Kirtane, Ajay J.

Hypertension is the single most important modifiable risk factor for preventable disability and death worldwide and disproportionately affects socially disadvantaged populations. We face a paradox—blood pressure control is low and recent trends suggest it is even declining, despite the availability of inexpensive and effective therapies. A variety of barriers on the system, patient, and healthcare provider side hinder effective drug-based risk factor management. Clinical inertia represents a major barrier on the clinician side, as well as workload and limited education. Common barriers on the patient side include limited English proficiency, low health literacy, and nonadherence with misaligned incentives, limited resources, lack of structured clinical pathways, and reimbursement issues. New innovations in the field of RNA-targeted therapies and device-based interventions could prevent and potentially even cure diseases previously designated as chronic health conditions, such as hypertension. Such novel therapies could potentially overcome several major barriers to effective treatment, including nonadherence. Drug development of novel, long-acting treatments requires consideration of specific clinical trial design aspects, including safety collection, benefit: risk assessment, the development and assessment of novel, qualitative surrogate end points, such as time-in-therapeutic range, the use of representative trial settings as well as the definition of standard of care in placebo-controlled trials, which should be of reasonably high-quality allowing for credible evaluation of effectiveness. Here, we provide an overview on barriers to effective treatment and a framework for trials assessing novel treatments for cardiovascular disease risk factors, including early and broad implementation programs.

Background: Predicting technical failure in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) can assist with decision making and planning of the procedure. Methods: We analyzed 6,946 CTO PCIs performed between 2016 and June 2022 at 36 international centers in the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO) and created a score for risk of technical failure. Logistic regression prediction modeling was used to identify independently associated variables with technical failure and model were internally validated with bootstrapping. Results: Mean patient age was 64.0±10 years, 82% were men and technical success was 86%. The following variables were independently associated with technical failure and were included in the final model: age (odds ratio [OR]: 1.08, 95% Confidence Intervals [CI]: [1.00-1.15], p=0.039; age≥ 65 years; 1 point), CTO length (OR: 1.13, 95% CI [1.10, 1.17]; length≥ 20 mm; 1 point), moderate/severe calcification (OR: 1.35, 95% CI [1.17, 1.56]; 1 point), proximal cap ambiguity (OR: 2.25, 95% CI [1.95, 2.59]; 2 points), lack of interventional collaterals (OR: 1.60, 95% CI [1.39, 1.84]; 1 point), and lack of good distal landing zone (OR: 1.51, 95% CI [1.31, 1.75]; 1 point). The resulting score showed acceptable performance on receiver-operating characteristic (ROC) curve, AUC: 0.68 (95% CI [0.67-0.71]). Internal validation with bootstrapping of 1000 samples demonstrated a good agreement with the model, observed AUC: 0.68, (95% bias corrected CI [0.67, 0.70]). PROGRESS-CTO technical failure score and corresponding risk percentage and the percentage of patients in the respective risk group within the PROGRESS-CTO registry are represented in Figure 1. Conclusion: The updated PROGRESS CTO score may be useful for assessing the likelihood of technical failure success in CTO PCI.

Background: In the ACUITY Trial, patients (pts) with chronic renal insufficiency (CRI) had significantly higher rates of ischemic events and major bleeding compared to pts without CRI at 30 days. Bivalirudin (Biv) monotherapy provided similar protection from ischemic events but with significantly less bleeding compared to heparin + a GPIIb/IIIa inhibitor (Hep+GPI). The impact of a Biv alone strategy on one year mortality is unknown. Methods: Pts with moderate and high risk acute coronary syndromes (ACS) were randomized to Hep + GPI, Biv + GPI, or Biv monotherapy. CRI was defined as baseline creatinine clearance (CrCl) <60 mL/min. We evaluated the impact of CRI and antithrombotic strategy on composite ischemia (death, MI, or revascularization) and mortality at one year. Results: Of the pts enrolled, 12,933 had baseline CrCl data: 2468 (19.1%) pts had CrCl ≥60 mL/min and 10,465 (80.9%) pts had CrCl <60 mL/min. Rates of major bleeding at 30 days in pts with CRI were significantly lower with Biv alone vs Hep+GPI (6.2% vs 9.8%, p<0.01). Pts with CRI had higher mortality at one year compared to those without CRI (8.7% vs 3.0%, p<0.001). There was no difference in composite ischemia for pts who received Biv monotherapy vs Hep + GPI (23.0% vs 21.4%, p=0.10). One year mortality by antithrombin strategy is shown in the Figure . Conclusions: CRI in pts with ACS is associated with higher rates of one year mortality. In these high risk pts, Biv monotherapy improved early clinical outcomes compared to Hep + GPI by reducing major bleeding, and resulted in similar rates of one year mortality. Cumulative Mortality at One Year, Patients with CRI

