Canadian Cardiovascular Society 2022 Guidelines for Peripheral Arterial Disease.

Patients with widespread atherosclerosis such as peripheral artery disease (PAD) have a high risk of cardiovascular and limb symptoms and complications, which affects their quality of life and longevity. Over the past 2 decades there have been substantial advances in diagnostics, pharmacotherapy, and interventions including endovascular and open surgical to aid in the management of PAD patients. To summarize the evidence regarding approaches to diagnosis, risk stratification, medical and intervention treatments for patients with PAD, guided by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework, evidence was synthesized, and assessed for quality, and recommendations provided-categorized as weak or strong for each prespecified research question. Fifty-six recommendations were made, with 27% (15/56) graded as strong recommendations with high-quality evidence, 14% (8/56) were designated as strong recommendations with moderate-quality evidence, and 20% (11/56) were strong recommendations with low quality of evidence. Conversely 39% (22/56) were classified as weak recommendations. For PAD patients, strong recommendations on the basis of high-quality evidence, include smoking cessation interventions, structured exercise programs for claudication, lipid-modifying therapy, antithrombotic therapy with a single antiplatelet agent or dual pathway inhibition with low-dose rivaroxaban and aspirin; treatment of hypertension with an angiotensin converting enzyme or angiotensin receptor blocker; and for those with diabetes, a sodium-glucose cotransporter 2 inhibitor should be considered. Furthermore, autogenous grafts are more effective than prosthetic grafts for surgical bypasses for claudication or chronic limb-threatening ischemia involving the popliteal or distal arteries. Other recommendations indicated that new endovascular techniques and hybrid procedures be considered in patients with favourable anatomy and patient factors, and finally, the evidence for perioperative risk stratification for PAD patients who undergo surgery remains weak.

Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial.

AIMS: In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described. METHODS AND RESULTS: The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding). CONCLUSION: Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.

Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial.

BACKGROUND: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. METHODS: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. RESULTS: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (P-interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P=0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding (P-interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding (P-interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P=0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (P=0.95) and postprocedural bleeding requiring intervention (P=0.93) was not significantly increased. CONCLUSIONS: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.

COMPASS for Vascular Surgeons: Practical Considerations.

PURPOSE OF REVIEW: To suggest a practical approach for the application of data from the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial in patients with peripheral artery disease (PAD). RECENT FINDINGS: The COMPASS trial showed that low-dose rivaroxaban 2.5 mg twice daily plus daily aspirin was superior to aspirin alone in reducing major adverse cardiovascular and cerebrovascular events, and major adverse limb events among patients with stable atherosclerotic vascular disease, including those with PAD. The risk for major bleeding, however, was higher with rivaroxaban plus aspirin. Critical limb ischemia at baseline (rest pain, ulcer, or gangrene), previous limb or foot amputation, or a history of peripheral revascularization surgery or stenting were independently associated with increased major adverse limb events within the trial. SUMMARY: Intensification of antithrombotic therapy with low-dose rivaroxaban plus aspirin should be considered in low bleeding risk PAD patients who are at increased risk for ischemic and/or limb events. A practical approach for clinicians is presented to help incorporate COMPASS data into practice.

Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk).

BACKGROUND: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. METHODS: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia. RESULTS: Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL. CONCLUSIONS: Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

A new metric for centralization of ruptured abdominal aortic aneurysm repair in large territories.

OBJECTIVE: This study proposes the DEDE (Door-from-Emergency to Door-to-EVAR [endovascular aneurysm repair]) time as a new metric for ruptured abdominal aortic aneurysm (RAAA) delay time to surgery, permitting coherent centralization in large territories. It demonstrates how the DEDE time can be applied, using data from the province of Quebec, and looks at its potential effect on 30-day mortality. METHODS: We used the Quebec Integrated Chronic Disease Surveillance System (QICDSS), the linkage of five health administrative databases, to build a retrospective cohort of RAAA patients repaired operatively between April 1, 2006, and March 31, 2013. A validated algorithm was used to identify open surgical repair (OSR) and EVAR patients. Hospitals performing these operations were further characterized according to their location, volume of RAAA, types of surgeries (OSR vs EVAR), and surgeon's volume. Logistic and log-binomial regression analyses identified the risk of 30-day mortality with age, sex, hospital volume, and surgical groups as variables. Using the DEDE 90 metric and the attributable fraction, we projected how centralization and increasing the number of EVAR would affect the 30-day mortality. RESULTS: Among patients aged ≥65 years, 895 RAAAs were identified. OSR was performed in 839 patients (93.7%) and EVAR in 56 (6.3%). The overall 30-day mortality was 34.4%, and more specifically, was 35.5% for OSR compared with 17.9% for EVAR (P = .0046). RAAAs were treated in 39 hospitals, including 16 centers averaging less than one RAAA repair per year. Low-volume (39.4%) vs high-volume centers (32.5%) had similar 30-day mortality (P = .2198). In the multivariate analysis, the relative risk for OSR was 1.95 (P = .0211) and was not significant for hospital volume. Applying the DEDE 90 metric and increasing access to EVAR to 50% of patients, the overall 30-day mortality would be 26.8%. CONCLUSIONS: DEDE 90 is a new metric for a coherent centralization model, particularly in large territories, where transport time is crucial. Increasing access to EVAR performed in high-volume centers, with consideration to transport time, could improve the 30-day mortality after a RAAA repair.

