Abstract
Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction
N Engl J Med. 2019, 19 September. doi: 10.1056/NEJMoa1911303.
McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators.
Background: In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless the presence or absence of type 2 diabetes.
Methods: In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association classes II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.
Results: Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (95% confidence interval [CI] [0.65, 0.85]; hazard ratio [HR]: 0.74; P < .001). A first worsening heart failure event occurred in 237 patients (10%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (95% CI [0.59, 0.83]; HR: 0.70). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (95% CI [0.69, 0.98]; HR: 0.82); while 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (95% CI [0.71, 0.97]; HR: 0.83). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.
Conclusions: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower in the group that received dapagliflozin than the group that received placebo, regardless of the presence or absence of diabetes (DAPA-HF ClinicalTrials.gov number, NCT03036124; funded by AstraZeneca).
Comments
Ticagrelor or Prasugrel in Patients With Acute Coronary Syndromes
N Engl J Med. 2019, September 1. doi: 10.1056/NEJMoa1908973.
Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J, Richardt G, Liebetrau C, Witzenbichler B, Antoniucci D, Akin I, Bott-Flügel L, Fischer M, Landmesser U, Katus HA, Sibbing D, Seyfarth M, Janisch M, Boncompagni D, Hilz R, Rottbauer W, Okrojek R, Möllmann H, Hochholzer W, Migliorini A, Cassese S, Mollo P, Xhepa E, Kufner S, Strehle A, Leggewie S, Allali A, Ndrepepa G, Schühlen H, Angiolillo DJ, Hamm CW, Hapfelmeier A, Tölg R, Trenk D, Schunkert H, Laugwitz KL, Kastrati A; ISAR-REACT 5 Trial Investigators.
Background: The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain.
Methods: In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary endpoint was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary endpoint (the safety end point) was bleeding.
Results: A total of 4018 patients underwent randomization. A primary-endpoint event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (95% CI [1.09, 1.70]; HR: 1.36; P = 0.006). The respective incidences of the individual components of the primary endpoint in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, while only definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (95% CI [0.83, 1.51]; HR: 1.12; P = 0.46).
Conclusions: Among patients who presented with acute coronary syndromes with or without ST segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor; and the incidence of major bleeding was not significantly different between the two groups (funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.).
Comments: The ISAR-REACT 5 trial is a landmark study as it is the first head-to-head comparison between prasugrel and ticagrelor. The trail demonstrated a higher efficacy of prasugrel compared to ticagrelor with similar safety profile. The study suggests that the use of prasugrel should increase in contradistinction to the current trend of preferable use of ticagrelor.
However, even the trialists state that the data should be interpreted with caution. The study was open label, the discontinuation rates were very high (33%), and interpretation was done using the entire study population. The results go against the current available body of evidence. Therefore, the results will need to be replicated by other studies before they can be fully accepted. And of course, we should never forget the contraindications for use of prasugrel.
Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups
Circulation. 2019, August 27;140(9):739-750. doi: 10.1161/CIRCULATIONAHA.119.042007.
Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Capuano G, de Zeeuw D, Greene T, Levin A, Pollock C, Sun T, Wheeler DC, Yavin Y, Zhang H, Zinman B, Rosenthal N, Brenner BM, Perkovic V.
Abstract
Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but its effects on specific cardiovascular outcomes are uncertain, as are its effects in people without previous cardiovascular disease (primary prevention).
Methods: In Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation, 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care.
Results: Primary prevention participants (n = 2181, 49.6%) were younger (61 vs. 65 years), more often female (37% vs. 31%), and had shorter duration of diabetes mellitus (15 vs. 16 years) compared with secondary prevention participants (n = 2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (95% CI [0.67, 0.95]; HR: 0.80; P = .01), with consistent reductions in both the primary (95% CI [0.49, 0.94]; HR 0.68) and secondary (95% CI [0.69, 1.06]; HR: 0.85) prevention groups (P for interaction = .25). Effects were also similar for the components of the composite including cardiovascular death (95% CI [0.61, 1.00]; HR: 0.78), nonfatal myocardial infarction (95% CI [0.59, 1.10]; HR: 0.81), and nonfatal stroke (95% CI [0.56, 1.15]; HR: 0.80). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction > .5 for each outcome).
Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including participants who did not have previous cardiovascular disease.
URL:
Unique identifier: NCT02065791.
