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The apparent shortfall in prevention of coronary heart disease (CHD) noted in early hypertension trials has been attributed to disadvantages of the diuretics and β blockers used. For a given reduction in blood pressure, some suggested that newer agents would confer advantages over diuretics and β blockers. Our aim, therefore, was to compare the effect on non-fatal myocardial infarction and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril. We did a multicentre, prospective, randomised controlled trial in 19 257 patients with hypertension who were aged 40–79 years and had at least three other cardiovascular risk factors. Patients were assigned either amlodipine 5–10 mg adding perindopril 4–8 mg as required (amlodipine-based regimen; n=9639) or atenolol 50–100 mg adding bendroflumethiazide 1·25–2·5 mg and potassium as required (atenolol-based regimen; n=9618). Our primary endpoint was non-fatal myocardial infarction (including silent myocardial infaction) and fatal CHD. Analysis was by intention to treat. The study was stopped prematurely after 5·5 years' median follow-up and accumulated in total 106 153 patient-years of observation. Though not significant, compared with the atenolol-based regimen, fewer individuals on the amlodipine-based regimen had a primary endpoint (429 vs 474; unadjusted HR 0·90, 95% CI 0·79–1·02, p=0·1052), fatal and non-fatal stroke (327 vs 422; 0·77, 0·66–0·89, p=0·0003), total cardiovascular events and procedures (1362 vs 1602; 0·84, 0·78–0·90, p<0·0001), and all-cause mortality (738 vs 820; 0·89, 0·81–0·99, p=0·025). The incidence of developing diabetes was less on the amlodipine-based regimen (567 vs 799; 0·70, 0·63–0·78, p<0·0001). The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen. On the basis of previous trial evidence, these effects might not be entirely explained by better control of blood pressure, and this issue is addressed in the accompanying article. Nevertheless, the results have implications with respect to optimum combinations of antihypertensive agents.

There is concern that patients taking renin–angiotensin–aldosterone system inhibitors have an increased risk of Covid-19, because angiotensin-converting enzyme 2 is a receptor for the virus. This study showed no increase in likelihood of a positive Covid-19 test or severe Covid-19 in patients taking any of five common classes of antihypertensive drugs.

In diffuse forms of arteriovenous malformation following Fontan procedure, “classical” medical therapy, inhaled nitric oxide and sildenafil, may play a role, until re-direction of hepatic flow to pulmonary circulation cures it. However, in refractory cases, as reported in our 2-year-old patient, unusual medications such as calcium channel blockers can be tried and continued if patients respond adequately.

ObjectiveTo compare the effect of exercise regimens and medications on systolic blood pressure (SBP).Data sourcesMedline (via PubMed) and the Cochrane Library.Eligibility criteriaRandomised controlled trials (RCTs) of angiotensin-converting enzyme inhibitors (ACE-I), angiotensin-2 receptor blockers (ARBs), β-blockers, calcium channel blockers (CCBs) and diuretics were identified from existing Cochrane reviews. A previously published meta-analysis of exercise interventions was updated to identify recent RCTs that tested the SBP-lowering effects of endurance, dynamic resistance, isometric resistance, and combined endurance and resistance exercise interventions (up to September 2018).DesignRandom-effects network meta-analysis.OutcomeDifference in mean change from baseline SBP between comparator treatments (change from baseline in one group minus that in the other group) and its 95% credible interval (95% CrI), measured in mmHg.ResultsWe included a total of 391 RCTs, 197 of which evaluated exercise interventions (10 461 participants) and 194 evaluated antihypertensive medications (29 281 participants). No RCTs compared directly exercise against medications. While all medication trials included hypertensive populations, only 56 exercise trials included hypertensive participants (≥140 mmHg), corresponding to 3508 individuals. In a 10% random sample, risk of bias was higher in exercise RCTs, primarily due to lack of blinding and incomplete outcome data. In analyses that combined all populations, antihypertensive medications achieved higher reductions in baseline SBP compared with exercise interventions (mean difference −3.96 mmHg, 95% CrI −5.02 to −2.91). Compared with control, all types of exercise (including combination of endurance and resistance) and all classes of antihypertensive medications were effective in lowering baseline SBP. Among hypertensive populations, there were no detectable differences in the SBP-lowering effects of ACE-I, ARB, β-blocker and diuretic medications when compared with endurance or dynamic resistance exercise. There was no detectable inconsistency between direct and indirect comparisons. Although there was evidence of small-study effects, this affected both medication and exercise trials.ConclusionsThe effect of exercise interventions on SBP remains under-studied, especially among hypertensive populations. Our findings confirm modest but consistent reductions in SBP in many studied exercise interventions across all populations but individuals receiving medications generally achieved greater reductions than those following structured exercise regimens. Assuming equally reliable estimates, the SBP-lowering effect of exercise among hypertensive populations appears similar to that of commonly used antihypertensive medications. Generalisability of these findings to real-world clinical settings should be further evaluated.

