Abstract
Objective
The beneficial effect of renin-angiotensin system (RAS) inhibitors has been well established in patients with cardiovascular disease; however, their effectiveness in patients with chronic limb-threatening ischemia (CLTI), a selected disease-burdened population, is largely unknown. The purpose of this study was to evaluate long-term outcomes of RAS inhibitor use in patients with CLTI undergoing a vascular intervention.
Methods
For this study, all CLTI patients undergoing a first-time revascularization (bypass or endovascular) were analyzed at our institution between 2005 and 2014. Patients discharged on a RAS inhibitor (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor [AR] blocker) were compared to those not on a RAS inhibitor. Inverse probability of treatment weighting with additional regression analyses were used to determine long-term risk of mortality and major adverse events. A sensitivity analysis was performed to assess the dose-related therapeutic response of RAS inhibitors (low-dose vs. high-dose therapy).
Results
Between 2005 and 2014, 1,303 limbs from 1,161 patients were identified. Of these patients, 52% were discharged on a RAS inhibitor, with 67% discharged on a high-dose therapy and 33% on a low-dose therapy. Patients discharged on a RAS inhibitor suffered more frequently from diabetes, hypertension, and myocardial infarction, whereas those not on a RAS inhibitor had more chronic kidney disease (all P<.05). There was no difference in the proportion of patients presenting with tissue loss. After adjustment for these and other baseline covariates, RAS inhibitor use was associated with lower late mortality (hazard ratio [HR] 0.78, [95% confidence interval] 0.65–0.94). Discharge on a high-dose RAS inhibitor was associated with lower mortality (HR 0.70 [0.57–0.86]), while a low-dose RAS inhibitor was not associated with lower mortality (HR 0.95 [0.73–1.24]) compared to patients not prescribed a RAS inhibitor. This association was still significant comparing high-dose to low-dose therapy (HR 0.74 [0.55–0.98]). No associations were found between RAS inhibitor use and major adverse limb event (HR 0.95 [0.73–1.22]), major amputation (HR 0.82 [0.57–1.18]), or reintervention (HR 1.05 [0.85–1.31]). These point estimates were not different for those on ACE inhibitors versus AR blockers, nor were they affected by the type of revascularization.
Conclusions
CLTI patients prescribed a RAS inhibitor at discharge demonstrated significantly lower long-term mortality, whereas limb events were unaffected. These data indicate that, in these heavily burdened patients, the benefit is restricted to those on a high-dose, which underscores the importance of attaining these doses.
Introduction
Physician adherence to guideline-recommended medical management for patients with peripheral arterial disease (PAD) is low, with multiple studies indicating that PAD patients are consistently undertreated.1–6 While several medications, including statins and antiplatelet agents, have emerged as standard therapies for mitigating surgical adverse events, renin-angiotensin system (RAS) inhibitors tend to be relatively underutilized. Particularly among patients with chronic limb-threatening ischemia (CLTI), aggressive risk factor modification poses a major opportunity to improve cardiac outcomes and survival.
Blockade of RAS by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor (AR) blockers is currently a moderate recommendation (class IIa) in the 2016 lower extremity PAD practice guidelines from the American College of Cardiology and American Heart Association.7 These recommendations are primarily based on well-designed cardiovascular trials showing major long-term benefit of RAS inhibitors.8–10 Aside from a few studies reporting outcomes in symptomatic and asymptomatic PAD patients treated with RAS inhibitors,6,11–14 there is limited evidence specifically in patients with CLTI. In a single study evaluating CLTI patients undergoing diagnostic angiography or endovascular intervention, Armstrong et al. determined that ACE inhibitor or AR blocker prescription was associated with significantly lower mortality and cardiac complications.15 It remains unclear, however, whether these favorable outcomes demonstrated in endovascular treatment modalities are different for those treated with bypass and, in particular, whether these effects are being realized in a dose-dependent manner. Despite recommendations in cardiovascular practice guidelines to achieve elevated target doses, patients often receive doses that are lower than used in the benchmark clinical trials.16,17
Therefore, with this study, we sought to evaluate long-term outcomes of RAS inhibitor use in CLTI patients undergoing a first-time vascular intervention, and determine whether these outcomes are different between low-dose and high-dose therapies.