Comments: The Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation trial has shown that canagliflozin protects against cardiovascular events (like all SGLT2 inhibitors) and against kidney failure in patients with diabetes and chronic kidney disease. Till date, angiotensin-converting enzyme inhibitor/angiotensin II blockers and spironolactone antagonists were the only nephroprotective drugs for this large group of patients. Canagliflozin now provides an additional agent with significant protection against myocardial infarction, stroke, and end-stage renal disease. The increased risk of amputation with canagliflozin (an effect apparently not shared with other SGLT2 inhibitors) remains a cause for concern.
Three Public Health Interventions Could Save 94 Million Lives in 25 Years
Circulation. 2019, August 27;140(9):715-725. doi: 10.1161/CIRCULATIONAHA.118.038160.
Kontis V, Cobb LK, Mathers CD, Frieden TR, Ezzati M, Danaei G.
Background: Preventable noncommunicable diseases, mostly cardiovascular diseases, are responsible for 38 million deaths annually. A few well-documented interventions have the potential to prevent many of these deaths, but a large proportion of the population in need does not have access to these interventions. We quantified the global mortality impact of 3 high-impact and feasible interventions: scaling up the treatment of high blood pressure to 70%, reducing the sodium intake by 30%, and eliminating the intake of artificial trans fatty acids.
Methods: We used global data on mean blood pressure levels and sodium and trans-fat intake by country, age, and sex from a pooled analysis of population health surveys, and regional estimates of current coverage of antihypertensive medications, and cause-specific mortality rates in each country, as well, with projections from 2015 to 2040. We used the most recent meta-analyses of epidemiological studies to derive relative risk reductions for each intervention.
We estimated the proportional effect of each intervention on reducing mortality from related causes by using a generalized version of the population-attributable fraction. The effect of antihypertensive medications and lowering of sodium intake were modeled through their impact on blood pressure and as immediate increase/reduction to the proposed targets.
Results: The combined effect of the 3 interventions delayed 94.3 million (95% uncertainty interval [85.7, 102.7]) deaths during 25 years. Increasing coverage of antihypertensive medications to 70% alone would delay 39.4 million deaths (35.9-43.0), whereas reducing sodium intake by 30% would delay another 40 million deaths (35.1-44.6) and eliminating trans fat would delay additional 14.8 million deaths (14.7-15.0). The estimated impact of trans fat elimination was largest in South Asia. Sub-Saharan Africa had the largest proportion of premature delayed deaths out of all delayed deaths.
Conclusions: The 3 effective interventions can save almost 100 million lives globally within 25 years. National and international efforts to scale up these interventions should be a focus of cardiovascular disease prevention programs.
Comments: Primary and primordial prevention of cardiovascular disease remains a neglected field. Other than the lack of awareness and interest, there is also a great deal of controversy about which measures will give the greatest benefit across the general population. This study has identified the three most beneficial interventions: optimum antihypertensive medication in the hypertensive population, reduction of sodium intake, and elimination of trans fat from the diet. Incidentally, the largest benefit of these measures was found in the South Asian population, which is now known to have the highest cardiovascular risk for the same risk parameters compared to other ethnic groups.
Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients
J Am Coll Cardiol. 2019, September 24;74(12):1532-1540. doi: 10.1016/j.jacc.2019.06.076.
Kolte D, Vlahakes GJ, Palacios IF, Sakhuja R, Passeri JJ, Inglessis I, Elmariah S.
Background: Transcatheter aortic valve replacement (TAVR) has emerged as a safe and effective therapeutic option for patients with severe aortic stenosis who are at prohibitive, high, or intermediate risk for surgical aortic valve replacement (SAVR). However, in low-risk patients, SAVR remains the standard therapy in current clinical practice.
Objectives: This study sought to perform a meta-analysis of randomized controlled trials (RCTs) comparing TAVR with SAVR in low-risk patients.
Methods: Electronic databases were searched from inception to March 20, 2019. RCTs comparing TAVR with SAVR in low-risk patients (Society of Thoracic Surgeons Predicted Risk of Mortality {STS-PROM} score < 4%) were included. Primary outcome was all-cause death at 1 year. Random-effects models were used to calculate pooled risk ratio (RR) and corresponding 95% CI.
