— Cardioprotective effect of PDE5 inhibitors did not pan out with anti-anginals in the picture
As expected, men taking nitrates for stable coronary artery disease (CAD) fared poorly if they added certain erectile dysfunction (ED) drugs to their medicine cabinet, a Swedish population-based study found.
Compared with nitrate users not on phosphodiesterase-5 (PDE5) inhibitor treatment for ED, those who had both types of drugs in their medication history tended to be at higher risk for events over a median follow-up of 5.9 years:
Mortality: HR 1.39 (95% CI 1.28-1.51)
Cardiovascular mortality: HR 1.34 (95% CI 1.11-1.62)
Noncardiovascular mortality: HR 1.40 (95% CI 1.27-1.54)
Myocardial infarction (MI): HR 1.72 (95% CI 1.55-1.90)
Heart failure: HR 1.67 (95% CI 1.48-1.90)
Cardiac revascularization: HR 1.95 (95% CI 1.78-2.13)
Major cardiovascular events (MACE): HR 1.70 (95% CI 1.58-1.83)
Notably, these risks were not increased within 28 days of dispensing the PDE5 inhibitors, reported Daniel Andersson, MD, PhD, of Karolinska Institutet and Karolinska University Hospital Huddinge in Stockholm, and colleagues in the Journal of the American College of Cardiologyopens in a new tab or window.
“The use of a PDE5 inhibitor in combination with nitrate medication in men with stable CAD may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5 inhibitors to patients with cardiovascular disease using nitrate medication is warranted,” the authors urged, based on their study of over 60,000 individuals.
PDE5 inhibitors on the market include sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra).
For years, FDA labeling and professional guidelines have agreed that these medications should not be prescribed with nitrates due to concerns about a potential significant drop in blood pressure.
“Organic nitrates, such as those used as antianginal therapy, increase the production of cGMP [cyclic guanosine monophosphate], resulting in systemic vasodilation,” explained Glenn Levine, MD, of Baylor College of Medicine in Houston, in an accompanying editorialopens in a new tab or window.
“Because PDE5 inhibitors reduce cGMP degradation, the combination of these 2 drugs synergistically leads to increased vasodilation and a greater hypotensive response,” he continued. “Compared with the decrease in systolic blood pressure with nitrate therapy alone, the decrease in systolic blood pressure with combined nitrate plus PDE5 inhibitor treatment in the 1 to several hours after exposure can be on the order of 20 to 25 mm Hg or more.”
Given the limited evidence of such hypotension, however, people are increasingly taking both drugs in the real world, so Andersson and colleagues tried to test whether concomitant use of PDE5 inhibitors with nitrates is as harmful as suggested. To them, it seemed plausible that PDE5 inhibitors might in fact have cardioprotective effects in this population, similar to what was seen in other studies in people with stable CAD not on nitrate therapy, but the study did not support that hypothesis.
These ED drugs remain “reasonably safeopens in a new tab or window in most patients with stable CAD and only mild angina if not on chronic nitrate therapy,” Levine wrote, while they are “ill-advised at best and generally contraindicated” for people on chronic oral nitrate therapy.
“In some patients on oral nitrate therapy who desire to use a PDE5 inhibitor, particularly those who have undergone revascularization and have minimal or no angina, it may be reasonable to initiate a several-week trial off the nitrate therapy (or on a different class of antianginal therapy) and assess if the patient remains relatively angina-free,” he suggested.
The large population-based cohort study was based on Swedish registry data, and included 55,777 men with previous MI or revascularization in 2006 to 2013 who had two dispensed nitrate prescriptions within 6 months, and another 5,710 peers who also had at least two filled prescriptions for any PDE5 inhibitor.
PDE5 inhibitor users tended to be younger (61.2 vs 70.3 years) and had fewer comorbidities despite a more advanced vascular disease than the nitrate-only cohort.
Andersson and team acknowledged that their observational study could not determine causality and may be subject to confounding. Importantly, they also had no way of knowing patients’ real medication habits after receiving their prescribed medications.
“Our data have no information regarding time of intake or usage at the same time. Neither do we know how stable the medication was over time. However, the fact that there were 2 filled prescriptions indicates usage,” they wrote.
“Our goal is to underscore the need for careful patient-centered consideration before prescribing PDE5 inhibitor medication to men receiving nitrate treatment,” Andersson said in a press release. “Furthermore, it justifies our efforts for continued research into the ambiguous effects of ED drugs on men with cardiovascular disease.”
A two-part research study suggests that frequent cannabis is a risk factor for coronary artery disease (CAD).
In the first part, in an observational study, daily cannabis use was associated with 34% higher odds for CAD compared with never-users in a large population-based US cohort. Less frequent use was not associated with increased odds for CAD.
In the second part, people with a genetic susceptibility to cannabis use disorder or severe cannabis dependency had an increased risk for CAD compared with other people.
Ishan Paranjpe, MD, the study’s lead author, reported these results in a press briefing and will present the study at the upcoming American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023.
