April 2024: New In Coagulation
by Donna Castellone • April 03, 2024
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation. Please Note: many linked teasers require account/subscription in order to view full articles. Medscape registration is free of charge.
What to Know About the Factor XIa Inhibitors on the Horizon
DOACs have been a major advancement in stroke patients with AF in preventing recurrent strokes, however there is still a risk for major bleeding up to 2% per year. The FXIa inhibitors are drugs that have the potential to prevent thrombosis without disrupting hemostasis. As a result, they could be as effective as DOACs for stroke prevention and AF and at the same time be safer.
In patients with congenital FXI deficiency, they have lower rates of stroke and clots but do not bleed, except in the nasophyarynx or urogenital tract. Those with low levels have lower rates of ischemic cardiovascular events and VTE. It looks at the potential of inhibiting an upstream factor in one pathway as opposed to directly inhibiting thrombin or Xa.
There are several FXI inhibitors. Antisense oligonucleotides reduce synthesis of FXI in the liver and monomclonal antibodies against FXI. Both can be administered subcutaneously and have a long half-life so they can be injected monthly. Small molecules have short a half-life of 13-16 hours and work within 2-4 hours. They are given once or twice daily. These include asundexian and milvexian.
Five phase II studies (PACIFIC program, PACIFIC-Stroke study, PACIFIC AMI study, AXIOMATIC deep venous thrombosis and AXIOMATIC-Secondary Stroke Prevention) have looked at the safety of FXIa inhibitors given orally to prevent thrombosis and if they cause bleeding. Results have shown when compared with placebo, PACIFIC-Stroke study and AXIOMATIC-Secondary Stroke Prevention in patients with ischemic stroke did cause a small increase in bleeding that was not statistically significant. There was a reduction in symptomatic ischemic stroke seen in safety studies that were looking for a dose to use in phase III studies. Results from these studies may not be until 2026 in order to have sufficient power and to determine if patients with acute non-cardioembolic ischemic stroke with mild-to-moderate severity. Patients will have to be randomized to asudexian or milvexian, to a standard dual or single antiplatelet therapy compared to the placebo.
These FXIa inhibitors are also being studied in patients with acute coronary syndrome since they may also reduce atherothrombosis in blood vessels to the heart. There is currently a trial that looks at apixaban in comparison to milvexian. A trial that looked a asundexian with a DOAC was stopped prematurely due to futility possibly results were not significant in reducing events.
Late Administration of Tenecteplase Limits Benefits in Stroke
The phase III TIMELESS trial investigated using Tenecteplase longer than the 4.5 hours in patients with large vessel occlusion stroke who presented with signs of salvageable brain tissue. The trial included 458 patients who received Tenecteplase or placebo 4.5-24 hours post stroke. Up to 77.3% underwent endovascular thrombectomy. Safety outcomes were death and symptomatic ICH. The primary outcome was the ordinal score at day 90 from 0-6, higher scores indicated greater disability. A score of 6 indicated death. Both groups showed a score of 3 at 90 days with no significant difference. Functional independence was also similar and there were no notable safety issues with the Tenecteplase. Mortality rates were 1.7% vs 8.2% which symptomatic ICH was 3.2% vs 2.3%. In patients with M1 segment occlusion, a significantly higher proportion (45.9% in the tenecteplase group vs 31% in the placebo group) achieved functional independence at 90 days.
Tentatively, the study suggests that pretreatment with Tenecteplase prior to thrombectomy may be beneficial in patients with occlusions in the M1 segment, but it doesn't seem to benefit patients with large-vessel occlusions. However, the trial was underpowered to investigate the benefits of late administration of Tenecteplase in patient not undergoing endovascular thrombectomy.
Low-Dose Aspirin Associated With Reduced CRC Risk
Population registries in Norway were used to identify people >50 years between 2014-2018. Sociodemographic information was obtained as well as low dose aspirin prescription data and the defined daily dose. Follow up begin at 6 months and continued until a colorectal cancer (CRC) diagnosis, another cancer diagnosis, death, emigration or end of follow up in 2018. CRC cases were categorized by site as well as clinical stage.