Results: The meta-analysis included 4 RCTs that randomized 2887 patients (1497 to TAVR and 1390 to SAVR). The mean age of patients was 75.4 years, and the mean STS-PROM score was 2.3%. As compared with SAVR, TAVR was associated with significantly lower risk of all-cause death (2.1% vs. 3.5%; 95% CI [0.39, 0.96]; I2 = 0%; P = .03; RR: 0.61) and cardiovascular death (1.6% vs. 2.9%; 95% CI [0.33, 0.90]; I2 = 0%; P = .02; RR: 0.55) at 1 year. Rates of new/worsening atrial fibrillation, life-threatening/disabling bleeding, and acute kidney injury stage 2/3 were lower, whereas those of permanent pacemaker implantation and moderate/severe paravalvular leak were higher after TAVR than after SAVR. There were no significant differences between TAVR and SAVR for major vascular complications, endocarditis, aortic valve reintervention, and New York Heart Association functional class ≥ II.
Conclusions: In this meta-analysis of RCTs comparing TAVR and SAVR in low-risk patients, TAVR was associated with significantly lower risk of all-cause death and cardiovascular death at 1 year. These findings suggest that TAVR may be the preferred option over SAVR in low-risk patients with severe aortic stenosis who are candidates for bioprosthetic AVR.
Comments: Till date, TAVR has been recommended as an alternative to SAVR only in patients who are unsuitable for open surgery or are high-risk candidates for surgery. This study evaluated the use of TAVR in low-risk patients. The findings show a major reduction in death in the first year. If this data is replicated in other studies, it may well lead to a change in guidelines, with TAVR being the preferred option even for low-risk patients who are going to undergo AVR with a bioprosthetic valve. Candidates suitable for a metallic valve will have no change in recommendations.
Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial
Circulation. 2019, September 17;140(12):992-1003. doi: 10.1161/CIRCULATIONAHA.118.039415.
Ouchi Y, Sasaki J, Arai H, Yokote K, Harada K, Katayama Y, Urabe T, Uchida Y, Hayashi M, Yokota N, Nishida H, Otonari T, Arai T, Sakuma I, Sakabe K, Yamamoto M, Kobayashi T, Oikawa S, Yamashita S, Rakugi H, Imai T, Tanaka S, Ohashi Y, Kuwabara M, Ito H.
Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C)-lowering therapy in older individuals, aged ≥ 75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients.
Methods: This multicenter, prospective, randomized, open-label, blinded endpoint evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥ 75 years, with elevated LDL-C without history of coronary artery disease. Patients who received dietary counseling were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke.
Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control group. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (95% CI [0.50, 0.86]; HR: 0.66; P = .002). Regarding the secondary outcomes, the incidences of composite cardiac events (95% CI [0.37, 0.98]; HR: 0.60; P = .039) and coronary revascularization (95% CI [0.18, 0.79]; HR: 0.38; P = .007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups.
Conclusions: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥ 75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution.
URL:
Unique identifier: UMIN000001988.
Comments
Multiple Versus Single Arterial Coronary Bypass Graft Surgery for Multivessel Disease
J Am Coll Cardiol. 2019, September 10;74(10):1275–1285. doi: 10.1016/j.jacc.2019.06.067.
Samadashvili Z, Sundt TM 3rd, Wechsler A, Chikwe J, Adams DH, Smith CR, Jordan D, Girardi L, Lahey SJ, Gold JP, Ashraf MH, Hannan EL.
Background: Despite recent guideline statements, there is still wide practice variation in the use of multiple arterial grafts (MAGs) versus single arterial grafts (SAGs) for patients with multivessel disease undergoing coronary artery bypass graft surgery. This may be related to differences in findings between observational and randomized controlled studies.
Objectives: This study sought to compare intermediate-term MAG and SAG outcomes with enhanced matching to reduce selection bias.
Methods: New York’s cardiac registry identified 63,402 multivessel disease patients undergoing coronary artery bypass graft (CABG) surgery between January 1, 2005, and December 31, 2014, to compare outcomes (median follow-up 6.5 years) for patients receiving SAGs and MAGs. SAG and MAG patients were propensity matched using 38 baseline characteristics to reduce selection bias. The primary endpoint was mortality and secondary endpoints included repeat revascularization and a composite endpoint of mortality, acute myocardial infarction, and stroke.