Background: Vascular and bleeding complications were commonly reported in transcatheter aortic valve replacement clinical trials. Little is known about complication rates in contemporary US clinical practice or clinical outcomes associated with these complications. Methods: In the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry, we evaluated patients undergoing transcatheter aortic valve replacement from November 1, 2011 to June 30, 2016. The primary outcomes were in-hospital vascular complications and bleeding events. Secondary outcomes included all-cause mortality, stroke, and rehospitalization at 1 year. P values for trends were calculated for rates over time, and multivariable logistic regression was used to determine the association between vascular/bleeding complications and in-hospital clinical outcomes. Results: Overall, 34 893 patients undergoing transcatheter aortic valve replacement at 445 hospitals were analyzed. Of these, 9.3% (n=3257) experienced a vascular complication while 7.6% (n=2651) had an in-hospital bleeding event. Rates of both vascular complications and bleeding events decreased over time ( P value for trend test <0.0001); however, there was significant variation in rates across hospital sites (adjusted median rate, 11.4%; IQR, 8.9–14.5). Vascular complications were independently associated with 30-day death (adjusted HR, 2.23 [95% CI, 1.80–2.77]) and death (adjusted HR, 1.17 [95% CI, 1.05–1.30]) and rehospitalization (adjusted HR, 1.14 [95% CI, 1.07–1.22]) at 1 year. Bleeding events were also associated with 30-day death (adjusted HR, 3.71 [95% CI, 2.94–4.69]), and with death (adjusted HR, 1.39 [95% CI, 1.23–1.56]) and hospital readmission (adjusted HR, 1.19 [95% CI, 1.11–1.27]) at 1 year. Conclusions: In patients undergoing transcatheter aortic valve replacement in the US, vascular complications and in-hospital bleeding events were common, but rates have declined over time with significant variation in complication rates across hospital sites. Vascular and bleeding complications are both associated with worse short- and long-term clinical outcomes including all-cause mortality. Further innovation to reduce sheath sizes and optimize antithrombotic therapy is necessary to reduce the incidence of these detrimental complications.

Background— The higher risk of adverse outcomes after transapical (TA) versus transfemoral (TF) transcatheter aortic valve replacement (TAVR) could be attributable to TA-TAVR being an open surgical procedure or to clinical differences between TA- and TF-TAVR patients. We compared outcomes after neutralizing patient differences using propensity score matching. Methods and Results— From April 2007 to February 2012, 1100 Placement of Aortic Transcatheter Valves (PARTNER)-I patients underwent TA-TAVR and 1521 underwent TF-TAVR with Edwards SAPIEN balloon-expandable bioprostheses. Propensity matching based on 111 preprocedural variables, exclusive of femoral access morphology, identified 501 well-matched patient pairs (46% of possible matches), 95% of whom had peripheral arterial disease. Matched TA-TAVR patients experienced more adverse procedural events, longer length of stay (5 versus 8 days; P <0.0001), and slower recovery (New York Heart Association class I, 31% versus 38% at 30 days, equalizing by 6 months at 51% versus 47%); stroke risk was similar (3.4% versus 3.3% at 30 days and 6.0% versus 6.7% at 3 years); mortality was elevated for the first 6 postprocedural months (19% versus 12%; P =0.01); but aortic regurgitation was less (34% versus 52% mild and 8.9% versus 12% moderate to severe at discharge, P =0.001; 36% versus 50% mild and 10% versus 15% moderate to severe at 6 months, P <0.0001). Conclusions— The likelihood of adverse periprocedural events and prolonged recovery is greater after TA-TAVR than TF-TAVR in vasculopathic patients after accounting for differences in cardiovascular risk factors, although stroke risk is equivalent and aortic regurgitation is less. As smaller delivery systems permit TF-TAVR in many of these patients, we recommend a TF-first access strategy for TAVR when anatomically feasible. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00530894.

Background— The clinical significance of incomplete coronary revascularization (ICR) after percutaneous coronary intervention in patients with acute coronary syndromes is unknown. Methods and Results— We performed quantitative angiography of the entire coronary tree in 2954 patients with acute coronary syndromes in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. ICR was variably defined if any lesion with diameter stenosis (DS) cutoffs ranging from ≥30% to ≥70% with reference vessel diameter ≥2.0 mm remained after percutaneous coronary intervention. The primary outcome was 1-year composite rate of major adverse cardiac events (death, myocardial infarction, or ischemia-driven unplanned revascularization). With the use of DS cutoffs ≥30%, ≥40%, ≥50%, ≥60%, and ≥70%, the prevalence of ICR after percutaneous coronary intervention was 75%, 55%, 37%, 25%, and 17%, respectively. The 1-year major adverse cardiac event rate was increased among patients with ICR using all of the DS cutoffs. ICR (≥50% DS) was associated with higher 1-year rates of myocardial infarction (12.0% versus 8.2%; hazard ratio, 1.50; 95% confidence interval, 1.18–1.89; P =0.0007) and ischemia-driven unplanned revascularization (15.7% versus 10.2%; hazard ratio, 1.58; 95% confidence interval, 1.28–1.96; P <0.0001), with a trend toward increased mortality (3.1% versus 2.2%; hazard ratio, 1.43; 95% confidence interval, 0.90–2.27; P =0.13). By multivariable analysis, ICR (≥50% DS) was an independent predictor of 1-year major adverse cardiac events (hazard ratio, 1.36; 95% confidence interval, 1.12–1.64; P =0.002). The impact of ICR on major adverse cardiac events was similar regardless of chronic total occlusion presence, but it was more pronounced with a greater number of nonrevascularized lesions. Conclusions— Depending on the threshold of percent DS, ICR was present in 17% to 75% of patients with acute coronary syndromes after percutaneous coronary intervention. Regardless of the threshold, ICR was strongly associated with 1-year myocardial infarction, ischemia-driven unplanned revascularization, and major adverse cardiac events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00093158.