Conduit vessel blood flow during the trek to Mount Everest base camp.

OBJECTIVE: Hemodynamic changes in response to the hypoxic environment of high altitude are vascular bed-specific. The aim of the present study was to investigate diameter and blood flow changes in conduit vessels in response to hypobaric hypoxia. METHODS: Eleven healthy subjects ascending Mount Everest to base camp participated in this study. Vessel diameter and blood velocity for brachial, carotid, common femoral, superficial femoral, and deep femoral arteries were measured by portable Doppler ultrasound. Blood flow was calculated from these values. Measurements were taken at sea level, at increasing altitudes on ascent to base camp (1310 m, 3470 m, 5330 m), and repeated on descent to lower altitude (1310 m). RESULTS: For all vessels except carotids, both vessel diameter and blood flow decreased between sea level and initial ascent to altitude, with subsequent persistence of these decreased values; there was no further significant change with continued ascent to higher altitude. Blood flow for all arteries (except carotids) increased significantly on descent to lower altitude, with an associated nonsignificant increase in velocity and decrease in diameter. CONCLUSIONS: This study showed that there is vasoconstriction of limb conduit vessels at altitude, which persists upon descent to lower altitude. Blood flow in these vessels also decreases with initial exposure to high altitude, yet increases when returning to lower altitude, reflecting variations in blood velocity. Carotid arteries responded differently to the stimulus of hypobaria than limb conduit vessels; there was no change in diameter seen on ascent or descent, but there was a progressive decrease in blood flow on ascent, with no change on subsequent descent.

Ankle-brachial index on Kilimanjaro: lessons from high altitude.

OBJECTIVE: This study investigated the effects of a high-sympathetic stimulus environment (high-altitude hypoxia) on limb-specific systolic blood pressure (sBP) and ankle-brachial index (ABI) in normal volunteers. We hypothesized that currently accepted normal values for ABI may in fact not reflect an actual normal vascular state in all patients. METHODS: Twenty climbers (17 males, 3 females) from Gatineau-Hull (Québec, Canada) participated in this study and ascended Mount Kilimanjaro, Africa. Ankle-brachial index measurements were performed at sea level and on Mount Kilimanjaro at approximately 4100 m. The data were analyzed using predictive analytics software SPSS 14.0. Data obtained at sea level were compared to those obtained at approximately 4100 m, with participants serving as their own controls. RESULTS: Ankle-brachial indices measured at approximately 4100 m (mean = 1.20) were greater than those measured at sea level (mean = 0.97) (n = -6.23; 95% CI: -.32 to -.17; P < .001). There were no significant differences between the systolic brachial pressures at approximately 4100 m when compared to those at sea level (P = .814). Contrarily, systolic ankle pressures at sea level (mean = 132) were significantly greater than those measured at approximately 4100 m (mean = 152) (t = -3.5, 95% CI: -29 to -7.4; P = .002). CONCLUSIONS: This study is the first to physiologically demonstrate that in response to a high adrenergic stimulus in healthy volunteers there is a greater increase in sBP in the legs vs the arms.

Modification of outcomes by lowering ischemic events after reconstruction of extracranial vessels (MOLIERE): an internet-based prospective study to evaluate and improve the effectiveness of carotid endarterectomy.