Results: Before matching, 20% of procedures employed MAG. At 1 year, there was no mortality difference between matched MAG and SAG patients (2.4% vs. 2.2%; 95% CI [0.93, 1.32]; adjusted HR [AHR]: 1.11). At 7 years, MAG patients had lower mortality (12.7% vs. 14.3%; 95% CI [0.79, 0.93]; AHR: 0.86), a lower composite outcome (20.2% vs. 22.8%; 95% CI [0.83, 0.93]; AHR: 0.88), and a lower repeat revascularization rate (11.7% vs. 14.6%; 95% CI [0.74, 0.87]; AHR: 0.80). At 7 years, the subgroups for which MAG did not have a lower mortality rate included patients with off-pump surgery, 2-vessel disease with right coronary artery disease, recent acute myocardial infarction, renal dysfunction, and patient ≥ 70 years of age.
Conclusions: Mortality and the composite outcome were similar between MAG and SAG patients at 1 year, but lower for MAG after 7 years. Patients of higher-volume MAG surgeons experienced lower MAG mortality.
Comments
Permanent Percutaneous Carotid Artery Filter to Prevent Stroke in Atrial Fibrillation Patients: The CAPTURE Trial
J Am Coll Cardiol. 2019, August 20;74(7):829-839. doi: 10.1016/j.jacc.2019.04.035.
Reddy VY, Neuzil P, de Potter T, van der Heyden J, Tromp SC, Rensing B, Jiresova E, Dujka L, Lekesova V.
Background: Patients with high stroke risk and atrial fibrillation who are unsuitable to oral anticoagulants require other stroke prevention strategies. A novel permanent coil filter directly placed into both common carotid arteries (CCAs) was designed to capture emboli > 1.4 mm in diameter.
Objectives: The multicenter, nonrandomized, first-in-human clinical Carotid Artery Implant for Trapping Upstream Emboli for Preventing Stroke in Atrial Fibrillation Patients trial sought to determine the feasibility and safety of bilateral CCA filter placement.
Methods: Eligible patients had atrial fibrillation, CHA2DS2-VASc (Congestive heart failure, Hypertension, Age 75 years, Diabetes, Stroke/transient ischemic attack, Vascular disease, Age 65 to 74 years, Sex category) ≥ 2, oral anticoagulant unsuitability, CCA size from 4.8 to 9.8 mm, and no carotid stenosis > 30%. Under ultrasound guidance, after direct transcutaneous carotid puncture with a 24-gauge needle, a motorized unit expels the filter to unfurl in the artery. Patients received aspirin/clopidogrel for 3 months, and aspirin thereafter. Primary endpoints were: (a) procedural success-bilateral, properly positioned CCA filters and (b) 30-day incidence of major adverse events, that is, death, stroke, major bleeding, filter migration, CCA thrombus, or stenosis. Carotid ultrasounds were conducted post-procedure, predischarge, at 1 week, and at 1, 3, 6, and 12 months.
Results: At 3 centers, 25 patients were enrolled: age 71 ± 9 years, CHA2DS2-VASc = 4.4 ± 1.0, prior embolism in 48%. Procedure success was 92% (23 of 25 patients); 1 patient had unilateral deployment. There were no device/procedure-related major adverse events; minor puncture site hematomas/edema occurred in 5 of 25 (20%). After 6-month mean follow-up, asymptomatic thrombi were detected in 4 patients (1 bilateral, 4 unilateral), adjudicated as captured (n = 3), unclassified (n = 2), or in situ (n = 0). In all patients, the thrombi dissolved with subcutaneous heparin. In 1 patient, 2 device/procedure-unrelated minor strokes occurred.
Conclusions: Permanent carotid filter placement for stroke prophylaxis is technically feasible and safe (carotid Artery Implant for Trapping Upstream Emboli for Preventing Stroke in Atrial Fibrillation Patients [CAPTURE]; NCT03571789).
Comments: Stroke prophylaxis in patients with atrial fibrillation has so far depended mainly on oral anticoagulants. Even though newer oral anticoagulants have simplified therapy, a significant subset of patients with high bleeding risk cannot tolerate any of these agents and remain at high stroke risk. This novel filter device is first of its kind and shows potential for stroke prophylaxis without long-term oral anticoagulation. While the device is very new and should be used with caution, this study demonstrates the potential of this alternative approach to stoke prevention in patients with atrial fibrillation.
Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease
N Engl J Med. 2019, September 19;381(12):1103-1113. doi: 10.1056/NEJMoa1904143.
Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H; AFIRE Investigators.
Background: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease.
Methods: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or CABG more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a nonvitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy endpoint was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this endpoint was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety endpoint was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this endpoint was analyzed for superiority.