Dr Ishan Paranjpe
“A couple of takeaway points are that daily cannabis use, but not less frequent cannabis use was associated with CAD” in the large population-based cohort, said Paranjpe, a resident physician at Stanford University, California, during the press conference.
“This analysis was adjusted for several possible confounders including age, sex at birth, [body mass index (BMI)], race, education, cigarette use, hypertension, high cholesterol, and diabetes,” he noted, and even after accounting for these risk factors, the association with heart disease remained.
“And the next thing, using Mendelian randomization, we sort of implied that there might be a causal relationship between cannabis and heart disease. Importantly this effect is independent of alcohol and cigarette use.
“The notion that cannabis is completely benign is probably wrong, and there might be certain risk of certain cardiovascular effects of cannabis we should be more on the lookout for,” Paranjpe said in an interview with theheart.org | Medscape Cardiology.
“Our main conclusion was that prevalent CAD is associated with cannabis consumption,” he added. “Other mechanistic work published in Cell, has also shown that cannabis causes vascular inflammation that may lead to CAD.
“Thus, there is growing evidence from both laboratory and population studies that cannabis consumption may be harmful for cardiovascular health,” he said. “However, we still need more work on whether it affects the risk of incident cardiovascular events (ie, stroke, heart attack) in patient[s] with existing CAD.”
ASCVD Risk
Invited to comment, Robert L. Page II, PharmD, chair of the writing group for the American Heart Association’s scientific statement Medical Marijuana, Recreational Cannabis, and Cardiovascular Health, published in 2020, said, “this adds to our hypothesis that if you are using marijuana over a longer period, greater exposure, you’re going to see an increase in the risk” for atherosclerotic cardiovascular disease (ASCVD).
“We’re seeing this increased risk for ASCVD in young adults between ages 18 to 40 — people who think that they’re invincible,” Page, a professor at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, who was not involved with this research, told theheart.org | Medscape Cardiology in an interview.
“The bottom line is that the risk that they are seeing is what has also been documented in other observational studies, and it adds fuel to the fire. We need to be paying close attention to this,” he said.
“Primary care [clinicians], cardiologists, need to address this, particularly in younger adults — because that’s where you’re seeing the highest amount of use.”
“All of Us” Observational Study
In the first part of the study, the researchers analyzed data from the “All of Us” cohort comprising adults age 18 and older from 340 inpatient and outpatient sites across the United States.
They identified 57,958 individuals who replied to a questionnaire asking about cannabis use (medicinal or recreational and whether it was edible or used by smoking or vaping) over the past 3 months.
There were 39,678 never-users, 8749 who used it once or twice, 2075 who used it monthly, 2720 who used it weekly, and 4736 who used it daily.
Of these, 3506 individuals had CAD, based on medical records.
Only daily users had a significantly higher risk for CAD compared with never-users (odds ratio [OR], 1.34; P = .001) after adjusting for age, sex, hypertension, hyperlipidemia, type 2 diabetes, BMI, education, insurance status, and cigarette use.
The median age for daily users was 41, whereas the median age for never-users was 59.
GWAS Analyses
The researchers then performed a Mendelian randomization analysis based on genome-wide association studies (GWAS) of cannabis use disorder and of CAD.
“Cannabis use disorder is a psychiatric diagnosis of severe cannabis dependency, equivalent to ‘alcohol use disorder’ for alcohol consumption,” Paranjpe explained. “The exact definition involves frequent use leading to significant dependence (but does not specify how often it is used).”
The GWAS data for cannabis use disorder came from a recent meta-analysis of three cohorts: the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE.
The GWAS statistics for CAD were obtained from the CARDIoGRAMplusC4D Consortium.
Cannabis use disorder was associated with significantly increased odds for CAD (OR, 1.05; P = .001), which remained after adjusting for both cigarette and alcohol use (OR, 1.04; P = 1.07).
In patients with coronary artery disease who are being evaluated for percutaneous coronary intervention (PCI), procedures can be guided by fractional flow reserve (FFR) or intravascular ultrasonography (IVUS) for decision making regarding revascularization and stent implantation. However, the differences in clinical outcomes when only one method is used for both purposes are unclear.
Methods
We randomly assigned 1682 patients who were being evaluated for PCI for the treatment of intermediate stenosis (40 to 70% occlusion by visual estimation on coronary angiography) in a 1:1 ratio to undergo either an FFR-guided or IVUS-guided procedure. FFR or IVUS was to be used to determine whether to perform PCI and to assess PCI success. In the FFR group, PCI was to be performed if the FFR was 0.80 or less. In the IVUS group, the criteria for PCI were a minimal lumen area measuring either 3 mm2 or less or measuring 3 to 4 mm2 with a plaque burden of more than 70%. The primary outcome was a composite of death, myocardial infarction, or revascularization at 24 months after randomization. We tested the noninferiority of the FFR group as compared with the IVUS group (noninferiority margin, 2.5 percentage points).