Methods
This was a retrospective chart review using data from a single institution between 2005 and 2014. All patients with CLTI undergoing a first-time infrainguinal vascular intervention (endovascular or surgical) were identified through a detailed review of procedure bookings, institutional Vascular Study Group of New England (VSGNE) data, and billing data. The study protocol was approved by the Institutional Review Board of the Beth Israel Deaconess Medical Center and a waiver of informed consent was granted due to the retrospective nature of the study.
RAS inhibitor
Medical management was determined in a standardized fashion by individually reviewing preprocedural and discharge medications. To ascertain longer use of RAS inhibitors, we defined our main exposure variable as discharge on an ACE inhibitor or AR blocker. Since we evaluated the effect of discharge medication, we excluded patients who died during their index hospitalization (N = 14; 1.1%). In a separate analysis, we classified those on RAS inhibitors according to their dose intensity into low-dose or high-dose therapy (Table I; presented as daily dose). Because there are no specific recommendations in place regarding appropriate dosing regimens, cutoff values were chosen based on medical and surgical guidelines, randomized controlled trails, and observational studies.17–20 Patients discharged on two RAS inhibitors were automatically designated to the high-dose group (N = 20; 1.5%). There were no protocols nor were there standardized prescriptions of RAS inhibitors. All other baseline variables were obtained through clinical notes, admission history, documentation during hospitalization, operative notes, and discharge summaries. Independent ambulation was defined as ambulation without assistance, which does not include patients that walk with a prosthesis.
Table I.
Treatment doses of drugs included in the study cohort
| Low-dose RAS inhibitor (N = 221) |
High-dose RAS inhibitor (N = 454) |
|||||
|---|---|---|---|---|---|---|
|
| ||||||
| Daily dose | N | % | Daily dose | N | % | |
| ACE inhibitor | ||||||
| Lisinopril | ≤ 5 mg | 116 | (52) | 10–80 mg | 305 | (67) |
| Enalapril | ≤ 5 mg | 7 | (3.2) | 10–40 mg | 23 | (5.1) |
| Captopril | ≤ 50 mg | 12 | (5.4) | 75–300 mg | 3 | (0.7) |
| Ramipril | ≤ 2.5 mg | 4 | (1.8) | 5–20 mg | 9 | (2.0) |
| Quinapril | ≤ 20 mg | 4 | (1.8) | > 20 mg | 4 | (0.9) |
| Fosinopril | ≤ 20 mg | 0 | (0) | > 20 mg | 2 | (0.4) |
| Moexipril | ≤ 7.5 mg | 0 | (0) | 15–30 mg | 4 | (0.9) |
| Benazepril | ≤ 10 mg | 0 | (0) | > 10 mg | 1 | (0.2) |
| AR blocker | ||||||
| Losartan | ≤ 50 mg | 40 | (18) | 75–200 mg | 25 | (5.5) |
| Valsartan | ≤ 80 mg | 29 | (13) | 120–320 mg | 44 | (9.7) |
| Irbesartan | ≤ 150 mg | 6 | (2.7) | 300 mg | 7 | (1.5) |
| Olmesartan | ≤ 20 mg | 2 | (0.9) | > 20 mg | 2 | (0.4) |
| Candesartan | ≤ 8 mg | 0 | (0) | 16–32 mg | 5 | (1.1) |
| Telmisartan | ≤ 40 mg | 1 | (0.5) | > 40 mg | 0 | (0) |
| Dual ACE or dual AR | 3 | (0.7) | ||||
| Combination ACE and AR | 17 | (3.7) | ||||
RAS: renin-angiotensin system, ACE: angiotensin-converting enzyme, AR: angiotensin receptor
Outcomes
The primary outcome of this study was death throughout follow-up. Death was captured through patient chart review and the Social Security Death Index, albeit data related to the cause of death was not gathered within our registry. Secondary outcomes included 30-day wound infection and a 30-day composite outcome of myocardial infarction or postdischarge mortality, as well as late limb events any time during follow-up, such as major adverse limb event (MALE), major amputation, and reintervention. Wound infection was considered when any surgical site infection was documented. MALE was defined as an ipsilateral major amputation (above or below knee) or major surgical revision, such as new bypass graft, jump or interposition bypass revision, thrombectomy, and pharmacologic or mechanical thrombolysis.21 Reintervention included any ipsilateral surgical or endovascular revision. Limb events were ascertained through post-procedural clinical visits. Typical follow-up with a vascular surgeon consisted of outpatient care every 3 to 4 months for the first 2 years and every 6 months for the years thereafter. In an attempt to account for repeated measures in patients operated on both limbs, we censored the initial limb at the procedure date of the contralateral limb for our survival analysis, whereas these were not censored when we evaluated limb events.