Results: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy endpoint, with event rates of 4.14% and 5.75% per patient-year, respectively (95% CI [0.55, 0.95] ;HR: 0.72; P < .001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety endpoint, with event rates of 1.62% and 2.76% per patient-year, respectively (95% CI [0.39, 0.89]; HR: 0.59; P = .01 for superiority).
Conclusions: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease (AFIRE UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419; funded by the Japan Cardiovascular Research Foundation).
Comments
Percutaneous Coronary Angioplasty Versus Coronary Artery Bypass Grafting in the Treatment of Unprotected Left Main Stenosis: Updated 5-Year Outcomes from the Randomized, Non-inferiority NOBLE Trial
Lancet. 2019, December 23; pii: S0140-6736(19)32972-1. doi:10.1016/S0140-6736(19)32972-1.
Holm NR, Mäkikallio T, Lindsay MM, Spence MS, Erglis A, Menown IBA, Trovik T, Kellerth T, Kalinauskas G, Mogensen LJH, Nielsen PH, Niemelä M, Lassen JF, Oldroyd K, Berg G, Stradins P, Walsh SJ, Graham ANJ, Endresen PC, Fröbert O, Trivedi U, Anttila V, Hildick-Smith D, Thuesen L, Christiansen EH; NOBLE investigators.
Background: PCI is increasingly used in revascularization of patients with left main coronary artery disease in place of the standard treatment, CABG. The NOBLE trial aimed to evaluate whether PCI was noninferior to CABG in the treatment of left main coronary artery disease and reported outcomes after a median follow-up of 3.1 years. We now report updated 5-year outcomes of the trial.
Methods: The prospective, randomized, open-label, noninferiority NOBLE trial was done at 36 hospitals in 9 northern European countries. Patients with left main coronary artery disease requiring revascularization were enrolled and randomly assigned (1:1) to receive PCI or CABG. The primary endpoint was major adverse cardiac or cerebrovascular event, a composite of all-cause mortality, nonprocedural myocardial infarction, repeat revascularization, and stroke.
Noninferiority of PCI to CABG was defined as the upper limit of the 95% CI of the HR not exceeding 1.35 after 275 major adverse cardiac or cerebrovascular events had occurred. Secondary endpoints included all-cause mortality, nonprocedural myocardial infarction, and repeat revascularization. Outcomes were analyzed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01496651.
Findings: Between December 9, 2008, and January 21, 2015, 1201 patients were enrolled and allocated to PCI (n = 598) or CABG (n = 603), with 17 subsequently lost to early follow-up. 592 patients in each group were included in this analysis. At a median of 4.9 years of follow-up, the predefined number of events was reached for adequate power to assess the primary endpoint. Kaplan–Meier 5-year estimates of major adverse cardiac or cerebrovascular events were 28% (165 events) for PCI and 19% (110 events) for CABG (95% CI [1.24, 2.01]; HR: 1.58); the HR exceeded the limit for noninferiority of PCI compared to CABG. CABG was found to be superior to PCI for the primary composite endpoint (P < 0.001). All-cause mortality was estimated in 9% patients after PCI versus 9% patients after CABG (95% CI [0.74, 1.59]; HR: 1.08; P = .68); nonprocedural myocardial infarction was estimated in 8% patients after PCI versus 3% patients after CABG (95% CI [1.66, 5.39]; HR: 2.99; P < 0.001); and repeat revascularization was estimated in 17% patients after PCI versus 10% patients after CABG (95% CI [1.25, 2.40]; HR: 1.73; P < 0.001).
Interpretation: In revascularization of left main coronary artery disease, PCI was associated with an inferior clinical outcome at 5 years compared with CABG. Mortality was similar after the two procedures, but patients treated with PCI had higher rates of nonprocedural myocardial infarction and repeat revascularization.
Funding: Biosensors.
Comments: The debate of PCI versus CABG has raged on for decades. After the MAIN-COMPARE and SYNTAX trials, use of PCI in left main disease increased. However, the long-term outcome of PCI remains in doubt. The NOBEL trial shows that even today CABG has better long-term outcome compared to PCI in patients with left main disease. However, the safety of left main PCI has also been demonstrated, as the mortality was similar for both procedures. PCI patients had a higher incidence of repeat vascularization, which, in the real world, is usually CABG.