Results
The frequency of PCI was 44.4% among patients in the FFR group and 65.3% among those in the IVUS group. At 24 months, a primary-outcome event had occurred in 8.1% of the patients in the FFR group and in 8.5% of those in the IVUS group (absolute difference, −0.4 percentage points; upper boundary of the one-sided 97.5% confidence interval, 2.2 percentage points; P=0.01 for noninferiority). Patient-reported outcomes as reported on the Seattle Angina Questionnaire were similar in the two groups.
Conclusions
In patients with intermediate stenosis who were being evaluated for PCI, FFR guidance was noninferior to IVUS guidance with respect to the composite primary outcome of death, myocardial infarction, or revascularization at 24 months.
In some patients with coronary artery disease, drug-coated balloons (DCB) represent an attractive therapeutic alternative to drug-eluting stents (DES), currently the undisputed gold standard for percutaneous coronary interventions.1,2 At present, DCB provide the best means to pursue a leave-nothing-behind strategy following studies demonstrating that bioresorbable scaffolds are inferior, regarding safety and efficacy, to new-generation DES. In Europe, current clinical practice guidelines for coronary revascularization recommend the use of DCB (Class 1, Level of Evidence: A) for patients with in-stent restenosis (ISR).1 Evidence supporting this recommendation stems from multiple randomized clinical trials (RCT) demonstrating that, in this unique anatomical setting, DCB are superior to classic treatment modalities and equivalent to new-generation DES.3 Notably, in patients with ISR, although DES provide better long-term angiographic results, these only translate into a marginal superiority over DCB regarding target lesion revascularization.3 This clinical benefit is considered insufficient by many to justify systematic implantation of an additional, permanent, metal layer on the vessel wall.2
The value of DCB in selected patients with de novo lesions has been investigated in observational studies, RCT, and meta-analyses,4 but the available evidence is clearly less robust than is available in the setting of ISR. A consensus document on DCB highlights the role of this technology in special clinical and anatomical scenarios (patients at high bleeding risk or with acute myocardial infarction and lesions in small vessels or involving bifurcations), outside the niche of ISR.2 In small vessels, the relatively large BASKET-SMALL-2 (Basel Stent Kosten Effektivitäts Trial Drug Eluting Balloons vs. Drug Eluting Stents in Small Vessel Interventions) RCT demonstrated that DCB are noninferior to DES for the primary combined clinical endpoint at 1 and 3 years,5 although some patients in the control group were treated with first-generation DES. Also in small vessels, the PICCOLETO-2 (Drug Eluting Balloon Efficacy for Small Coronary Vessel Disease Treatment) RCT demonstrated that DCB have a lower angiographic late lumen loss (LLL), as compared with new-generation DES,6 though minimal lumen diameter and percent diameter stenosis at follow-up, valuable endpoints in this setting, were similar in both treatment groups. In selected patients with acute myocardial infarction, 2 small RCT supported the use of a DCB-alone strategy.7,8 In the PEPCAD-NSTEMI (Bare Metal Stent Versus Drug Coated Balloon With Provisional Stenting in Non-ST-Elevation Myocardial Infarction) RCT, DCB were noninferior to stents for the primary composite clinical endpoint at 1 year.7 Similarly, the REVELATION (Revascularization With Paclitaxel-Coated Balloon Angioplasty Versus Drug-Eluting Stenting in Acute Myocardial Infarction) RCT suggested that DCB and new-generation DES provided a similar physiological outcome (fractional flow reserve) in the culprit vessel at 9-month follow-up.8 For lesions involving bifurcations, the small PEPCAD-BIF (The Paclitaxel-Eluting Percutaneous Coronary Angioplasty [PTCA]-Balloon Catheter for the Treatment of Coronary Bifurcations) RCT showed a lower restenosis rate with DCB compared with conventional balloon angioplasty (BA).9 Last, but not least, in high-bleeding risk patients, the DEBUT (Drug-Eluting Balloon in Stable and Unstable Angina) RCT demonstrated that DCB reduced the occurrence of adverse clinical events compared with bare-metal stents.10 Due to the limitations of the totallity of the evidence for this indication, the use of DCB in de novo lesions is not yet recommended by clinical practice guidelines in any specific clinical or anatomical niche,1 suggesting that more robust evidence remains an unmet need.1,2
Some additional important issues shape the field of DCB in the coronary space. First, most RCT on DCB are small and focus on surrogate angiographic endpoints, but large “pivotal” RCT, powered for major hard clinical endpoints, are lacking.1,2 This may explain why this technology has not yet been approved for clinical use in some countries, including the United States. Second, most of the available evidence supporting the efficacy of DCB in the coronary territory was obtained with DCB eluting paclitaxel and, in particular, with a specific DCB technology.1,2 Therefore, a class effect cannot be assumed for these devices: not all DCB are created equal.1,2 Paclitaxel has been classically selected for DCB because its lipophilic properties facilitate the transit and retention at the vessel wall.2 Paclitaxel is a cytotoxic drug with a narrow therapeutic range that irreversibly blocks cell division, preventing depolymerization of intracellular microtubules. The safety concerns and controversy regarding the use of paclitaxel-DCB in peripheral vessels have never affected the coronary space where, recently, a large and exhaustive meta-analysis completely dissipated doubts on any potential adverse signal.11 Nevertheless, in new-generation DES, limus-type drugs have completely displaced taxane derivatives, as a result of superior safety and efficacy.1 Limus-type drugs are potent cytostatic drugs with a wider therapeutic window and reversible effects at the vessel wall. However, limus drugs do not exhibit high lipophilicity and face major difficulties in achieving adequate tissue penetration and retention when eluted from a DCB.2
Fortunately, recent technological advances have been able to overcome these pharmacodynamics challenges, and currently limus-DCB are available for clinical use in many countries. Preliminary clinical experience with the use of limus-DCB has been encouraging.2,12,13 The largest experience encompasses the use of sirolimus-DCB for real world patients, with either ISR or de novo lesions, with satisfactory mid-term clinical results.2,12,13 However, RCT comparing limus-DES with reliable comparators are scarce and involve a very limited number of patients (Table 1).14-16 Whether limus-DCB will fulfil the expectation of being superior to paclitaxel-DCB remains unsettled.