Statistical analysis
In our primary analysis, patients discharged on any RAS inhibitor were compared to those not discharged on a RAS inhibitor. Next, we determined whether these associations varied for those patients on different dose intensities (low-dose vs. high-dose therapy). In an additional sensitivity analysis, by incorporating interaction terms, we assessed whether the associations found were modified by the type of RAS inhibitor (ACE inhibitor vs. AR blocker), coronary artery disease, symptom status, or revascularization strategy. Categorical variables were evaluated with the Pearson’s χ2 and Fisher’s exact test, and continuous variables were analyzed with the Student’s t-test and Mann Whitney U test, where appropriate. Inverse probability of treatment weighting (IPTW) using propensity scores was performed in an attempt to reduce potential confounding and eliminate the bias of nonrandom treatment assignment. Covariates were generously introduced to construct the propensity score and included: age, gender, index procedure (bypass or endovascular), year of procedure, symptom status (rest pain, ulcer, gangrene), race, smoking (prior and current), chronic obstructive pulmonary disease, hypertension, coronary artery disease, history of myocardial infarction, history of coronary intervention, chronic heart failure, hyperlipidemia, diabetes, chronic kidney disease, dialysis dependence, and discharge on statin medications. Balance diagnostics were examined to verify adequate overlap of propensity scores between treatment groups and included visual inspection of the kernel density plot and assessment of standardized differences and variance ratios. Doubly robust estimation was used, which combines Cox proportional hazard models with IPTW, to additionally adjust for residual confounding and to further increase the precision of the estimates.22 These confounders were determined using purposeful selection combining covariates selected a priori and by univariate screen (P < .10).23 We evaluated the proportional hazards assumptions with the scaled Schoenfeld residuals on time and visually by log-log plots. Exact logistic regression was performed to evaluate 30-day outcomes, as an alternative for the maximum likelihood estimation of conventional logistic regression, which appropriately accounts for the rarity of the adverse events. Crude survival between treatment groups was compared using the log-rank test, and adjusted survival curves were constructed after IPTW of the total cohort. All analyses were conducted with SPSS Statistics 23 (IBM Corp, Armonk, NY) and STATA 14 (StataCorp, College Station, Tex).
Results
A total of 1,303 limbs from 1,161 patients were included. Over the study period, 52% of patients with CLTI were discharged on a RAS inhibitor and of those patients 67% were discharged on a high-dose therapy and 33% on a low-dose therapy. Between 2005 and 2014, the proportion of patients who were discharged on a RAS inhibitor within our institution varied but gradually increased, from 53% to 66% after a first-time vascular intervention (Figure 1). This increase was evident among patients discharged on both a low-dose (19% to 27%) and a high-dose therapy (34% to 39%).
Figure 1.
Proportions of patients on various renin-angiotensin system (RAS) inhibitor intensities by year
Baseline characteristics
As detailed in Table II, demographics were comparable between patients discharged on a RAS inhibitor to those not discharged on a RAS inhibitor. In terms of comorbidities, CLTI patients discharged on a RAS inhibitor were more likely to have diabetes, hypertension, history of myocardial infarction, and hyperlipidemia, while they less frequently had a history of chronic kidney disease and dialysis dependence (all P < .05). Patients receiving RAS inhibitors had similar rates of other discharge medications compared to those who did not receive a RAS inhibitor, including antiplatelet agents, statins, and beta-blockers. Finally, independent ambulation was more common in patients discharged on a RAS inhibitor. Univariate outcomes stratified by dose intensity are presented in Supplementary Table I.
Table II.