Effect of Alirocumab on Stroke in Odyssey Outcomes
Circulation. 2019 December 17;140(25):2054-2062. doi: 10.1161/CIRCULATIONAHA.119.043826.
Jukema JW, Zijlstra LE, Bhatt DL, Bittner VA, Diaz R, Drexel H, Goodman SG, Kim YU, Pordy R, Reiner Ž, Roe MT, Tse HF, Montenegro Valdovinos PC, White HD, Zeiher AM, Szarek M, Schwartz GG, Steg PG; Odyssey Outcomes Investigators.
Background: Lowering of atherogenic lipoproteins, including LDL-C, reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C levels and a potential increased risk of hemorrhagic stroke. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18,924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy, targeting LDL-C levels of 25 to 50 mg/dL and avoiding sustained LDL-C < 15 mg/dL. This prespecified analysis was designed to assess the effect of alirocumab on ischemic and hemorrhagic stroke. We hypothesized that for patients treated with alirocumab there would be a reduction in risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of baseline LDL-C and of history of cerebrovascular disease.
Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after acute coronary syndrome. The risk of nonfatal or fatal ischemic or hemorrhagic stroke was evaluated, stratified by baseline LDL-C concentration and history of cerebrovascular disease. A potential association of very low achieved LDL-C with alirocumab treatment at month 4 and subsequent hemorrhagic stroke was assessed.
Results: Median follow-up was 2.8 years. In total, 263 ischemic and 33 hemorrhagic strokes occurred. Alirocumab reduced the risk of any stroke (95% CI [0.57, 0.91]; HR: 0.72) and ischemic stroke (95% CI [0.57, 0.93]; HR: 0.73) without increasing hemorrhagic stroke (95% CI [0.42, 1.65]; HR: 0.83). In total, 7164 (37.9%), 6128 (32.4%), and 5629 (29.7%) patients had a baseline LDL-C of < 80, 80 to 100, and > 100 mg/dL, respectively. The treatment effect on stroke appeared numerically greater for patients with higher baseline LDL-C, but there was no formal evidence of heterogeneity (P interaction = .31). The effect of alirocumab on stroke was similar among 944 patients (5.0%) with a history of previous cerebrovascular disease and among those without a history of cerebrovascular disease (P interaction = .37). There was no apparent adverse relation between lower achieved LDL-C and incidence of hemorrhagic stroke in the alirocumab group.
Conclusions: In patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy, alirocumab decreased the risk of stroke, irrespective of baseline LDL-C and history of cerebrovascular disease, over a median follow-up of 2.8 years. Furthermore, risk of hemorrhagic stroke did not depend on achieved LDL-C levels within the alirocumab group.
Comments: Achieving very low lipid levels has always been looked at with trepidation. While there is a growing body of evidence suggesting that targeting LDL-C to very low levels has a major effect on reducing incidence of coronary artery disease, the effect on ischemic stroke was doubtful. The ODYSSEY trial demonstrates that reducing LDL-C to very low levels using alirocumab shows a major reduction in risk of ischemic stroke above and beyond that may be achieved by statin therapy. There has been a lot of doubt due to small reports suggesting that very low LDL-C levels are associated with a higher risk of hemorrhagic stroke. However, this study has demonstrated no such correlation. The study adds to the ever-growing body of evidence that reducing LDL-C is beneficial for prevention and therapy of atherosclerotic disease and is safe. Hopefully, this study will help to put to rest the dramatic but misleading reports claiming that high lipid levels are good for health.
Long-Term Follow-Up of Complete Versus Lesion-Only Revascularization in STEMI and Multivessel Disease: The CvLPRIT Trial
J Am Coll Cardiol. 2019 December 24;74(25):3083-3094. doi: 10.1016/j.jacc.2019.10.033.
Gershlick AH, Banning AS, Parker E, Wang D, Budgeon CA, Kelly DJ, Kane PO, Dalby M, Hetherington SL, McCann GP, Greenwood JP, Curzen N.
Background: Randomized trials have shown that complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) with multivessel disease results in lower major adverse cardiovascular events (MACE) (all-cause death, myocardial infarction, ischemia-driven revascularization, and heart failure).
Objectives: The goal of this study was to determine whether the benefits of complete revascularization are sustained long-term and their impact on hard endpoints.
Methods: Complete versus Lesion-only Primary PCI Trial was a randomized trial of complete inpatient revascularization versus infarct-related artery revascularization only at the index admission. Randomized patients have been followed longer term. The components of the original primary endpoint were collected from physical and electronic patient records, and from local databases for all readmissions.