BA = conventional plain balloon angioplasty; DCB = drug-coated balloon; DES = drug-eluting stent; DES-ISR = drug-eluting stent in-stent restenosis; LLL = late lumen loss; RCT = randomized clinical trials; SVD = small vessel disease; TLR = target lesion revascularization.
a P < 0.05.
In this issue of JACC: Cardiovascular Interventions, Xu et al16 present results of the BIO-RISE CHINA (A Randomized Trial of a Biolimus-Coated Balloon Versus POBA in Small Vessel Coronary Artery Disease) RCT, where a novel biolimus-DCB was compared with BA in patients with de novo lesions in small vessels. The study was conducted in 10 Chinese centers, enrolled 212 patients, with 177 patients (86%) entering in the per-protocol population, and used a superiority design. Lesions were to be <25 mm in length and in vessels with a reference diameter of 2.00 to 2.75 mm on visual estimation. Patients were only randomized after a satisfactory angiographic result was obtained following predilation of the target lesion. The primary endpoint, in-segment LLL at 9 month, was met (biolimus-DCB 0.16 ± 0.29 vs BA 0.30 ± 0.35 mm; P = 0.001). In addition, late lumen enlargement (ie, negative LLL) occurred in one-third of patients in the biolimus-DCB arm vs one-tenth of those in the BA arm (P = 0.007). From a clinical standpoint, target lesion failure (6.7% vs 13.9%) and a patient-oriented combined outcome measure (14.3% vs 21.8%) were similar, although numerically favored the biolimus-DCB group.
Considering the potential implications of this RCT and addressing some methodological nuances are important.16 First, using conventional BA as the comparator deviates from standard of care for these patients. According to clinical practice guidelines, new-generation DES are the treatment of choice across the spectrum of lesion and patients subtypes including lesions in small vessels.1,17 Methodologically, however, removing the confounding effects of stent implantation, allows better definition of the treatment effect of biolimus in isolation. Nevertheless, using a classical paclitaxel-DCB as the comparator would have provided unique mechanistic and efficacy insights. Notwithstanding these considerations, BA are still frequently used in clinical practice to treat small vessels, and in this regard, the results of this RCT are of certain clinical relevance.17
Second, patients with suboptimal angiographic results after lesion preparation were excluded, and this explains a cross-over to stents after randomization of only 3%. The number of patients assessed for eligibility, but eventually not randomized, was also very low 12 of 224 (5.3%). Therefore, it remains unclear whether additional patients were excluded due to inadequate results after predilation requiring DES implantation. This issue should be kept in mind when considering the general clinical applicability of this strategy.
Third, this RCT is a first-in-man study of this novel limus-DCB, using biolimus A9 at a dosage of 3 μg/mm2 and polyethylene oxide as excipient. Thus, additional manufacturing details would have been of interest. In this regard provision of preclinical pharmacokinetic and histopathological results, both at the vessel wal and downstream myocardium would have been of major scientific value.
Fourth, angiographic data are paramount considering that LLL was the primary endpoint. The superiority of biolimus-DCB compared with BA regarding LLL was clearly demonstrated. Indeed, this superiority was observed despite a better-than-expected performance of BA in the control arm: LLL after BA was lower than expected and previously reported. This may be explained by the inclusion of very small vessels with rather short lesions (reference vessel diameter 2 mm, lesion length 11 mm, by quantitative angiography) as compared with other studies in small vessels.1,2,17 By contrast, although the LLL of the biolimus-DCB was halved as compared with BA, it remains significantly higher than in previous studies using paclitaxel-DCB.2 Similarly, late lumen enlargement after biolimus-DCB only occurred in one-third of lesions, whereas this phenomenon appears to be more frequently found after paclitaxel-DCB.2 Of note, the term positive vascular remodeling should probably be avoided when intracoronary imaging results are not available. One could speculate that a lower rate of late lumen enlargement might suggest a lower cytotoxicity of biolimus compared with paclitaxel. Conversely, the relatively high LLL might also suggest a lower efficacy of biolimus-DCB compared with paclitaxel-DCB. However, historical comparisons are always flawed, and this issue can only be resolved by adequately powered head-to-head comparative studies.3,4 One such trial is ongoing in the setting of ISR (Biolimus A9™ [BA9™] Drug Coated Balloon [DCB] Study [REFORM]; NCT04079192). Finally, as the methodology and precise system used for the quantitative angiographic analysis (performed at a core lab run by the study’s contract research organization), was not clarified, its potential influence on these differences remains difficult to elucidate.