Baseline characteristics of patients with and without a renin-angiotensin system (RAS) inhibitor at discharge
| No RAS inhibitor (N = 628; 48%) |
Any RAS inhibitor (N = 675; 52%) |
||||
|---|---|---|---|---|---|
|
| |||||
| N | % | N | % | P-value | |
| Age (years, mean ± SD) | 71.6 | (13) | 71.3 | (12) | .64 |
| Male gender | 389 | (62) | 384 | (57) | .06 |
| Bypass (vs. Endovascular) | 313 | (50) | 341 | (51) | .81 |
| Race | .08 | ||||
| White | 502 | (80) | 515 | (77) | |
| Black | 63 | (10) | 95 | (14) | |
| Other | 60 | (9.6) | 63 | (9.4) | |
| Smoking history | 375 | (61) | 406 | (61) | .84 |
| Current smoker | 129 | (21) | 143 | (22) | .75 |
| Symptom status | .16 | ||||
| Rest pain | 127 | (20) | 125 | (19) | |
| Ulcer | 312 | (50) | 371 | (55) | |
| Gangrene | 189 | (30) | 179 | (27) | |
| Diabetes mellitus | 429 | (69) | 534 | (80) | <.001 |
| Coronary artery disease | 305 | (50) | 352 | (53) | .24 |
| History of myocardial infarction | 145 | (24) | 189 | (29) | .04 |
| Atrial fibrillation | 122 | (22) | 110 | (18) | .07 |
| History of CABG/PCI | 217 | (35) | 239 | (36) | .74 |
| Congestive heart failure | 192 | (31) | 206 | (31) | .98 |
| Hypertension | 499 | (81) | 600 | (90) | <.001 |
| Hyperlipidemia | 357 | (58) | 425 | (64) | .03 |
| Chronic kidney disease | 241 | (39) | 183 | (28) | <.001 |
| Dialysis dependence | 164 | (27) | 93 | (14) | <.001 |
| COPD | 79 | (13) | 75 | (11) | .41 |
| CVA | 75 | (13) | 86 | (14) | .86 |
| Preoperative medication | |||||
| Antiplatelet | 381 | (64) | 445 | (69) | .06 |
| Lipid-lowering agents | 373 | (60) | 477 | (73) | <.001 |
| Beta-blocker | 360 | (60) | 391 | (60) | .79 |
| Discharge medication | |||||
| Antiplatelet | 561 | (91) | 616 | (93) | .16 |
| Lipid-lowering agents | 474 | (76) | 540 | (80) | .07 |
| Beta-blocker | 460 | (74) | 494 | (74) | >.99 |
| Ambulatory independent | 313 | (54) | 383 | (61) | .02 |
SD: standard deviation, CABG: coronary artery bypass grafting, PCI: percutaneous coronary intervention, COPD: chronic obstructive pulmonary disease, CVA: cerebrovascular accident
Univariate outcomes
Any RAS inhibitor vs. no RAS inhibitor
The median follow-up was 1.5 years (Interquartile range [IQR]: 0.4 – 3.8). The unadjusted survival rates for patients discharged on a RAS inhibitor were significantly higher, with 85% alive at one year, 67% at three years, and 46% at five years, compared to 80%, 54%, and 39% for those not discharged on a RAS inhibitor (log-rank: P < .001, standard error [SE] < .10). The incidence of five-year MALE (22% vs. 20%, P = .50), major amputation (11% vs. 11%, P = .60), and reintervention (31% vs. 27%, P = .11) did not significantly differ between those receiving and not receiving a RAS inhibitor. On univariate analysis, 30-day myocardial infarction or post-discharge mortality was lower among patients discharged on a RAS inhibitor compared to those who were not (1.6% vs. 4.3%, P < .01). Myocardial infarction occurred less often in those prescribed a RAS inhibitor (0.4% vs. 1.9%, P = .01), while post-discharge mortality was not significantly different (1.2% vs. 2.5%, P = .07).
RAS inhibitor dose intensity
Survival was higher in those discharged on high-dose compared to low-dose RAS at one year (89% vs. 79%), three years (71% vs. 59%), and five years (50% vs. 39%) (log-rank P < .01, SE < .10). Limb events through five years were comparable between patients discharged on different dose intensities (Table III). There was no difference in 30-day myocardial infarction or post-discharge mortality between patients on a high-dose versus low-dose RAS inhibitor (P = .37).