Results: The median follow-up (achieved in > 90% patients) from randomization to first event or last follow-up was 5.6 years (0.0 to 7.3 years). The primary MACE endpoint rate at this time point was 24.0% in the complete revascularization group but 37.7% of the infarct-related artery-only group (95% CI [0.37, 0.87]; HR: 0.57; P = .0079). The composite endpoint of all-cause death/myocardial infarction was 10.0% in the complete revascularization group versus 18.5% in the infarct-related artery-only group (95% CI [0.25, 0.89]; HR: 0.47; P = .0175). In a landmark analysis (from 12 months to final follow-up), there was no significant difference between MACE, death/myocardial infarction, and individual components of the primary endpoint.
Conclusions: Long-term follow-up of the Complete versus Lesion-only Primary PCI Trial shows that the significantly lower rate of MACE in the complete revascularization group, previously seen at 12 months, is sustained to a median of 5.6 years. A significant difference in composite all-cause death/myocardial infarction favoring the complete revascularization was also observed (complete versus Lesion-only Primary PCI Trial; ISRCTN70913605;).
Comments: There has been a lot of controversy over culprit lesion intervention versus complete revascularization in patients with STEMI. Since stenting stable coronary artery lesions has not shown any benefit, it was proposed that only the culprit lesion should be stented in patients with STEMI, while other lesions ought to be treated medically. However, this trial now joins a growing body of evidence which shows reduced mortality if the nonculprit lesions are treated as well. It is reasonable to believe that if one lesion is vulnerable, the others will also be lipid rich with active inflammation. Another point made by this study is that the nonculprit lesions were treated during the same admission, though not always in the same sitting. The benefit was known to be significant at 1 year but has now been shown to persist to beyond 5 years.
Cardiovascular Effects of Switching From Tobacco Cigarettes to Electronic Cigarettes
J Am Coll Cardiol. 2019 December 24;74(25):3112-3120. doi: 10.1016/j.jacc.2019.09.067.
George J, Hussain M, Vadiveloo T, Ireland S, Hopkinson P, Struthers AD, Donnan PT, Khan F, Lang CC.
Background: E-cigarette (EC) use is increasing exponentially worldwide. The early cardiovascular effects of switching from tobacco cigarettes (TC) to EC in chronic smokers are unknown. Meta-analysis of flow-mediated dilation studies indicates 13% lower pooled, adjusted relative risks of cardiovascular events with every 1% improvement in flow-mediated dilation.
Objectives: This study sought to determine the early vascular impact of switching from TC to EC in chronic smokers.
Methods: The authors conducted a prospective, RCT with a parallel nonrandomized preference cohort and blinded endpoint of smokers ≥ 18 years of age who had smoked ≥ 15 cigarettes per day for ≥ 2 years and were free from established cardiovascular disease. Participants were randomized to EC with nicotine or EC without nicotine for 1 month. Those unwilling to quit continued with TC in a parallel preference arm. A propensity score analysis was done to adjust for differences between the randomized and preference arms. Vascular function was assessed by flow-mediated dilation and pulse wave velocity. Compliance with EC was measured by carbon monoxide levels.
Results: Within 1 month of switching from TC to EC, there was a significant improvement in endothelial function (95% CI [0.41, 1.05]; 95% CI [0.93, 2.04]; linear trend β = 0.73%; P < .0001; P < .0001; TC vs. EC combined: 1.49%) and vascular stiffness (95% CI [–0.946 to –0.112]; P = .014; –0.529 m/s). Females benefited from switching more than males did in every between-group comparison. Those who complied best with EC switch demonstrated the largest improvement. There was no difference in vascular effects between EC with and without nicotine within the study timeframe.
Conclusions: TC smokers, particularly females, demonstrated significant improvement in vascular health within 1 month of switching from TC to EC. Switching from TC to EC may be considered a harms reduction measure.
(ISRCTN59133298; NCT02878421; Vascular Effects of Regular Cigarettes Versus Electronic Cigarette Use {VESUVIUS}).
Comments: Use of EC has been mired in controversy with proponents claiming that EC are virtually harmless and opponents claiming that they are as bad or worse than TC. This study convincingly shows that while EC do increase cardiovascular risk, the increase is significantly lower than TC. In fact, switching from TC to EC reduces cardiovascular risk significantly in TC smokers who are unable to quit. The effect is more marked in females compared to males. This study demonstrates the importance of avoiding knee-jerk legislation in public health policy.