There were 2,186,390 subjects included and 38,577 were diagnosed with CRC after a median follow up of 10.9 years. Low dose aspirin was used a minimum of once by 579,196 subjects and was more common is males, older, those of lower education or income, Norwegian origin, individuals using other medications including those targeting cardiovascular conditions.
When compared with those who never used aspirin were associated with a lower CRC risk. Current aspirin use was associated with a lower CRC risk. Longer use of aspirin also correlated with a decreased CRC risk. Results showed that aspirin averted 1073 cases of CRC throughout the study.
Limitations of the study include it was observational, lack of information for known risk factors for CRC resulting in an over or under estimation. There is no way to confirm if the recommended daily dose was taken or how often it was taken.
What Level of Lp(a) Indicates Increased CVD Risk?
A new focus of interest as an independent CV risk factor is Lipoprotein a (Lp( a)) along with several new drugs that lower this parameter. Lp(a) levels are mostly genetically determined, elevated levels have increased CV risk, however what threshold indicates a significant CV risk and do threshold differ for various groups.
A registry study suggests that the threshold related to increased risk may be different for primary and secondary populations. Individuals already at CV risk were found to be in the 70th percentile which corresponds to levels of 112nm/L. True high risk is about 216nm/L. It is important to understand how it increases CV risk and who is affected.
The study included 16,419 subjects with measured Lp(a) between 2000 and 2019. Up to 62% were already diagnosed with CV disease and 38% did not have a baseline CV disease. CV events including death, MI, stroke or revascularization were recorded over 12 years. There were 10181 patients with baseline CV disease. When compared with the reference group (Lp(a) levels below the 50th percentile) Lp(a) levels in the 71-90th percentile had a 21% increased hazard of CV events. Within the 6238 subjects without CV disease there was a higher hazard of CV events with increasing levels. The secondary prevention population is a much higher risk for events regardless in the levels are increased or not. Those who do not have CV disease but are in the 90th percentile of Lp(a) have an absolute event rate of 22% vs. 1.1% when levels are below the 50th percentile.
Future trials will look at lowering Lp(a)levels. Presently the two ongoing phase 3 trials of Lp(a) lowering medications: 175 nm/L in the HORIZON trial and 200 nm/L in the OCEAN(a)-OUTCOMES trial. These levels are much higher than the 112nm/L.
Trials will also look at lowering Lp(a)in the primary prevention group using a threshold above the 90th percentile. This is a much larger group than the secondary prevention group. The goal would be to prevent an event prior to one happening. This could be as much as 10% of the general population. Levels should be universally checked at least once so that individuals can be stratified by risk and treated with therapies being developed targeting Lp(a).
New Data on Antithrombotics in Cervical Artery Dissection
The STOP-CAD study looked at cervical artery dissection which causes only about 2% of strokes, but it occurs mostly in young adults but causing major disability. There is insufficient data from controlled prospective trials to guide antithrombotic therapy which includes anticoagulants and antiplatelet drugs.
The study included 3636 patients with CAD from 63 sites in 16 countries with a mean age of 47. Anticoagulation (VKA, UFH, DOAC, LMWH) only was given in 11.1% and 67.5 % only were given antiplatelets (single agent or dual; dual therapies were mostly aspirin and clopidogrel.) Ischemic stroke and major hemorrhage were the study outcomes.
Results of the study showed no significant different in outcomes with either form of treatment. There was a nonsignificant trend toward lower stroke rate with anticoagulation without a risk for major hemorrhage at 30 days, but it did become significant at 180 days. The overall rates of subsequent ischemic stroke and major bleeding were low; by day 180, 4.4% of patients had a new ischemic stroke, and 0.8% had a major hemorrhage. About 87.0% of ischemic strokes occurred by day 30, and 98.1% were confirmed with imaging.
Based on this using anticoagulation requires mitigating the bleeding risk. This can be done by shortening the duration of treatment or stopping it at 30 days or to a max of 90 days and switching to antiplatelet therapy.
Treatment bias is possible in the study due to the retrospective and observational design. The study was also conducted at large academic institutions in high income countries, so they may not be generalizable to patients in community hospitals or lower-income countries. Due to the low numbers, the study couldn't reliably perform propensity score matching for the major hemorrhage outcome and the majority of dual antiplatelet therapies.