Table III.
Univariate outcomes of patients on various renin-angiotensin system (RAS) inhibitor intensities
| No RAS inhibitor (N = 628; 48%) |
High-dose RAS inhibitor (N = 221; 17%) |
Low-dose RAS inhibitor (N = 454; 35%) |
P-value | |||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| N | % | N | % | N | % | Overall | Low- vs. high-dose | |
| 30-day outcomes | ||||||||
|
| ||||||||
| Mortality or myocardial infarction | 27 | (4.3) | 5 | (2.3) | 6 | (1.3) | .01 | .37 |
| Mortality | 16 | (2.5) | 4 | (1.8) | 4 | (0.9) | .13 | .45 |
| Myocardial infarction | 12 | (1.9) | 1 | (0.5) | 2 | (0.4) | .046 | >.99 |
| Wound infection | 39 | (6.2) | 10 | (4.5) | 22 | (4.8) | .50 | .85 |
|
| ||||||||
| Long-term outcomes | ||||||||
|
| ||||||||
| MALE | 128 | (20) | 49 | (22) | 99 | (22) | .79 | .91 |
| Major amputation | 66 | (11) | 22 | (10) | 55 | (12) | .61 | .41 |
| Reintervention | 171 | (27) | 68 | (31) | 143 | (32) | .27 | .88 |
MALE: major adverse limb event
Multivariable analysis
Any RAS inhibitor vs. no RAS inhibitor
Following inverse probability of treatment weighting with additional adjustment for key confounders (e.g., age, symptom status, cardiovascular disease, and chronic kidney disease), RAS inhibitor use was associated with a 22% lower rate of death (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.65 – 0.94) (Figure 2A). No significant associations were found regarding RAS inhibitor use and MALE (HR 0.95, 95% CI 0.73 – 1.22), major amputation (HR 0.82, 95% CI 0.57 – 1.18), and reintervention (HR 1.05, 95% CI 0.85 – 1.31) (Table IV). After adjustment, RAS inhibitors were independently associated with reduced incidence of 30-day myocardial infarction or post-discharge mortality (odds ratio [OR] 0.41, 95% CI 0.18 – 0.88).
Figure 2.
Adjusted survival curves of patients on various renin-angiotensin system (RAS) inhibitor intensities A. Any RAS inhibitor vs. no RAS inhibitor B. RAS inhibitor dose intensity (with no RAS inhibitor as the reference group)
Table IV.
Adjusted associations between various renin-angiotensin system (RAS) inhibitor intensities and adverse outcomes
| Any RAS inhibitor | Low-dose RAS inhibitor | High-dose RAS inhibitor | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 5-year limb events | HR | [95% CI] | P-value | HR | [95% CI] | P-value | HR | [95% CI] | P-value |
| MALE | 0.95 | [0.73 – 1.22] | .68 | 1.00 | [0.71 – 1.43] | .98 | 0.93 | [0.70 – 1.23] | .61 |
| Major amputation | 0.82 | [0.57 – 1.18] | .29 | 0.72 | [0.43 – 1.22] | .23 | 0.87 | [0.59 – 1.30] | .50 |
| Reintervention | 1.05 | [0.85 – 1.31] | .63 | 1.16 | [0.87 – 1.56] | .31 | 1.01 | [0.79 – 1.28] | .95 |
HR: hazard ratio, CI: confidence interval, MALE: major adverse limb event
Additionally adjusted for: age, gender, race, symptom status, diabetes, coronary artery disease, hypertension, history of myocardial infarction, congestive heart failure, COPD, chronic kidney disease, procedure, procedure year, discharged on statin
A sensitivity analysis showed similar point estimates between patients prescribed ACE inhibitors versus AR blockers. In addition, survival associated with RAS inhibitor use was not modified by a history of coronary artery disease, symptom status (rest pain, ulcers, or gangrene), or the type of procedure (surgical vs. endovascular) (interaction: P > .05).