Last but not least, the clinical implications of surrogate angiographic parameters are particularly elusive on small vessels, where the presence of asymptomatic restenosis may disconnect anatomical results from clinically driven target lesion revascularization.17 Larger studies are required to confirm the favorable clinical results obtained with this novel biolimus-DCB.
Previous Studies with Sirolimus DCB
Information on the clinical value of limus-DCB remains limited.12-16,18 In the family of limus-DCB, sirolimus has been the drug most frequently selected and several technologies have been developed that accord coating stability of the drug on the balloon surface and then adequate transfer, concentration, and retention at the vessel wall.12-16,18 These include the use of nanocarriers, nanoencapsulated sirolimus liquid formulations, and crystalline sirolimus on a butylated hydroxytoluene excipient.12-16,18 Small single-arm studies with systematic angiographic follow-up have demonstrated the antirestenotic efficacy of limus-DCB. Moreover, several prospective registries of sirolimus-DCB in patients with ISR or de novo lesions have reported satisfactory clinical results with low rates of target lesion revascularization.12,13 However, data from controlled RCT are scarce (Table 1).14-16 Ali et al,14 in a head-to-head RCT including 50 patients with DES-ISR, demonstrated a similar in-segment LLL at 6-month (0.17 ± 0.55 vs 0.21 ± 0.54 mm) and similar rate of 1-year clinical events, with a novel crystalline sirolimus-DCB versus the standard paclitaxel-DCB. In another small RCT in 70 patients with de novo lesions (mean reference vessel diameter 2.76 mm) Ahmad et al15 showed a similar LLL with crystalline sirolimus-DCB and paclitaxel-DCB (0.10 ± 0.32 vs 0.01 ± 0.33; noninferiority P < 0.05) but, interestingly, late lumen enlargement was more frequently found in the paclitaxel-DCB arm (60% vs 32%; P = 0.019).
In summary, Xu et al16 should be commended for designing and conducting this RCT providing evidence supporting the efficacy of this biolimus-DCB for de novo lesions in small vessels. Although these results are certainly promising, they remain preliminary, considering that the small sample size was unpowered to detect differences in clinical endpoints. Further studies are required to confirm the relative value of limus-DCB compared with new-generation DES in patients with ISR and de novo lesions. Similarly, additional RCT are warranted to characterize the efficacy of limus-DCB compared with standard paclitaxel-DCB in different clinical and anatomic scenarios.
A 74-year-old man with a history of end-stage kidney disease and coronary artery disease, as well as a 3-day history of anorexia and generalized weakness, was brought to the emergency department for evaluation of decreased responsiveness during hemodialysis. On examination, he appeared ill and provided only brief responses to questions. A chest radiograph showed a widened mediastinum. Computed tomography of the chest, performed without the administration of intravenous contrast material, showed intramural gas in the ascending and descending aorta and aortic calcifications (Panels A and B). Gram’s staining of samples obtained from anaerobic blood cultures showed gram-positive rods (Panel C), and there was subsequent growth of Clostridium septicum. A diagnosis of infectious emphysematous aortitis was made. C. septicum infection is strongly associated with gastrointestinal cancer. The organism is thought to enter the bloodstream from the gastrointestinal tract; in cases of endovascular infection, such as that seen in this patient, it seeds atherosclerotic plaques. Three years before the current presentation, the patient had positive results on fecal immunohistochemical testing, but he declined colonoscopy. Abdominal imaging performed during the current hospitalization showed no overt signs of cancer. Intravenous penicillin G and clindamycin were administered. Although surgery is considered to be the definitive treatment for this type of infection, the level of risk was determined to be unacceptable in this case. The patient died on hospital day 7 while receiving comfort care.