Testing antiplatelet therapy against anticoagulation did not show any significant difference in the entire cohort, but subgroups that were looked at seemed they benefited more from anticoagulation. One of those groups were occlusive dissection.
Smoking cannabis associated with increased risk of heart attack, stroke
An observational study found that frequent cannabis smoking may increase thes risk for heart attack and stroke from data obtained from 435,000 American adults (18-74). Participants were from 27 US states; 60% were white, 12% black, 19% Hispanic and 9% other ethnicities. The risk was 25% increased likelihood of heart attack and 42% increased risk for stroke. Weekly users presented with a 3% increased likelihood of heart attack and 5% increased likelihood of stroke.
Most participants (75%) used cannabis by smoking and 25% used via vaping, drinking or eating the drug. While the exact mechanisms that link cannabis to heart disease are unclear, several factors could play a role. In addition to toxins, endocannabinoid receptors — the part of cells responsible for recognizing tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis — are widespread in the body’s cardiovascular tissues and might facilitate heart risks.
DAPT Maintains Early Neurologic Function in Mild-Moderate Stroke
The ATAMIS trial was a multicenter Chinese randomized trial that looked at patients with mild to moderate acute ischemic stroke on dual (DAPT) of aspirin and clopidogrel. Results showed that DAPT reduced early neurologic deterioration (which was classified as a score of >2 on the NIHSS Scale at 7 days) better than just aspirin. There were no differences in secondary endpoints including functional outcome at 90 days. Occurrence of new ischemic or hemorrhage stroke or other vascular events. Patients in the study were not eligible for IV thrombolysis or endovascular therapy. DAPT or aspirin was given within 48 hours of symptom onset.
DAPT was superior to aspirin alone to reducing early neurologic deterioration at 7 days. Currently, guidelines recommend aspirin monotherapy in this cohort and early neurologic deterioration is a challenge to overcome.
The study looked at adult patients with acute ischemic stroke who were functioning independently prior to the stroke and enrolled within 48 hours of symptoms. Included were 3000 patients ( 64.6% men mean age 65.9) from 66 Chinese sites randomized to either clopidogrel plus aspirin (n=1541 75 mg of clopidogrel and 100 mg of aspirin) or just aspirin (n=1459 100-300 mg aspirin until day 14, followed by 100 mg aspirin per day until day 90.). Patients were excluded if they met criteria for thrombolysis, or indication of anticoagulation, a history of intracerebral hemorrhage.
Results cannot be generalized due to study limitations including imbalance in sample size, Chinese populations, as well as a large proportion of patients with mild neurologic deficit. Also needs to be confirmed in other populations.
JOURNAL CLUB
Postprocedural Anticoagulation After Primary Percutaneous Coronary Intervention for ST-Segment–Elevation Myocardial Infarction: A Multicenter, Randomized, Double-Blind Trial
Yan Yan, Jincheng Guo, Xiao Wang, Guozhong Wang, Zeyuan Fan, Delu Yin, Zhifang Wang, Fuchun Zhang, Changming Tian, Wei Gong, Jiamin Liu, Jiapeng Lu, Yongjun Li, 26 Feb 2024 Circulation. 2024;0
Abstract
Background: Postprocedural anticoagulation (PPA) is frequently administered after primary percutaneous coronary intervention in ST-segment–elevation myocardial infarction, although no conclusive data support this practice.
Methods: The RIGHT trial (Comparison of Anticoagulation Prolongation vs no Anticoagulation in STEMI Patients After Primary PCI) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled, superiority trial conducted at 53 centers in China. Patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention were randomly assigned by center to receive low-dose PPA or matching placebo for at least 48 hours. Before trial initiation, each center selected 1 of 3 PPA regimens (40 mg of enoxaparin once daily subcutaneously; 10 U•kg•h of unfractionated heparin intravenously, adjusted to maintain activated clotting time between 150 and 220 seconds; or 0.2 mg•kg•h of bivalirudin intravenously). The primary efficacy objective was to demonstrate superiority of PPA to reduce the primary efficacy end point of all-cause death, nonfatal myocardial infarction, nonfatal stroke, stent thrombosis (definite), or urgent revascularization (any vessel) within 30 days. The key secondary objective was to evaluate the effect of each specific anticoagulation regimen (enoxaparin, unfractionated heparin, or bivalirudin) on the primary efficacy end point. The primary safety end point was Bleeding Academic Research Consortium 3 to 5 bleeding at 30 days.