RAS inhibitor dose intensity
To evaluate the dose-related therapeutic response of RAS inhibitors, outcomes were compared between dose intensities in an adjusted analysis after inverse probability of treatment weighting. Treatment with a high-dose RAS inhibitor was significantly associated with 30% lower mortality (HR 0.70, 95% CI 0.57 – 0.86), while we found no association between late survival and treatment with a low-dose RAS inhibitor (HR 0.95, 95% CI 0.73 – 1.24) compared to no RAS inhibitor (Figure 2B). The association found was still significant comparing high-dose to low-dose therapy (HR 0.74 [0.55–0.98]). Similar to the primary analysis, there were no notable associations between either RAS inhibitor dose group and patients without a RAS inhibitor in respect to MALE, major amputation, or reintervention (Table IV). Patients on a RAS inhibitor at a high-dose demonstrated a 65% lower rate of the composite endpoint, 30-day myocardial infarction or post-discharge mortality (OR 0.35, 95% CI 0.11 – 0.88), whereas this association was not significant in those on low-dose therapy (OR 0.53, 95% CI 0.16 – 1.45) (Figure 3).
Figure 3.
Adjusted associations between renin-angiotensin system (RAS) inhibitors and 30-day myocardial infarction or postdischarge mortality, with no RAS inhibitor as the reference group
OR: odds ratio, LCI: lower confidence interval, UCI: upper confidence interval Confidence intervals are 95%.
Adjusted for: age, gender, symptom status, coronary artery disease
Discussion
This study demonstrates that CLTI patients prescribed RAS inhibitors at discharge had significantly lower periprocedural cardiac events or death, as well as improved survival up to five years after a first-time revascularization. There was no significant benefit of RAS inhibitors in regard to adverse limb events, including MALE and major amputation. Patients prescribed a high-dose therapy experienced a lower mortality (reduction of 30%), whereas those on a low-dose RAS inhibitor did not demonstrate any survival or limb-related benefits over those not discharged on a RAS inhibitor.
Smoking cessation, weight loss, and exercise programs are common secondary prevention measures in PAD patients, as is the prescription of some form of antiplatelet or statin. Adherence to secondary prevention strategies seems to improve over time, however, only about half of patients are prescribed a RAS inhibitor, ranging from 20% to 60% in the current literature, despite compelling evidence of their known cardiovascular benefit.1–6 In a selected subset of patients from the multicenter HOPE trial, Östergren et al. reported that ramipril treatment (10 mg/day) in 1,725 symptomatic PAD patients was associated with a 25% relative risk reduction of cardiovascular death, a non-significant 15% lower rate of all-cause mortality, and a 25% myocardial infarction risk reduction.11 It is interesting to note that these findings could only be partly attributed to a blood pressure lowering effect, since there was only a modest decrease in mean blood pressure (systolic of 3 mmHg and diastolic of 2 mmHg). Rather by antagonizing angiotensin II and promoting the production of bradykinin, RAS blockade may result in a number protective pleiotropic properties, such as a decrease in pre- and afterload by reduced vasoconstriction and water retention, the potential to stabilize atherosclerotic plaques, inhibit proliferation of smooth muscle cells, improve vascular endothelial function, reduce left ventricular hypertrophy, and enhance fibrinolysis.24–26 Observational studies have shown similar results. With a median follow-up of eight years in 2,420 PAD patients (defined as ankle-brachial index ≤0.9), Feringa et al. determined that not only statins, antiplatelets, and beta-blockers were independently associated with lower mortality but also ACE inhibitors (HR 0.80, 95% CI 0.69–0.94).6
The above-mentioned studies clearly show a benefit in patients with atherosclerotic disease of the lower extremities; however, limited studies specifically address the most severe manifestation of PAD: CLTI. One other single-institution study was conducted among 464 CLTI patients undergoing diagnostic angiography or endovascular intervention using a similar propensity weighted analysis. Although not stratified by dose intensity, this study did demonstrate a significantly lower risk of major adverse cardiovascular event (HR 0.76, 95% CI 0.58 – 0.99) and mortality (HR 0.71, 95% CI 0.53 – 0.95) at three years in those prescribed either an ACE inhibitor or AR blocker.15 This highlights the value of best medical management and, ultimately, prescription of RAS inhibitors should be considered in all CLTI patients, as this is a particularly vulnerable population that seems to benefit from optimization of cardiovascular health. Similar to the current study, the prior report failed to demonstrate a limb-specific benefit in those with more advanced disease on RAS inhibitors. However, this does not necessarily imply that there is no effect on lower extremity vasculature. Among patients with claudication, it has been suggested that RAS inhibitors may reduce symptoms and improve functional capacity, such as walking distance and pain-free walking time.12–14 This study did not specifically investigate these parameters and, therefore, further data are needed to explore whether RAS inhibitors could play a role in improving these quality of life measures in the CLTI population.
