect of the drug was offset by excess blood pressure fall. Another group from Germany found that, when candesartan was given both 2 h before and in the days after the cerebral insult, the size of the infarction became smaller [18]. Another ARB, irbesartan, given in the ventricles of the brain, has been shown to have a similar effect [19]. Furthermore, the neuroprotective effect of irbesartan in this latter study was eliminated when an angiotensin II subtype 2 blocker was given simultaneously. It is not yet clear whether the cerebroprotective effect takes place in the brain tissue itself or in the vessels of the brain. If the effect is located in the brain, any difference between the neuroprotective effect of different ARBs might be due to differences in their ability to cross the blood–brain barrier. Candesartan is the ARB that appears to cross the barrier fastest. It does have an intracerebral effect 4 h after oral intake in the rat [20]. Studies in the gerbil, which does not have a complete circle of Willis, have provided valuable information on the effect of ACE inhibitors and ARBs in cerebral ischemia. When one of the carotid arteries of the gerbil is ligated, the animal suffers severe cerebral ischaemia with high mortality. When the gerbil is treated with an ARB, the survival increases whereas the ACE inhibitor has no such effect. Simultaneous administration of both the ARB, losartan, and the ACE inhibitor, enalapril, resulted in no neuroprotection [21,22]. These studies, together with the fact that the angiotensin II subtype 2 receptor is upregulated in the brain in cerebral ischemia, support Fournier's hypothesis that the neuroprotective effect of the ARB is mediated via the subtype 2 receptor in the brain tissue. It should be noted that there are some studies that do not appear to be in agreement with Fournier's hypothesis. A group from Japan found that, in a rat model where one of the medial cerebral arteries was occluded, the effect of 28 days of treatment with either the ARB, candesartan, or the ACE inhibitor, captopril, had the same reduction of infarct size (31 versus 25%) compared to an untreated group of rats. The authors suggested that this effect is of a vascular nature [23]. Clinical studies of angiotensin receptor blockers in acute stroke In the ACCESS study, 342 patients who had suffered ischaemic stroke were randomized to receive either candesartan or placebo in the first week after ischaemic stroke. After the first week, both arms were able to receive candesartan as part of their antihypertensive treatment. The aim was to achieve a blood pressure below 140/90 mmHg. Almost all of the patients received candesartan in the following 12 months. Primary end-point was death and disability after 3 months and a combined secondary end-point was death, cerebrovascular event and cardiovascular event after 12 months. The blood pressure was almost identical in the two arms. The study was stopped because of a significantly higher mortality rate in the placebo group during the first 2 weeks. There was no difference in the disability after 12 months between the two arms and hence no neuroprotection of the ARB was demonstrated [24]. An ongoing study, the Scandinavian Candesartan Acute Stroke Trial (SCAST), is readdressing the question of a beneficial effect of angiotensin receptor blockade in acute ischemic stroke [http://www.scast.no]. Treatment of patients with ARBs in the acute phase of stroke appears to be safe because no complications to treatment were reported in the ACCESS study. Conclusion The study by Elewa et al. [1] demonstrates that, in a rat model of experimental ischemic stroke with reperfusion, treatment with hydralazine and enalapril causes a fall in blood pressure and a decrease in infarct size, similar to that the group previously demonstrated with candesartan. By contrast, rats treated acutely with candesartan had a better neurological outcome than those treated with hydralazine or enalapril, suggesting a nonvascular effect of candesartan in this stroke model [2]. Experimental ischaemic stroke with reperfusion may resemble clinical acute stroke with spontaneous or therapeutic thrombolysis, where the infarcted area of the brain goes through a period of hyperaemia. Blood pressure lowering would expectedly be beneficial in this hyperaemic phase, which unfortunately cannot be discerned clinically. The possible beneficial effects of ARBs beyond blood pressure lowering would also be expected to be most marked after early thrombolysis. It will be very interesting to see whether this can be demonstrated in the SCAST trial. Other clinical trials, COSSACS and CHIPPS, are under way to test blood pressure manipulation in acute stroke [25,26]. While awaiting the results of the trials, it seems wisest to approach high blood pressure in the acute stroke patient with caution, leaving most transient pressure elevations to settle spontaneously. After 1–2 weeks, a persistently elevated blood pressure should be treated and, based on the MOSES trial, treatment should probably include an ARB.