Results: Between January 10, 2019, and September 18, 2021, a total of 2989 patients were randomized. The primary efficacy end point occurred in 37 patients (2.5%) in both the PPA and placebo groups (hazard ratio, 1.00 [95% CI, 0.63 to 1.57]). The incidence of Bleeding Academic Research Consortium 3 or 5 bleeding did not differ between the PPA and placebo groups (8 [0.5%] vs 11 [0.7%] patients; hazard ratio, 0.74 [95% CI, 0.30 to 1.83]).
Conclusions: Routine PPA after primary percutaneous coronary intervention was safe but did not reduce 30-day ischemic events.
LDL-C Levels and Bleeding Risk in Patients Taking DAPT After Minor Ischemic Stroke or TIA
Aichun Cheng, MD; Jing Xue, PhD1; Anxin Wang, PhD; et alQin Xu, PhD; Zhiyuan Feng, MD; Jinxi Lin, MD, PhD; Hao Li, MD, PhD; Xia Meng, MD, PhD; Jie Xu, MD, PhD; Yongjun Wang, MD
Abstract
Importance: Evidence on the bleeding risk associated with low-density lipoprotein cholesterol (LDL-C) levels in patients receiving dual antiplatelet therapy (DAPT) remains sparse.
Objective: To investigate the association of LDL-C levels with bleeding risk in patients with minor ischemic stroke (MIS) or high-risk transient ischemic attack (HRTIA) receiving DAPT.
Design, Setting and Participants: This cohort study was an analysis of pooled data from 2 randomized, double-blind, placebo-controlled clinical trials in China of patients with MIS or HRTIA who were receiving DAPT: the CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) trial enrolled patients at 114 sites from October 2009 to July 2012, and the CHANCE-2 enrolled patients at 202 centers from September 2019 to March 2021. Both sets of patients were followed up for 90 days. Data analysis was performed from August 2022 to May 2023.
Exposures: Baseline LDL-C levels and receipt of ticagrelor-aspirin and clopidogrel-aspirin DAPT.
Main Outcomes and Measures: The primary outcome was any bleeding, and the secondary outcome was severe or moderate bleeding within 3 months after randomization. The association of LDL-C levels and all outcomes was assessed by using the Cox proportional hazard model. Hazard ratios (HRs) with 95% CIs were calculated on univariable (unadjusted) Cox regression models. Adjusted HRs (aHRs) and their 95% CIs were calculated on multivariable Cox regression models.
Results: In total, 8996 patients with acute MIS or HRTIA who were receiving DAPT were included in the 2 trials, of whom 1066 without serum specimens and 490 patients with missing baseline LDL-C value were excluded. Finally, 7440 patients with DAPT (4486 in the clopidogrel-aspirin group and 2954 in the ticagrelor-aspirin group) were included in this study. The median (IQR) age was 64.32 (56.56-71.30) years, and 2479 patients (33.32%) were women. A total of 270 (3.63%) bleeding events were reported at 3 months, and LDL-C less than 70 mg/dL was associated with an increased risk of both any bleeding (aHR, 1.48; 95% CI, 1.03-2.12), and severe or moderate bleeding (aHR, 2.78; 95% CI, 1.18-6.53). The risk of any bleeding was increased at lower LDL-C levels in the ticagrelor-aspirin group (aHR, 1.71; 95% CI, 1.08-2.72). However, an increased risk of any bleeding was not observed in the clopidogrel-aspirin group (aHR, 1.30; 95% CI, 0.73-2.30). There was no significant association between LDL-C levels and the risk of severe or moderate bleeding in either the ticagrelor-aspirin or clopidogrel-aspirin group.
Conclusions and Relevance: These findings suggest that low LDL-C levels are associated with an increased bleeding risk within 3 months among patients with MIS or HRTIA receiving DAPT, especially those taking ticagrelor-aspirin. Weighing the risks and benefits is crucial when simultaneously considering the selection of LDL-C target strategies and DAPT regimens among these patients.