Our data extend previous findings and support the idea of titration to higher doses of RAS inhibitors to achieve better clinical outcomes in patients with CLTI, unless limited by side effects. This is reflected by numerous clinical trials in primarily patients with congestive heart failure.16,20,27,28 Prescription of low-dose therapy may be based upon the belief that high and low doses exert similar benefits but without the side effects of high doses. Yet, our study, together with multiple others, indicates that high doses result in improved clinical outcomes.20,27 The treatment of symptoms or blood pressure may not be parallel to the dose-response relationship for survival, and thus survival rather than blood pressure should be used as an endpoint to titrate the effective dose. Although not assessed in the present analysis, additional toxicity of high doses is only infrequently documented (approximately less than 5%) and this may be instigating overly cautious reluctance among physicians to continue RAS inhibitors after only a modest decrease in blood pressure or after a decline in renal function. It is a misconception that patients with chronic kidney disease cannot be treated with RAS inhibitors. While close monitoring is recommended, particularly among patients with renal artery stenosis, RAS inhibition is associated with reducing proteinuria and slowing the rate of progression of kidney disease.29–31 In the occurrence of acute renal failure, which most commonly develops shortly after initiation, RAS inhibitors can easily be discontinued whereupon renal deterioration is reversible. These reservations may have limited the widespread utilization and appropriate dosing of RAS inhibitors, while the advantages grossly outweigh the potential risks. Since low-dose therapy did not prolong life expectancy in CLTI patients, low dosing regimens that are now widely used in clinical practices may deprive these patients from the potential benefit of RAS inhibitors.
These data further suggest that the cardiovascular protective effects illustrated in this study were not different among patients discharged on ACE inhibitors or AR blockers. The proportion of patients prescribed an AR blocker was smaller, and thus we may have failed to detect a difference due to lack of power. However, our results are consistent with a prior meta-analysis that showed, in a pooled estimate of 49,924 patients, equal benefits between both RAS-based medications in respect to myocardial infarction, cardiovascular mortality, and overall mortality.32 In addition, the survival benefit of RAS inhibitors did not vary across the type of procedure (surgical or endovascular) or among patients with and without coronary artery disease. Therefore, these data support the implementation of guideline-recommended prescription of RAS inhibitors in the vast majority of patients with CLTI.
Several limitations warrant discussion. Firstly, our study was subject to the general limitations inherent to observational studies, and although we have attempted to account for this with propensity-adjusted analyses, the possibility of residual and unmeasured confounding still exists. Secondly, caution must be taken when generalizing these findings beyond the boundaries of our institution. As this was a retrospective analysis, the blood pressure lowering effect of RAS inhibitor therapy could not be reliably determined. Moreover, the main exposure variable was based on discharge medications and, unfortunately, we lack specific data on compliance and change in doses over time, nor did we capture the clinician who prescribed the medication. Understanding the reason for non-adherence or intolerance to RAS inhibitors would have added extra detail, however, side effects were not documented within our registry, such as hypotension, hyperkalemia, and renal deterioration. In addition, direct renin inhibitors, the most recent class of RAS inhibitors, were not assessed in the present study. Finally, patients treated with primary amputation or medical management only were not identified in the current cohort and, although this is a relatively small subgroup, it may compromise the study’s generalizability to the entire CLTI population.
Conclusion
This study demonstrates that RAS inhibitor use in CLTI patients was associated with lower cardiovascular adverse events and improved long-term survival, although this benefit was only observed in those on a high-dose therapy. Therefore, physicians should strive to maintain patients on a high-dose RAS inhibitor, provided that such doses are tolerated. It is likely that a change in current prescribing patterns would benefit a large number of patients with CLTI, which provides an opportunity for physicians to not only optimize surgical care but also medical management.
Supplementary Material
Acknowledgments
Supported by the NIH T32 Harvard-Longwood Research Training in Vascular Surgery grant HL007734.
Footnotes
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