Nitric oxide (NO) has multiple effects that may be beneficial in acute stroke, including lowering blood pressure, and promoting reperfusion and cytoprotection. Some forms of nitric oxide synthase inhibition (NOS-I) may also be beneficial. However, high concentrations of NO are likely to be toxic to brain tissue. This is an update of a Cochrane review first published in 1998, and last updated in 2002. To assess the safety and efficacy of NO donors, L-arginine, and NOS-I in people with acute stroke. We searched the Cochrane Stroke Group Trials Register (last searched 6 February 2017), MEDLINE (1966 to June 2016), Embase (1980 to June 2016), ISI Science Citation Indexes (1981 to June 2016), Stroke Trials Registry (searched June 2016), International Standard Randomised Controlled Trial Number (ISRCTN) (searched June 2016), Clinical Trials registry (searched June 2016), and International Clinical Trials Registry Platform (ICTRP) (searched June 2016). Previously, we had contacted drug companies and researchers in the field. Randomised controlled trials comparing nitric oxide donors, L-arginine, or NOS-I versus placebo or open control in people within one week of onset of confirmed stroke. Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. The review authors cross-checked data and resolved issues through discussion. We obtained published and unpublished data, as available. Data were reported as mean difference (MD) or odds ratio (OR) with 95% confidence intervals (CI). We included five completed trials, involving 4197 participants; all tested transdermal glyceryl trinitrate (GTN), an NO donor. The assessed risk of bias was low across the included studies; one study was double-blind, one open-label and three were single-blind. All included studies had blinded outcome assessment. Overall, GTN did not improve the primary outcome of death or dependency at the end of trial (modified Rankin Scale (mRS) > 2, OR 0.97, 95% CI 0.86 to 1.10, 4195 participants, high-quality evidence). GTN did not improve secondary outcomes, including death (OR 0.78, 95% CI 0.40 to 1.50) and quality of life (MD -0.01, 95% CI -0.17 to 0.15) at the end of trial overall (high-quality evidence). Systolic/diastolic blood pressure (BP) was lower in people treated with GTN (MD -7.2 mmHg (95% CI -8.6 to -5.9) and MD -3.3 (95% CI -4.2 to -2.5) respectively) and heart rate was higher (MD 2.0 beats per minute (95% CI 1.1 to 2.9)). Headache was more common in those randomised to GTN (OR 2.37, 95% CI 1.55 to 3.62). We did not find any trials assessing other nitrates, L-arginine, or NOS-I. There is currently insufficient evidence to recommend the use of NO donors, L-arginine or NOS-I in acute stroke, and only one drug (GTN) has been assessed. In people with acute stroke, GTN reduces blood pressure, increases heart rate and headache, but does not alter clinical outcome (all based on high-quality evidence).

High blood pressure (BP) is common in acute stroke and might be associated with a poor outcome, although observational studies have given varying results. In a systematic review, articles were sought that reported both admission BP and outcome (death, death or dependency, death or deterioration, stroke recurrence, and hematoma expansion) in acute stroke. Data were analyzed by the Cochrane Review Manager software and are given as odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs). Altogether, 32 studies were identified involving 10 892 patients. When all data were included, death was significantly associated with an elevated mean arterial BP ([MABP] OR, 1.61; 95% CI, 1.12 to 2.31) and a high diastolic BP ([DBP] OR, 1.71; 95% CI, 1.33 to 2.48). Combined death or dependency was associated with high systolic BP ([SBP] OR, 2.69; 95% CI, 1.13 to 6.40) and DBP (OR, 4.68; 95% CI, 1.87 to 11.70) in primary intracerebral hemorrhage (PICH). Similarly, high SBP (+11.73 mm Hg; 95% CI, 1.30 to 22.16), MABP (+9.00 mm Hg; 95% CI, 0.92 to 17.08), and DBP (+6.00 mm Hg; 95% CI, 0.19 to 11.81) were associated with death or dependency in ischemic stroke. Combined death or deterioration was associated with a high SBP (OR, 5.57; 95% CI, 1.42 to 21.86) in patients with PICH. In summary, high BP in acute ischemic stroke or PICH is associated with subsequent death, death or dependency, and death or deterioration. Moderate lowering of BP might improve outcome. Acute BP lowering needs to be tested in 1 or more large, randomized trials.

Major Ongoing Stroke Trials

Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. To evaluate NO donors for cervical ripening before first-trimester surgical abortion, in terms of efficacy, side effects, and reduction of complications. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and POPLINE. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. Two review authors independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan 5) software. We included 9 studies involving 766 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the included trials.NO donors were more effective in cervical ripening when compared with placebo or no treatment. Baseline cervical dilatation before the procedure was higher in NO donors group (mean difference (MD) 0.30, 95% confidence interval (CI) 0.01 to 0.58) The cumulative force required to dilate the cervix to 8 mm (MD -4.29, 95% CI -9.92 to 1.35), headache (risk ratio (RR) 1.73, 95% CI 0.86 to 3.46), abdominal pain (RR 0.87, 95% CI 0.50 to 1.50), or patient satisfaction (RR 0.95, 95% CI 0.84 to 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07 to 6.45).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8 mm to 9 mm was higher (MD 13.12, 95% CI 9.72 to 16.52), and baseline cervical dilatation was less (MD -0.73, 95% CI -1.01 to -0.45) in the NO donor group. However, the probability of dilation greater than 8 mm at three hours was higher in the NO donor group (RR 6.67, 95% CI 2.21 to 20.09). Side effects including headache (RR 5.13, 95% CI 3.29 to 8.00), palpitation (RR 3.43, 95% CI 1.64 to 7.15), dizziness (RR 3.29, 95% CI 1.46 to 7.41), and intraoperative blood loss (MD 33.59 ml, 95% CI 24.50 to 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25 to 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07 to 0.27) were less in the NO donor group. No difference for nausea/vomiting in both groups(RR 1.17, 95% CI 0.94 to 1.46). Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (MD 14.50, 95% CI 0.50 to 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38 to 2.00), abdominal pain (RR 0.14, 95% CI 0.02 to 1.07), or intraoperative blood loss (MD -50, 95% CI -164.19 to 64.19). NO donors are superior to placebo or no treatment, but inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects.