Cardiac imaging by computed tomography (CT) is a remarkable technological accomplishment and, yet CT imaging for coronary heart disease (CHD) risk assessment in asymptomatic subjects still has not achieved full acceptance. Hundreds of research reports support the prognostic usefulness of coronary artery calcium (CAC) testing1 for risk assessment. Practice guidelines from the American Heart Association/American College of Cardiology (AHA/ACC),2 from Canada,3 Europe,4 Australia, and New Zealand5 support the use of CAC in selected patients, but these recommendations lack Class Ia Level of Evidence. In the absence of convincing trial data, insurance coverage for CAC tests in asymptomatic people is variable, despite strong guideline endorsement. Clinical trials are urgently needed to determine whether CAC scores should be routinely used for risk assessment based on evidence of improved patient outcomes.6
Several ongoing trials may finally answer whether CAC scanning improves clinical outcomes. The Risk Or Benefit IN Screening for CArdiovascular disease (ROBINSCA) trial began in the Netherlands in 2014 and is due to conclude soon.7,8 The ROBINSCA trial enrolled 43,447 people, and the primary endpoints were coronary disease morbidity and mortality after 5 years. These results are eagerly awaited, and, because of the size and breadth of the study, could result in practice changes if results are convincing.
The Coronary Artery calcium score: Use to Guide management of Hereditary Coronary Artery Disease (CAUGHT-CAD) trial9,10 was a randomized trial that compared management using CAC scoring versus usual care in approximately 700 intermediate-risk participants with a family history of CHD who did not satisfy current Australian guidelines for primary prevention. The primary endpoint was change of coronary plaque volume at 3 years, and the secondary endpoint was clinical events after 9 years. Because of the size and scope of the study, it is unlikely that any results from this study would convince naysayers of the value of CAC testing for risk assessment.
The SCOT-HEART 2 (Computed Tomography Coronary Angiography [CTCA] for the Prevention of Myocardial Infarction) trial11 is a randomized controlled trial of at least 6,000 subjects at risk for atherosclerotic cardiovascular disease (ASCVD) and will test whether CTCA-guided management will be associated with better targeted intervention, prevent overmedication, and result in fewer cardiac events than traditional risk assessment. This trial is large enough to yield valuable clinical endpoint data, and is expected to report clinical outcomes in 2027, but the use of CTCA instead of simpler and cheaper CAC imaging may deter patients from participating and physicians from using the results, even if results are significant.
A trial was recently funded by the National Heart, Lung, and Blood Institute called the CAC PREVENTABLE (Coronary Artery Calcium in the Pragmatic Evaluation of Events and Benefits of Lipid Lowering in the Elderly) ancillary study.12 This is an ancillary study of a large pragmatic clinical trial that is currently randomizing 20,000 adults age 75 years or older to atorvastatin 40 mg or placebo and following them for ASCVD events. At trial conclusion, outcome analyses will be stratified by CAC to determine heterogeneity of statin effects by CAC status. These results will only be applicable to people age 75 years and older, whereas the greatest need for statin use is undoubtedly in younger people.
In addition, the CorCal (Effectiveness of a Proactive Cardiovascular Primary Prevention Strategy, With or Without the Use of Coronary Calcium Screening, in Preventing Future Major Adverse Cardiac Events) trial is ongoing and plans to end in 2024. CorCal is a pragmatic trial assessing the effectiveness of a proactive cardiovascular primary prevention strategy, with or without CAC screening, conducted among 9,000 patients within the Intermountain Healthcare System in the United States. This open-label study is randomizing eligible participants to receive a statin recommendation based on either CAC screening results or on standard risk assessment results using the AHA/ACC recommended pooled cohort equation (PCE). The final decision regarding treatment is in the hands of the patient and their personal clinician.
In this issue of iJACC, Muhlestein et al13 report the results of a feasibility study conducted to assist in the overall design of the CorCal study. Patients (n = 601) without known ASCVD, diabetes, or previous statin use, were enrolled from primary care clinics and randomized to a CAC-guided clinical recommendation for statin prescription or to a recommendation based on the PCE risk estimate. Patients and physicians made the final decision about treatment in both groups. A statin was recommended in 35.9% of the CAC arm and in 47.9% of the PCE arm, indicating more restricted use because of reclassification to lower risk with CAC testing. There was also evidence of greater statin adherence at 12 months in the CAC-guided patient group than with usual care (63.3% vs 45.6%).
However, the feasibility study also pointed to some potential pitfalls in the larger CorCal study. Approximately 30% of the participants in the CAC arm who qualified for a statin based on their score never started the medication; 54.5% stated that it was because their physicians advised against a statin or never prescribed it. Leaving treatment decisions to patients and providers reduces the cost and complexity of the study. However, when the study is finished, we may find no difference in event rates between the 2 treatment arms, perhaps because too many patients and providers did not follow the advice.
Furthermore, a large proportion of patients will have zero scores, allowing them to forego statin therapy. The ability of CAC to sort patients into higher and lower risk groups is one of its most appealing characteristics as a screening tool. However, the incidence of ASCVD is directly associated with low-density lipoprotein cholesterol (LDL-C) levels. This represents an inherent challenge when designing trials of CAC testing. Although adherence to statins was greater in the CAC arm of Muhlestein et al13 study, the absolute difference in LDL-C levels between groups was only 13.6 mg/dL, in part because adherence rates were still relatively low, and the boost in adherence with CAC was offset by fewer patients needing statins. We struggled with these design challenges when we and others proposed a large clinical trial of CAC testing several years ago.14 The sample size ranged from 20,000 to 30,000 participants depending on our assumptions about several variables, including statin adherence and baseline risk of the population. We also chose to have the study control statin prescriptions and take a more active role to enhance statin adherence. Such factors will be important to consider when interpreting the results of the full CorCal study.