Despite successful treatment of the culprit artery lesion by primary percutaneous coronary intervention (PCI) with stent implantation, thrombotic embolisation occurs in some cases, which impairs the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). We aimed to assess the clinical outcomes of deferred stent implantation versus standard PCI in patients with STEMI. We did this open-label, randomised controlled trial at four primary PCI centres in Denmark. Eligible patients (aged >18 years) had acute onset symptoms lasting 12 h or less, and ST-segment elevation of 0·1 mV or more in at least two or more contiguous electrocardiographic leads or newly developed left bundle branch block. Patients were randomly assigned (1:1), via an electronic web-based system with permuted block sizes of two to six, to receive either standard primary PCI with immediate stent implantation or deferred stent implantation 48 h after the index procedure if a stabilised flow could be obtained in the infarct-related artery. The primary endpoint was a composite of all-cause mortality, hospital admission for heart failure, recurrent infarction, and any unplanned revascularisation of the target vessel within 2 years' follow-up. Patients, investigators, and treating clinicians were not masked to treatment allocation. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01435408. Between March 1, 2011, and Feb 28, 2014, we randomly assigned 1215 patients to receive either standard PCI (n=612) or deferred stent implantation (n=603). Median follow-up time was 42 months (IQR 33–49). Events comprising the primary endpoint occurred in 109 (18%) patients who had standard PCI and in 105 (17%) patients who had deferred stent implantation (hazard ratio 0·99, 95% CI 0·76–1·29; p=0·92). Procedure-related myocardial infarction, bleeding requiring transfusion or surgery, contrast-induced nephopathy, or stroke occurred in 28 (5%) patients in the conventional PCI group versus 27 (4%) patients in the deferred stent implantation group, with no significant differences between groups. In patients with STEMI, routine deferred stent implantation did not reduce the occurrence of death, heart failure, myocardial infarction, or repeat revascularisation compared with conventional PCI. Results from ongoing randomised trials might shed further light on the concept of deferred stenting in this patient population. Danish Agency for Science, Technology and Innovation, and Danish Council for Strategic Research.

Prednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach. This study was a multicentre, randomised, double-blind, placebo-controlled trial done in ten specialised headache centres in Germany. Patients with episodic cluster headaches who were aged between 18 and 65 years and within a current pain episode for not more than 30 days, received 100 mg oral prednisone for 5 days followed by tapering of 20 mg every 3 days, or matching placebo (17 days total exposure). All patients received oral verapamil for long-term prevention, starting with 40 mg three times daily and increasing to 120 mg three times daily by day 19; patients then continued with verapamil 120 mg throughout the study. Randomisation was computer-generated at a 1:1 ratio by use of an interactive web-response system, with stratification according to age, sex, and participating site. Participants, investigators, and those assessing outcomes were unaware of treatment allocation. The primary endpoint was the mean number of attacks within the first week of treatment with prednisone compared with placebo. An attack was defined as a unilateral headache with moderate-to-severe intensity of at least five on a numerical rating scale. All efficacy and safety analyses were done in the modified intention-to-treat (mITT) population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of prednisone or placebo. The study was stopped early due to slow recruitment and expired funding. The study was registered with EudraCT (2011–006204–13) and with the German Clinical Trials Register (DRKS00004716). Between April 5, 2013, and Jan 11, 2018, 118 patients were enrolled in the study. Two patients dropped out immediately and 116 patients were randomly assigned (57 patients to prednisone and 59 patients to placebo); 109 patients were included in the mITT analysis (53 patients assigned to prednisone and 56 patients assigned to placebo). Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks within the first week compared with 9·5 (6·0) attacks in the placebo group (difference −2·4 attacks, 95% CI −4·8 to −0·03; p=0·002). Two serious adverse events occurred, both in the placebo group (inguinal hernia and severe deterioration of cluster headache). A total of 270 adverse events were observed: in the prednisone group, 37 (71%) of 52 patients reported 135 adverse events (most common were headache, palpitations, dizziness, and nausea) and in the placebo group, 39 (71%) of 55 patients had 135 adverse events (most common were nausea, dizziness, and headache). Oral prednisone was an effective short-term preventive therapy in our population of patients with episodic cluster headache. Our findings support the use of prednisone as a first-line treatment in parallel to the up-titration of verapamil, although the efficacy of prednisone alongside other long-term prevention requires additional investigation. German Federal Ministry for Education and Research.

Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.

