Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the “white-coat effect” (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.

Objective Resistant hypertension (res-HTN) is a challenging problem, but little is known of res-HTN in patients with coronary artery disease (CAD). In this post-hoc INternational VErapamil SR-Trandolapril STudy (INVEST) analysis, we assessed prevalence, predictors, and impact on outcomes of res-HTN in CAD patients with hypertension. Methods Participants (n=17 190) were divided into three groups according to achieved blood pressure (BP): controlled (BP <140/90 mmHg on three or fewer drugs); uncontrolled (BP ≥140/90mmHg on two or fewer drugs); or resistant (BP ≥140/90 mmHg on three drugs or any patient on at least four drugs). Results The prevalence of res-HTN was 38%: significant predictors of res-HTN included heart failure [odds ratio (OR) 1.73], diabetes (OR 1.63), Black race (OR 1.50), and US residence (OR 1.50). Compared with controlled HTN, res-HTN had multivariate-adjusted association with higher risk of adverse outcomes {first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke [hazard ratio 1.27, 95% confidence interval (CI) 1.13–1.43], and individual outcomes of all-cause death (hazard ratio 1.29, 95% CI 1.13–1.48), cardiovascular mortality (hazard ratio 1.47, 95% CI 1.21–1.78), and nonfatal stroke (hazard ratio 1.61, 95% CI 1.17–2.22), but not nonfatal myocardial infarction (hazard ratio 0.98, 95% CI 0.72–1.34)}. Adverse outcomes, except nonfatal stroke, did not differ in patients with res-HTN compared to uncontrolled HTN. Conclusions Res-HTN is common in patients with CAD and hypertension, associated with poor prognosis, and linked with a number of conditions. Emphasis should be placed on recognizing those at risk for res-HTN and future studies should examine whether more aggressive treatment of res-HTN improves outcomes.

Inhibition of H1/H2HR reverses PSC-associated damage and decreases CCA growth, angiogenesis, and EMT; because PSC patients are at risk of developing CCA, using HR blockers may be therapeutic for these diseases. (Hepatology 2018).

SUMMARYWhat is known and objective: Although non-steroidal antiinflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk. Methods: We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib.

Using population-based data, incident use of SGLT-2 inhibitors was associated with a decreased incidence of CVD compared to use of sulfonylureas and DPP-4 inhibitors. These findings were consistent between dapagliflozin and canagliflozin, suggesting that CVD reduction is a class effect for SGLT2 inhibitors. In addition, SGLT2 inhibitors portended lower risk of hospitalization because of heart failure (vs sulfonylureas and DPP-4 inhibitors) and lower risk of lower extremity amputation (vs sulfonylureas).

PHEN/TPM is a new, once-daily, controlled-release, combination weight-loss product approved as an adjunct to diet and exercise for chronic weight management of obese or overweight patients with weight-related comorbidities. PHEN/TPM is modestly effective and a viable option for patients interested in losing weight, although long-term safety data are lacking.

Objective: Phase I, open-label, randomized, single-dose, 3-period crossover study assessing pharmacokinetics (PK) and safety of ZX008, a liquid oral formulation of fenfluramine (FFA) under development for adjunctive treatment of Dravet syndrome and Lennox-Gastaut syndrome, administered with and without a combined antiepileptic drug (AED) regimen of stiripentol (STP), valproate (VPA), and clobazam (CLB) (STP regimen). Materials and methods: 26 healthy adults were administered the following treatments: ZX008 0.8 mg/kg; STP 3,500 mg, CLB 20 mg, VPA 25 mg/kg (max. 1,500 mg); and ZX008 0.8 mg/kg + STP regimen. Dose periods were 17 days apart. Blood samples were obtained for 72 hours after drug administration and used to calculate non-compartmental PK parameters. Results: Statistical bioequivalence-type analysis demonstrated ZX008 had no significant impact on the PK of any drug in the STP regimen, while the STP regimen moderately affected FFA PK. The 3-drug combination increased the geometric mean Cmax, AUC0–t, and AUC0–inf of FFA while reducing the Cmax and AUC0–t of its major metabolite, norfenfluramine (norFFA). Adverse events (AEs) were mild to moderate and resolved spontaneously. ZX008 + STP regimen co-administration to healthy adult subjects modestly impacted the number but not severity of AEs. Conclusion: Results show that the STP regimen had a moderate impact on FFA and norFFA PK and ZX008 had no significant impact on the 3 STP regimen drugs. ZX008 would not be expected to alter the clinical response of patients to this regimen by means of an effect on PK. When administering these drugs together, a downward dose adjustment of ZX008 may be warranted.

BackgroundWomen are more likely than men to develop resistant hypertension, which is associated with excess risk of major adverse outcomes; however, the impact of resistant hypertension in women with ischemia has not been explicitly studied. In this Women's Ischemia Syndrome Evaluation (WISE) analysis, we assessed long‐term adverse outcomes associated with apparent treatment‐resistant hypertension (aTRH) among women with suspected myocardial ischemia referred for coronary angiography.Methods and ResultsWomen (n=927) were grouped according to baseline blood pressure (BP): normotensive (no hypertension history, BP <140/90 mm Hg, no antihypertensive drugs); controlled (BP <140/90 mm Hg and a hypertension diagnosis or on 1 to 3 drugs); uncontrolled (BP ≥140/90 mm Hg on ≤2 drugs); or aTRH (BP ≥140/90 mm Hg on 3 drugs or anyone on ≥4 drugs). Adverse outcomes (first occurrence of death [any cause], nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or angina) were collected over 10 years of follow‐up. Apparent treatment‐resistant hypertension prevalence was 10.4% among those with hypertension. Women with aTRH had a greater incidence of adverse outcomes, compared with normotensive women (adjusted hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.94 to 5.43), and women with controlled (HR, 1.77; 95% CI, 1.26 to 2.49) and uncontrolled (HR, 1.62; 95% CI, 1.15 to 2.27) hypertension; outcome differences were evident early in follow‐up. Risk of all‐cause death was greater in the aTRH group, compared to the normotensive women and women with controlled and uncontrolled hypertension.ConclusionsIn this cohort of women with evidence of ischemia, aTRH was associated with a profoundly increased long‐term risk of major adverse events, including death, that emerged early during follow‐up.