There are many lessons in this 40-year story of technical advances,15 large population studies, improved image quality, reduced radiation exposure, and lower test costs. All of those accomplishments are incredibly important and have influenced clinical practice across the globe to some degree. However, at this time, trial evidence is long overdue, and we are eager to learn the results of all of the ongoing trials. We congratulate the team led by Muhlestein et al13 for their tenacity and courage to answer a question 40 years in the making.
Testing rates fall short of expectations, even among those managed by cardiologists
People with new-onset heart failure (HF) continued to lack adequate testing for coronary artery disease (CAD), a common and treatable cause of HF, and nationwide variations in testing rates suggested room for quality improvement across physicians and geographic regions.
From a large pool of patients with incident HF in 2004-2019, just 34.8% underwent CAD testing during the 90 days before and after the initial diagnosis — 21.7% getting noninvasive testing and 20.7% coronary angiography, according to Alexander Sandhu, MD, MS, of Stanford University School of Medicine in California, and colleagues.
Cardiologists were roughly five times more likely than primary care providers (PCPs) to have their HF patients get tested for CAD, though there was wide variation among cardiologists, too, they reported in the Journal of the American College of Cardiology.
“The wide discrepancy in testing rates between PCPs and cardiologists is particularly striking, because nearly 50% of our cohort were linked to a PCP without cardiology comanagement,” Sandhu’s group wrote.
With this report, the authors extend prior observations of underutilization of testing for CAD to HF outpatients in the contemporary era. Since 2013, guidelines have recommended consideration of noninvasive imaging or coronary angiography among patients with incident HF eligible for revascularization.
“Barring a sea change in how noncardiovascular clinicians manage HF, it is not unreasonable to argue that absent major contraindications, every patient diagnosed with new-onset HF should be referred to a cardiovascular clinician, with establishment of GDMT [guideline-directed medical therapy] goals and CAD testing,” commented James Januzzi Jr, MD, of Massachusetts General Hospital in Boston, and E. Magnus Ohman, MB BCh, of Duke Clinical Research Institute in Durham, North Carolina.
Given the overall testing rate of 57% by cardiologists, however, “even this might leave us short of the goal of routine CAD testing for our affected patients,” they wrote in an accompanying editorial.
Sandhu and colleagues found that CAD testing stayed flat even after the 2016 STICHES report showing a long-term mortality benefit to revascularization among patients with ischemic cardiomyopathy. Ultimately, 9.3% of people with new-onset HF underwent revascularization in the study.
“Our findings raise concern that patients with new-onset HF are not only undertested but also undertreated for CAD,” the authors wrote. “Omission of timely testing precludes management of the most common and potentially reversible etiology of HF.”
“A call to action to address the massive gaps in quality of HF care is sorely needed, with a concerted effort to close the shortfalls in GDMT and CAD treatment in persons with HF. The question exists however: who will make this call, and how many will answer?” Januzzi and Ohman wrote.
The observational study relied on Clinformatics DataMart, an administrative claims database from Optum.
Included were 558,322 adults with a new diagnosis of HF, excluding people with a prior CAD diagnosis and those who had recently received dialysis. Participants averaged age 71.7, and 55.5% were women.
Patient characteristics associated with greater likelihood of CAD testing included ages 40-64 versus older people, men over women, Asian and white patients over Black ones, and greater acuity at presentation.
“Importantly, prominent CAD risk factors such as hypertension, diabetes, obesity, and sleep apnea were not strongly associated with testing, revealing missed opportunities for high-yield CAD workup. In contrast, negative predictors included alcohol use disorder and chronic obstructive pulmonary disease, both of which increase mortality in patients with ischemic heart disease,” Sandhu’s group found.
Disproportionately low rates of CAD testing were also shown in patients with a history of psychotic disorder and dementia.
Additionally, testing rates varied geographically — from a low of 20% in San Luis Obispo County, California, to a high of 45% in Clay County, Florida.
“The root causes of observed geographic differences are unclear, but prior research has identified disparities in resource availability, health care access, socioeconomic conditions, and healthy public policies. Regional gaps in testing highlight the importance of continued surveillance to uncover underlying drivers,” according to Sandhu and colleagues.
They cautioned that the study was subject to local differences in coding practices, unmeasured confounding, and limitations in the granularity of the available clinical data.
“Regardless of these limitations, there is little chance the results would meaningfully change had other data sources been used,” Januzzi and Ohman said.
“Given that CAD has such an established role as a major cause of a leading diagnosis associated with hospitalization and death, widespread availability of tools for its diagnosis, and a dramatic benefit from its treatment in those with HF, one might think that clinicians would pursue the presence of ischemic heart disease with dogged determination. Disappointingly this has not been the case,” they stated.