BACKGROUND: Independent audits have been proposed to improve carotid endarterectomy (CEA) effectiveness. This study used the online registry Modification of Outcomes by Lowering Ischemic Events after Reconstruction of Extracranial Vessels (MOLIERE) to evaluate the effectiveness of CEA in the Province of Quebec. The concept of MOLIERE is that surgeon involvement in a prospective manner is a prerequisite for them to evaluate, compare, and improve their practice. METHODS: All Quebec surgeons who performed CEA were invited to participate in this study sponsored by the Société des sciences vasculaires du Québec, the Canadian Society for Vascular Surgery and the Association des chirurgiens vasculaires du Québec. Surgeons prospectively entered data for 60 variables relevant to CEA in an online, secure, and confidential database between May 24, 2004, and May 31, 2005. Patient inclusion had to occur before surgery. After the study was completed, charts of all CEAs performed in each participating center were reviewed to validate the results of MOLIERE. For each participating institution, results of CEA that were not entered in the registry were also reviewed. RESULTS: A total of 279 patients (mean age, 69 years; range, 46-91 years) undergoing a CEA were enrolled in MOLIERE by 23 surgeons from 10 institutions in Quebec; 157 (56%) were symptomatic, and 122 (44%) were asymptomatic. Carotid endarterectomies were performed with patch angioplasty in 252 (89%), primary closure in 24 (9%), and by eversion in six (2%). Follow-up at 30 days was achieved for all patients. The 30-day stroke or death rates for symptomatic and asymptomatic patients were 3.2% (5 of 157, 95% confidence interval [CI], 1.2%-7.4%) and 0%. Validation was excellent for patients who were entered in the registry, with no additional deaths or strokes than those reported by the surgeons. The validation process revealed that participating surgeons entered 66% (279 of 424) of their patients in the registry. Indications and stroke or death rates (SDRs) for those patients who were not entered in the registry were not statistically different (symptomatic, 54% [79 of 145]; SDR of 1.3% [1 of 76] for symptomatic and 1.5% [1 of 66] for asymptomatic). In participating institutions, 11 surgeons did not participate. The SDRs for patients operated on by nonparticipating surgeons were higher but not statistically different than rates for patients operated on by participating surgeons (3.7% [5 of 136] vs 1.7% [7 of 424], P = .16). There was a trend toward higher stroke rate for patients operated on by nonparticipating surgeons (3.7% [5 of 136] vs 1.2% [5 of 424], P = .056). Mean postoperative length of stay was statistically higher for patients operated on by nonparticipating surgeons (4.7 vs 3.4 days, P = .046). The SDRs were adequate for all surgeons in participating centers, with 95% CI within accepted standards for symptomatic and asymptomatic patients. CONCLUSION: MOLIERE is the first Canadian online prospective registry allowing surgeons to audit CEA results. The SDRs for participating surgeons were valid and within standards. Scientific vascular societies played a key role in supporting this project. Such audits allow surgeons and medical stroke experts to examine the appropriateness and results of CEAs in their institutions to improve them. The future of MOLIERE is in validation of its concept, increased participation by surgeons, and integration of a multidisciplinary approach.

Cardiac medical therapy among patients undergoing abdominal aortic aneurysm repair.

Open abdominal aortic aneurysm (AAA) repair is a common surgical procedure associated with high mortality rates. Our objective was to describe the use of in-hospital cardiac medical therapy among patients undergoing open AAA repair and to examine the effect of perioperative cardiac medical therapy on in-hospital mortality. We examined clinical data and in-hospital medication use among 223 patients who underwent open AAA repair at three North American hospitals, all of which used the Transition resource and cost accounting system. Medication use was described [angiotensin converting enzyme (ACE) inhibitors, aspirin, ss-blockers, and statins] within the cohort at five specific periods of time: presurgery, day of surgery, 1 day after surgery, postsurgery, and discharge. We then performed a matched case-control study where cases were defined as patients who died in-hospital. We compared medication use between cases and controls to assess its impact on in-hospital mortality. Most patients were elderly (mean age 72.5 +/- 9.8 years), 70.4% were male, and in-hospital mortality within the cohort was 10.8%. Medication use in all periods of administration was low. ss-Blocker use was highest among all classes on the day of surgery, with 20.6% of patients undergoing AAA repair receiving the medication. Less than 50% of patients received any of the medications at discharge. After adjusting for baseline differences, perioperative ACE inhibitor use showed a trend toward a protective effect [odds ratio (OR) = 0.09, 95% confidence interval (CI) 0.01-1.31, p = 0.08], and perioperative ss-blocker use was significantly associated with a decrease in mortality (OR = 0.07, 95% CI 0.01-0.87, p = 0.04). Cardiac medical therapy among patients undergoing AAA repair is low throughout all periods of hospitalization. ACE inhibitor and ss-blocker use may be associated with decreased in-hospital mortality.