Angiotensin 1/2 (1-9)

A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache

Objective: To compare the effectiveness and side effects of migraine prophylactic medications. Design: We performed a network meta-analysis. Data were extracted independently in duplicate and quality was assessed using both the JADAD and Cochrane Risk of Bias instruments. Data were pooled and network meta-analysis performed using random effects models. Data sources: PUBMED, EMBASE, Cochrane Trial Registry, bibliography of retrieved articles through 18 May 2014. Eligibility criteria for selecting studies: We included randomized controlled trials of adults with migraine headaches of at least 4 weeks in duration. Results: Placebo controlled trials included alpha blockers (n = 9), angiotensin converting enzyme inhibitors (n = 3), angiotensin receptor blockers (n = 3), anticonvulsants (n = 32), beta-blockers (n = 39), calcium channel blockers (n = 12), flunarizine (n = 7), serotonin reuptake inhibitors (n = 6), serotonin norepinephrine reuptake inhibitors (n = 1) serotonin agonists (n = 9) and tricyclic antidepressants (n = 11). In addition there were 53 trials comparing different drugs. Drugs with at least 3 trials that were more effective than placebo for episodic migraines included amitriptyline (SMD: -1.2, 95% CI: -1.7 to -0.82), -flunarizine (-1.1 headaches/month (ha/month), 95% CI: -1.6 to -0.67), fluoxetine (SMD: -0.57, 95% CI: -0.97 to -0.17), metoprolol (-0.94 ha/month, 95% CI: -1.4 to -0.46), pizotifen (-0.43 ha/month, 95% CI: -0.6 to -0.21), propranolol (-1.3 ha/month, 95% CI: -2.0 to -0.62), topiramate (-1.1 ha/month, 95% CI: -1.9 to -0.73) and valproate (-1.5 ha/month, 95% CI: -2.1 to -0.8). Several effective drugs with less than 3 trials included: 3 ace inhibitors (enalapril, lisinopril, captopril), two angiotensin receptor blockers (candesartan, telmisartan), two anticonvulsants (lamotrigine, levetiracetam), and several beta-blockers (atenolol, bisoprolol, timolol). Network meta-analysis found amitriptyline to be better than several other medications including candesartan, fluoxetine, propranolol, topiramate and valproate and no different than atenolol, flunarizine, clomipramine or metoprolol. Conclusion: Several drugs good evidence supporting efficacy. There is weak evidence supporting amitriptyline's superiority over some drugs. Selection of prophylactic medication should be tailored according to patient preferences, characteristics and side effect profiles.

Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial

Background: Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of neprilysin inhibition on the course of renal function in patients with type 2 diabetes.
Methods: In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255.
Findings: eGFR decreased by 1·1 mL/min per 1·73 m² per year (95% CI 1·0-1·2) in patients without diabetes, but by 2·0 mL/min per 1·73 m² per year (1·9-2·1) in those with diabetes (p<0·0001). Compared with patients treated with enalapril, those treated with sacubitril/valsartan had a slower rate of decline in eGFR (-1·3 vs -1·8 mL/min per 1·73 m² per year; p<0·0001), and the magnitude of the benefit was larger in patients with versus those without diabetes (difference 0·6 mL/min per 1·73 m² per year [95% CI 0·4-0·8] in patients with vs 0·3 mL/min per 1·73 m² per year [0·2-0·5] in those without diabetes; p_interaction=0·038). The greater effect of neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA_1c. The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0·41).
Interpretation: In patients in whom the renin-angiotensin system is already maximally blocked, the addition of neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure.
Funding: Novartis.

Comparative Effectiveness of Angiotensin II Receptor Blockers in Patients With Hypertension in Japan - Systematic Review and Network Meta-Analysis

Background: Angiotensin II receptor blockers (ARBs) are widely used for the management of hypertension in Japan; however, comparative efficacy data within the ARB drug class remain limited. Methods and Results: This systematic literature review identified randomized controlled trials (RCT) indexed in PubMed and Ichushi in Japanese patients with hypertension receiving ARB monotherapy (azilsartan, candesartan cilexetil, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan) in at least 1 arm. Of 763 RCTs identified, 77 met the eligibility criteria; of which, 37 reported mean change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline in the office setting and were used to construct the network. A fixed-effects model (FEM) showed the effect of each drug vs. the reference, azilsartan. Using the FEM, the mean (95% credible interval) change from baseline in SBP/DBP for candesartan cilexetil, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, and valsartan was 3.8 (2.9-4.8)/2.6 (2.0-3.1), 4.8 (2.0-7.5)/3.7 (1.8-5.6), 3.0 (0.8-5.1)/1.9 (0.5-3.3), 3.2 (1.2-5.1)/2.7 (1.3-4.1), 3.2 (0.8-5.6)/2.0 (0.3-3.6), and 3.1 (1.1-5.1)/2.4 (1.1-3.8) mmHg, respectively. Conclusions: The results of this meta-analysis provide evidence that azilsartan has a more favorable efficacy profile than the other ARBs in reducing SBP and DBP.

Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction

Background: Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects.
Methods: We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a β-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire.
Results: From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m² (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change.
Conclusions: In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)-ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)-chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow-derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP(+) cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm(2)) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm(2)) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80(+)) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm(2); reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm(2)). In both study cohorts, intracapillary bone marrow-derived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.