Major Ongoing Stroke Trials

Since the initial description of angiotensin II–mediated hypertension >40 years ago, basic and clinical investigations of the renin-angiotensin system (RAS) have resulted in a broader understanding of cardiovascular pathophysiology and significant advances in therapy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists are now widely prescribed for the treatment of hypertension and left ventricular (LV) dysfunction; more recently, the aldosterone receptor antagonist, spironolactone, has proven beneficial in severe heart failure. This article will focus on our current understanding of the RAS and how pharmacological manipulation of this system can improve clinical outcomes in patients with cardiovascular disease. ### Pathophysiological Rationale for RAS Manipulation Renin is released by juxtuloglomerular cells in the kidney in response to renal hypoperfusion, decreased sodium delivery, and sympathetic activation (Figure 1). Angiotensinogen produced by the liver is cleaved by renin to yield the inactive decapeptide angiotensin I. Circulating angiotensin I is, in turn, converted to angiotensin II in the lungs by the action of ACE. ACE, or kininase II, also plays a key role in the kallikrein-kinin system by cleaving bradykinin to inactive peptides. In addition to the hormonal effects of circulating angiotensin II, all of the necessary components of the RAS exist in several organs and tissues, including the heart, kidneys, and vasculature. Figure 1. Pathophysiology of the RAS. SMC indicates smooth muscle cell. Angiotensin II exerts its actions in target organs and tissues by binding to both angiotensin II type 1 and 2 (AT1 and AT2) receptors, although adverse effects in humans seem to be mediated primarily by the AT1 receptor (Figure 1). In the kidney, angiotensin II causes sodium and water retention and efferent arteriolar vasoconstriction. Constriction of the systemic vasculature by angiotensin II causes hypertension, whereas coronary vasoconstriction may cause myocardial ischemia and arrhythmias. Angiotensin II–stimulated secretion of aldosterone by the adrenal cortex and arginine …

Abstracts of literature

The effects of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure, cerebral and cardiac hemodynamics, and plasma nitric oxide levels in acute stroke

Contrast-induced nephropathy (CIN) is associated with increased mortality and morbidity in patients undergoing coronary angiography (CAG) and percutaneous coronary intervention (PCI). We aimed to assess the latest evidence on the preventive effects of nitric oxide (NO) donors in CIN patients undergoing CAG/PCI. We conducted a comprehensive systematic review and meta-analysis of RCTs from PubMed, Web of Science, Scopus, Embase, and Cochrane searches until May 5th, 2024. Dichotomous data were pooled using risk ratio (RR), and continuous data were pooled using mean difference (MD), both with a 95% confidence interval (CI), using (R version 4.3). Our analysis included 13 RCTs encompassing 3,550 patients. NO donors were significantly associated with a decreased incidence of CIN compared to placebo either as an oral administration (RR: 0.33 with 95% CI [0.26, 0.42], P < 0.01) or IV infusions (RR: 0.56 with 95% CI [0.40, 0.78], P < 0.01). Moreover, NO donors were significantly associated with decreased serum creatinine levels compared to placebo either as an oral administration (MD: - 0.07 with 95% CI [- 0.10, - 0.04], P < 0.01) or IV infusions (MD: - 0.07 with 95% CI [- 0.09, - 0.04], P < 0.01). In terms of safety, NO donors were significantly associated with a decreased incidence of major adverse cardiac events (MACE) compared to placebo as an oral administration (RR: 0.64 with 95% CI [0.45, 0.89], P < 0.01). However, there was no significant difference between NO donors as IV infusions and placebo in MACE (RR: 0.68 with 95% CI [0.38, 1.21], P = 0.18). Finally, NO donors were significantly associated with a decreased incidence of all-cause mortality compared to placebo as an oral administration (RR: 0.58 with 95% CI [0.36, 0.94], P = 0.03). Nevertheless, there was no statistically significant difference in all-cause mortality between IV infusions of NO donors and placebo (RR: 1.84 with 95% CI [0.40, 8.52], P = 0.44). NO donors as adjunct therapy are associated with reduced incidence of CIN and decreased serum creatinine levels, either as an oral or IV administration. They were also associated with reduced incidence of MACE, all-cause mortality, and recurrent myocardial infarction as an oral administration, which makes this simple, low-cost intervention an important therapeutic option in patients undergoing CAG/PCI.