Metoprolol for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease
N Engl J Med. 2019, December 12;381(24):2304-2314. doi: 10.1056/NEJMoa1908142.
Dransfield MT, Voelker H, Bhatt SP, Brenner K, Casaburi R, Come CE, Cooper JAD, Criner GJ, Curtis JL, Han MK, Hatipoğlu U, Helgeson ES, Jain VV, Kalhan R, Kaminsky D, Kaner R, Kunisaki KM, Lambert AA, Lammi MR, Lindberg S, Make BJ, Martinez FJ, McEvoy C, Panos RJ, Reed RM, Scanlon PD, Sciurba FC, Smith A, Sriram PS, Stringer WW, Weingarten JA, Wells JM, Westfall E, Lazarus SC, Connett JE; BLOCK COPD Trial Group.
Background: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.
Methods: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years, who had COPD, to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary endpoint was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.
Results: A total of 532 patients underwent randomization. The mean ( ± SD) age of the patients was 65.0 ± 7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1 ± 16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary endpoint and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (95% CI [0.84, 1.32]; HR for metoprolol vs. placebo: 1.05; P = .66;). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (95% CI [1.29, 2.83]; HR: 1.91). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.
Conclusions: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group.
Hospitalization for exacerbation was more common among the patients treated with metoprolol (BLOCK COPD ClinicalTrials.gov number, NCT02587351; funded by the Department of Defense).
Comments: While beta-blockers are no longer considered to be absolutely contraindicated in COPD, caution is always recommended in their use as some patients develop exacerbation of their lung condition. The few observational studies have counterintuitively suggested that beta-blockers might reduce the risk of exacerbations and death in COPD. This is the first RCT to evaluate role of metoprolol in COPD patients who do not have an established indication for beta blockade. The trial was stopped prematurely as metoprolol showed no protective effect on COPD exacerbations. On the contrary, the risk of hospitalization for exacerbation was increased in the metoprolol group. Thus, the trial clearly shows that the conventional wisdom about the effect of beta-blockers in COPD is correct and caution should be exercised while using beta blockers in patients of COPD.
A Comparison of Two Low-Density Lipoprotein Cholesterol Targets After Ischemic Stroke
N Engl J Med. 2020, January 2;382(1):9. doi: 10.1056/NEJMoa1910355.
Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Béjot Y, Cabrejo L, Cha JK, Ducrocq G, Giroud M, Guidoux C, Hobeanu C, Kim YJ, Lapergue B, Lavallée PC, Lee BC, Lee KB, Leys D, Mahagne MH, Meseguer E, Nighoghossian N, Pico F, Samson Y, Sibon I, Steg PG, Sung SM, Touboul PJ, Touzé E, Varenne O, Vicaut É, Yelles N, Bruckert E; Treat Stroke to Target Investigators.
Background: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for LDL-C to reduce cardiovascular events after stroke has not been well studied.
Methods: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL-C level of less than 70 mg/dL (1.8 mmol/L) (lower target group) or to a target range of 90 to 110 mg/dL (2.3-2.8 mmol/L) (higher target group).
All the patients had evidence of cerebrovascular or coronary artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary endpoint of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes.
Results: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL-C target group. The mean LDL-C level at baseline was 135 mg/dL (3.5 mmol/L), and the mean achieved LDL-C level was 65 mg/dL (1.7 mmol/L) in the lower-target group and 96 mg/dL (2.5 mmol/L) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 endpoint events had occurred. The composite primary endpoint occurred in 121 patients (8.5%) in the lower-target group and in 156 patients (10.9%) in the higher-target group (95% CI [0.61, 0.98]; AHR: 0.78; P = .04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups.
Conclusions: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL-C level of less than 70 mg/dL had a lower risk of subsequent cardiovascular events than those who had a target range of 90 to 110 mg/dL (funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).
Comments: With abuse of lipid-lowering therapy coming front and center, thanks to tabloid journalism and social media, any additional data supporting the use of lipid-lowering therapy is most welcome. This study clearly demonstrates that patient with TIA or ischemic stroke should be treated to a lower lipid target than is currently done, just as in coronary artery disease. The trial also convincingly shows the safety of the intensive therapy approach.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding
The authors received no financial support for the research, authorship and/or publication of this article.