Efficacy and safety of dual antiplatelet therapy in the elderly for stroke prevention: a subgroup analysis of the CHANCE-2 trial
Zhang X, Jing J, Wang A, et al
Abstract
Objectives: Evidence of the optimal antiplatelet therapy for elderly patients who had a stroke is limited, especially those elder than 80 years. This study aimed to explore the efficacy and safety of dual antiplatelet therapy (DAPT) in old-old patients compared with younger patients in the ticagrelor or Clopidogrel with aspirin in High-risk patients with Acute Non-disabling Cerebrovascular Events-II (CHANCE-2) trial.
Methods: CHANCE-2 was a randomised, double-blind, placebo-controlled trial in China involving patients with high-risk transient ischaemic attack or minor stroke with CYP2C19 loss-of-function alleles. In our substudy, all enrolled patients were stratified by age: old-old (≥80 years), young-old (65–80 years) and younger (<65 years). The primary outcomes were stroke recurrence and moderate to severe bleeding within 90 days, respectively.
Results Of all the 6412 patients, 406 (6.3%) were old-old, 2755 (43.0%) were young-old and 3251 (50.7%) were younger. Old-old patients were associated with higher composite vascular events (HR 1.41, 95% CI 1.00 to 1.98, p=0.048), disabling stroke (OR 2.43, 95% CI 1.52 to 3.88, p=0.0002), severe or moderate bleeding (HR 8.40, 95% CI 1.95 to 36.21, p=0.004) and mortality (HR 7.56, 95% CI 2.23 to 25.70, p=0.001) within 90 days. Ticagrelor-aspirin group was associated with lower risks of stroke recurrence within 90 days in younger patients (HR 0.68, 95% CI 0.51 to 0.91, p=0.008), which was no differences in old-old patients.
Conclusion: Elderly patients aged over 80 in CHANCE-2 trial had higher risks of composite vascular events, disabling stroke, severe or moderate bleeding and mortality within 90 days. Genotype-guided DAPT might not be as effective in old-old patients as in younger ones.
Prothrombin Complex Concentrate vs Conservative Management in ICH Associated With Direct Oral Anticoagulants
Bonaventure Ip, MD; Sangqi Pan, MSc; Zhong Yuan, BEng; et alTrista Hung, BSocSc; Ho Ko, PhD1; Xinyi Leng, PhD; Yuying Liu, MSc; Shuang Li, MSc; SingYau Lee, MS; Cyrus Cheng, MBChB; Howard Chan, PhD; Vincent Mok, MD; Yannie Soo, MD; Xiaoli Wu, PhD; Leong,Ting Lui, PhD; Rosa Chan, PhD; Jill Abrigo, MD; Qi Dou, PhD; David Seiffge, MD; Thomas Leung, MD
Abstract
Importance: Intracerebral hemorrhage (ICH) associated with direct oral anticoagulant (DOAC) use carries extremely high morbidity and mortality. The clinical effectiveness of hemostatic therapy is unclear.
Objective: To compare the clinical and radiological outcomes of DOAC-associated ICH treated with prothrombin complex concentrate (PCC) vs conservative management.
Design, Setting, and Participants: In this population-based, propensity score–weighted retrospective cohort study, patients who developed DOAC-associated ICH from January 1, 2016, to December 31, 2021, in Hong Kong were identified. The outcomes of patients who received 25 to 50 IU/kg PCC with those who received no hemostatic agents were compared. Data were analyzed from May 1, 2022, to June 30, 2023.
Main Outcomes and Measures: The primary outcome was modified Rankin scale of 0 to 3 or returning to baseline functional status at 3 months. Secondary outcomes were mortality at 90 days, in-hospital mortality, and hematoma expansion. Weighted logistic regression was performed to evaluate the association of PCC with study outcomes. In unweighted logistic regression models, factors associated with good neurological outcome and hematoma expansion in DOAC-associated ICH were identified.