The risk of cancer from antihypertensive drugs has been much debated, with a recent analysis showing increased risk with angiotensin-receptor blockers (ARBs). We assessed the association between antihypertensive drugs and cancer risk in a comprehensive analysis of data from randomised clinical trials. We undertook traditional direct comparison meta-analyses, multiple comparisons (network) meta-analyses, and trial sequential analyses. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from 1950, to August, 2010, for randomised clinical trials of antihypertensive therapy (ARBs, angiotensin-converting-enzyme inhibitors [ACEi], β blockers, calcium-channel blockers [CCBs], or diuretics) with follow-up of at least 1 year. Our primary outcomes were cancer and cancer-related deaths. We identified 70 randomised controlled trials (148 comparator groups) with 324 168 participants. In the network meta-analysis (fixed-effect model), we recorded no difference in the risk of cancer with ARBs (proportion with cancer 2·04%; odds ratio 1·01, 95% CI 0·93–1·09), ACEi (2·03%; 1·00, 0·92–1·09), β blockers (1·97%; 0·97, 0·88–1·07), CCBs (2·11%; 1·05, 0·96–1·13), diuretics (2·02%; 1·00, 0·90–1·11), or other controls (1·95%, 0·97, 0·74–1·24) versus placebo (2·02%). There was an increased risk with the combination of ACEi plus ARBs (2·30%, 1·14, 1·02–1·28); however, this risk was not apparent in the random-effects model (odds ratio 1·15, 95% CI 0·92–1·38). No differences were detected in cancer-related mortality for ARBs (death rate 1·33%; odds ratio 1·00, 95% CI 0·87–1·15), ACEi (1·25%; 0·95, 0·81–1·10), β blockers (1·23%; 0·93, 0·80–1·08), CCBs (1·27%; 0·96, 0·82–1·11), diuretics (1·30%; 0·98, 0·84–1·13), other controls (1·43%; 1·08, 0·78–1·46), and ACEi plus ARBs (1·45%; 1·10, 0·90–1·32). In direct comparison meta-analyses, similar results were recorded for all antihypertensive classes, except for an increased risk of cancer with ACEi and ARB combination (OR 1·14, 95% CI 1·04–1·24; p=0·004) and with CCBs (1·06, 1·01–1·12; p=0·02). However, we noted no significant differences in cancer-related mortality. On the basis of trial sequential analysis, our results suggest no evidence of even a 5–10% relative risk (RR) increase of cancer and cancer-related deaths with any individual class of antihypertensive drugs studied. However, for the ACEi and ARB combination, the cumulative Z curve crossed the trial sequential monitoring boundary, suggesting firm evidence for at least a 10% RR increase in cancer risk. Our analysis refutes a 5·0–10·0% relative increase in the risk of cancer or cancer-related death with the use of ARBs, ACEi, β blockers, diuretics, and CCBs. However, increased risk of cancer with the combination of ACEi and ARBs cannot be ruled out. None.

Preclinical research with rodents suggests that the L-type calcium channel blocker isradipine can enhance long-term extinction of conditioned place preference for addictive substances when it is administered in conjunction with extinction training. Although isradipine alone, which is FDA-approved for hypertension, has not shown a direct effect on craving in human drug users, its potential to augment behavioral treatments designed to reduce craving remains unknown. We conducted a triple-blind, randomized placebo-controlled pilot clinical trial of isradipine combined with a novel virtual reality cue exposure therapy (VR-CET) approach with multimodal cues that targeted craving. After 24 hours of abstinence, 78 adults with an ongoing history of daily cigarette use received isradipine (n = 40) or placebo (n = 38) and reported craving levels after each of 10 trials of VR-CET. Consistent with pre-registered hypotheses, the isradipine group had significantly lower mean craving across cue exposure trials at the medication-free 24-hour follow-up (d = -0.42, p = 0.046). There were no serious adverse events; however, side effects such as headache and dizziness occurred more frequently in the isradipine group. The findings of the current study support follow-up clinical trials that specifically test the efficacy of isradipine-augmented VR-CET for reducing smoking relapse rates after an initial quit attempt. clinicaltrials.gov: NCT03083353.

Verapamil hydrochloride (VRP), an antihypertensive calcium channel blocker drug has limited bioavailability and short half-life when taken orally. The present study was aimed at developing cubosomes containing VRP for enhancing its bioavailability and targeting to brain for cluster headache (CH) treatment as an off-label use. Factorial design was conducted to analyze the impact of different components on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and percent drug release. Various in-vitro characterizations were performed followed by pharmacokinetic and brain targeting studies. The results revealed the significant impact of glyceryl monooleate (GMO) on increasing EE%, PS, and ZP of cubosomes with a negative influence on VRP release. The remarkable effect of Poloxamer 407 (P407) on decreasing EE%, PS, and ZP of cubosomes was observed besides its influence on accelerating VRP release%. The DSC thermograms indicated the successful entrapment of the amorphous state of VRP inside the cubosomes. The design suggested an optimized formulation containing GMO (50% w/w) and P407 (5.5% w/w). Such formulation showed a significant increase in drug permeation through nasal mucosa with high E r value (2.26) when compared to VRP solution. Also, the histopathological study revealed the safety of the utilized components used in the cubosomes preparation. There was a significant enhancement in the VRP bioavailability when loaded in cubosomes owing to its sustained release favored by its direct transport to brain. The I.N optimized formulation had greater BTE% and DTP% at 183.53% and 90.19%, respectively in comparison of 41.80% and 59% for the I.N VRP solution. Graphical Abstract