A diagnosis of depression increases the risk of mortality and hospital readmission due to myocardial infarction (MI) in patients with stable coronary artery disease (CAD), according to a Canadian study presented at the recent American College of Cardiology’s 65th Annual Scientific Session in Chicago, Illinois, US.
CAD patients who were diagnosed with depression had an elevated risk of mortality (hazard ratio [HR], 1.83, 95 percent CI, 1.62-2.07) and readmission for MI (HR, 1.36, 95 percent CI, 1.10-1.67). This risk was highest when depression was diagnosed 90-180 days after diagnosis of stable CAD. Depression did not appear to affect the risk of requiring bypass surgery or coronary stent placements. [ACC 2016, abstract 16-A-10562]
Women (HR, 1.31, 95 percent CI, 1.23-1.39) and individuals with severe angina based on the Canadian Cardiovascular Society (CSS) class (HR, 1.43, 95 percent CI, 1.16-1.76) were at higher risk of depression.
“Based on these findings, there may be an opportunity to improve outcomes in people with coronary heart disease by screening for and treating mood disorders, but this needs to be further studied,” said Dr. Natalie Szpakowski, Internal Medicine Resident at the University of Toronto, Canada, and lead author of the study.
Participants in this retrospective cohort study were 22,917 CAD patients, 18.8 percent of whom had depression after being diagnosed with CAD.
In a separate study involving 7,550 individuals aged ≥40 years, researchers from the Intermountain Medical Center Heart Institute, Salt Lake City, Utah, US found that treating depression appeared to reduce the risk of future major adverse cardiac events (MACE).
Based on results of two questionnaires, incidence of MACE among individuals who were no longer depressed was 4.6 percent (similar to those who were not depressed at all [4.8 percent]) compared to 6.0 and 6.4 percent in those who remained or became depressed (p=0.03). [ACC 2016, abstract 16-A-9223]
“Our study shows that prompt, effective treatment of depression appears to improve the risk of poor heart health,” said Dr. Heidi May, a Cardiovascular Epidemiologist at the Intermountain Institute and one of the investigators of the study. “The key conclusion of our study is, if depression isn’t treated, the risk of cardiovascular complications increases significantly,” she said.
Study authors were unable to confirm if depression led to cardiovascular risk factors or vice versa.
“What we’ve done thus far is simply observe data that has previously been collected. In order to dig deeper, we need to do a full clinical trial to fully evaluate what we’ve observed,” said May.
High parathyroid hormone levels and bone loss may predict progression of coronary artery calcification (CAC) in patients receiving dialysis, according to a study published online April 2 in the Journal of the American Society of Nephrology.
“We discovered that high parathyroid hormone and the consequential bone loss are major risk factors for progression of vascular calcifications,” Hartmut H. Malluche, MD, from the Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, commented in a news release.
“These two factors were heretofore not appreciated and were independent from traditional known risk factors,” he added.
Elevated parathyroid hormone levels cause the release of calcium from bone, leading to bone loss and thinning. Most patients receiving dialysis for chronic kidney disease have CAC. CAC increases the risk for cardiovascular events, which in turn cause the majority of deaths in patients with CKD, the authors note.
Therefore, Dr Malluche and colleagues recommend monitoring bone loss with measurements of parathyroid hormone or bone mineral density (BMD) as a way to predict progression of CAC in patients receiving dialysis.
Between August 2009 and April 2013, the researchers enrolled 213 participants from 38 dialysis centers in Kentucky. Participants underwent measurement of routine laboratory tests, serum markers of bone metabolism, and CAC at baseline and 1 year. The researchers also evaluated BMD at both points using dual-energy X-ray absorptiometry scans and quantitative computed tomography. They assessed CAC using multislide computed tomography of the heart and CAC square root of coronary artery calcification volume, an analytic technique that accounts for variability in scanning.
About 80% of participants had CAC at baseline, and almost 50% of these had measurements suggesting high risk for cardiovascular events. One third of participants had osteoporosis.
Independent positive predictors of baseline CAC included coronary artery disease, diabetes, length of time receiving dialysis, age, and concentration of fibroblast growth factor 23, which regulates serum phosphate levels and helps maintain bone strength. In contrast, BMD of the spine inversely predicted baseline CAC.
CAC progression at 1 year occurred among three quarters of the 122 patients who completed the study. Independent risk factors for CAC progression included age, osteoporosis (β = 4.6; 95% confidence interval, 1.8 – 7.5; P = .002), and baseline total or whole parathyroid hormone more than nine times the normal value, after adjusting for age (β = 6.9; 95% confidence interval, 2.4 – 11.4; P = .003).
The researchers note several limitations for the study, including exclusion of about 20% of screened patients because of severe comorbidities or impaired mental status. In addition, the prospective, short-term nature of the study precluded determination of disease mechanisms and long-term relationships.
Dr Malluche noted in the press release that important links may exist between the level of calcification in bones and calcifications in blood vessels.
“Studies need to be done to find out whether prevention of bone loss will reduce progression of vascular calcifications,” he emphasized.
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