Results: A total of 232 patients with DOAC-associated ICH, with a mean (SD) age of 77.2 (9.3) years and 101 (44%) female patients, were included. Among these, 116 (50%) received conservative treatment and 102 (44%) received PCC. Overall, 74 patients (31%) patients had good neurological recovery and 92 (39%) died within 90 days. Median (IQR) baseline hematoma volume was 21.7 mL (3.6-66.1 mL). Compared with conservative management, PCC was not associated with improved neurological recovery (adjusted odds ratio [aOR], 0.62; 95% CI, 0.33-1.16;
Conclusions and Relevance: In this cohort study, Chinese patients with DOAC-associated ICH had large baseline hematoma volumes and high rates of mortality and functional disability. PCC treatment was not associated with improved functional outcome, hematoma expansion, or mortality. Further studies on novel hemostatic agents as well as neurosurgical and adjunctive medical therapies are needed to identify the best management algorithm for DOAC-associated ICH.
Ticagrelor or Clopidogrel Monotherapy vs Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: A Systematic Review and Patient-Level Meta-Analysis
Marco Valgimigli, MD, PhD; Felice Gragnano, MD, PhD; Mattia Branca, PhD et alAnna Franzone, MD, PhD; Bruno R. da Costa, PhD; Usman Baber, MD; Takeshi Kimura, MD; Yangsoo Jang, MD, PhD; Joo-Yong Hahn, MD; Stephan Windecker, MD; Charles M. Gibson, MD; Hirotoshi Watanabe, MD; Byeong-Keuk Kim, MD; Young Bin Song, MD; Yunpeng Zhu, MD; Pascal Vranckx, MD, PhD; Shamir Mehta, MD; Kenji Ando, MD; Sung Jin Hong, MD; Hyeon-Cheol Gwon, MD; Patrick W. Serruys, MD; George D. Dangas, MD; Eùgene P. McFadden, MD; Dominick J. Angiolillo, MD, PhD; Dik Heg, PhD; Paolo Calabrò, MD, PhD; Peter Jüni, MD; Roxana Mehran, MD; for the Single Versus Dual Antiplatelet Therapy (Sidney-3) Collaboration
Abstract
Importance: Among patients undergoing percutaneous coronary intervention (PCI), it remains unclear whether the treatment efficacy of P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) depends on the type of P2Y12 inhibitor.
Objective: To assess the risks and benefits of ticagrelor monotherapy or clopidogrel monotherapy compared with standard DAPT after PCI.
Data Sources: MEDLINE, Embase, TCTMD, and the European Society of Cardiology website were searched from inception to September 10, 2023, without language restriction.
Study Selection: Included studies were randomized clinical trials comparing P2Y12 inhibitor monotherapy with DAPT on adjudicated end points in patients without indication to oral anticoagulation undergoing PCI.
Data Extraction and Synthesis: Patient-level data provided by each trial were synthesized into a pooled dataset and analyzed using a 1-step mixed-effects model. The study is reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data.
Main Outcomes and Measures: The primary objective was to determine noninferiority of ticagrelor or clopidogrel monotherapy vs DAPT on the composite of death, myocardial infarction (MI), or stroke in the per-protocol analysis with a 1.15 margin for the hazard ratio (HR). Key secondary end points were major bleeding and net adverse clinical events (NACE), including the primary end point and major bleeding.
Results: Analyses included 6 randomized trials including 25 960 patients undergoing PCI, of whom 24 394 patients (12 403 patients receiving DAPT; 8292 patients receiving ticagrelor monotherapy; 3654 patients receiving clopidogrel monotherapy; 45 patients receiving prasugrel monotherapy) were retained in the per-protocol analysis. Trials of ticagrelor monotherapy were conducted in Asia, Europe, and North America; trials of clopidogrel monotherapy were all conducted in Asia. Ticagrelor was noninferior to DAPT for the primary end point (HR, 0.89; 95% CI, 0.74-1.06; P for noninferiority = .004), but clopidogrel was not noninferior (HR, 1.37; 95% CI, 1.01-1.87;
Conclusions and Relevance: This systematic review and meta-analysis found that ticagrelor monotherapy was noninferior to DAPT for all-cause death, MI, or stroke and superior for major bleeding and NACE. Clopidogrel monotherapy was similarly associated with reduced bleeding but was not noninferior to DAPT for all-cause death, MI, or stroke, largely because of risk observed in 1 trial that exclusively included East Asian patients and a hazard that was driven by an excess of noncardiovascular death.