Page 2424 - Hematology_ Basic Principles and Practice ( PDFDrive )

2164 Part XII Hemostasis and Thrombosis

PAD, bezafibrate did not affect the rate of coronary events or stroke. pioglitazone. Several recent studies have evaluated the cardiovascular
In addition, in the FIELD (Fenofibrate Intervention and Event effects of newer classes of glucose-lowering agents including the
Lowering in Diabetes) study, fenofibrate did not reduce coronary glucagon-like peptide-1 (GLP-1) analogues, such as semaglutide and
events in diabetics, although its use was associated with fewer nonfatal liraglutide, and sodium glucose co-transporter-2 (SGLT-2) agents,
MIs and revascularization procedures. Although niacin also reduces such as empagliflozin. These studies have demonstrated the safety and
lipid levels, its efficacy for reducing cardiovascular events has been efficacy in reducing cardiovascular events in patients with diabetes
9a-c
called into question based on recent studies showing no added benefit with existing cardiovascular disease or at high cardiovascular risk.
17
in patients with established atherosclerotic vascular disease. Sub- A recent meta-analysis also showed no significant differences among
group analyses showed no meaningful differences in the subset of nine different classes of glucose-lowering drugs and risk of cardiovas-
9d
patients with established PAD. cular or all-cause mortality. Consequently, although the optimal
glycemic control required to reduce macrovascular complications in
patients with type II diabetes remains unclear, guidelines recommend
Hypertension treatments that maintain the level of hemoglobin A1c below 7%.
Foot care is a critical component of diabetes management, par-
Treatment of hypertension is a critical component of the manage- ticularly in those with PAD. Diabetes increases the risk of foot injury
ment of patients with atherosclerotic PAD. Such treatment reduces because of the associated peripheral neuropathy and decreased sensa-
the risk of stroke, MI, and congestive heart failure. Management of tion, thereby increasing the risk of ulcer formation. Resting limb
hypertension should follow current guidelines. Although there is ischemia and amputation are more frequent in patients with PAD
concern that lower systemic blood pressure may exacerbate symptoms with diabetes than in those without diabetes. Therefore careful atten-
of claudication or CLI, the majority of patients experience no change tion to foot care is imperative to prevent skin breakdown, infections,
in their symptoms. Several studies have found that antihypertensive ulceration, and amputation.
drugs reduce cardiovascular events in patients with PAD. The HOPE
(Heart Outcomes Prevention) study demonstrated a 22% reduction
in cardiovascular events with ramipril in patients with atherosclerotic Antiplatelet Therapy
disease, including those with PAD. ONTARGET (Ongoing Telmis-
artan Alone and in Combination with Ramipril Global Endpoint Antiplatelet therapy is recommended for patients with atherosclerosis,
10
Trial) demonstrated that telmisartan and ramipril produced similar including patients with symptomatic PAD. The Antiplatelet Trial-
reductions in cardiovascular death, MI, stroke, or hospitalization for ists’ Collaboration meta-analysis showed that antiplatelet therapy
heart failure (16.7% and 16.5%, respectively; relative risk [RR], 1.01; produces a 22% to 32% reduction in the relative risk of stroke, MI,
95% confidence interval, 0.94–1.09), albeit at the cost of greater risk or vascular death in patients with high-risk vascular disease, including
of hypotension, syncope, and renal insufficiency when the combina- prior stroke or transient ischemic attack or MI. In a subset of patients
tion of telmisartan and ramipril was used. In a substudy of the ABCD with evidence of PAD based on symptoms of claudication or prior
(Appropriate Blood Pressure Control in Diabetes) trial, intensive lower extremity bypass or angioplasty, antiplatelet therapy also pro-
blood pressure lowering in patients with PAD was associated with a duced a 22% relative risk reduction. The meta-analysis included
65% relative reduction in the risk of MI, stroke, or cardiovascular studies that evaluated a variety of antiplatelet agents, such as aspirin,
death compared with modest blood pressure–lowering therapy. The dipyridamole, picotamide, and ticlopidine. The benefits of aspirin
INVEST study (International Verapamil-SR/Trandolapril Study) have been called into question with a recent meta-analysis showing
demonstrated that a calcium channel blocker–based antihypertensive no significant effect of aspirin on cardiovascular events in patients
18
strategy was comparable to a beta-blocker–based strategy in patients with PAD. The largest of the studies included in this meta-analysis
with concomitant PAD. A J-shaped relationship was noted between was the POPADAD (The Prevention Of Progression of Asymptom-
19
achieved systolic blood pressure and outcomes with the best outcomes atic Diabetic Arterial Disease) study, which randomized patients
noted in individuals achieving a systolic blood pressure between 135 with ABI below 0.99 and no known cardiovascular disease to 100 mg
and 145 mmHg. of aspirin or placebo, and showed no significant difference between
the groups (hazards ratio [HR], 0.98; 95% CI, 0.76–1.26). The AAA
(Aspirin for Asymptomatic Atherosclerosis) trial explored whether
Diabetes aspirin (100 mg/day) was of benefit in asymptomatic individuals with
20
PAD diagnosed solely on the basis of an abnormal ABI. Compared
In patients with PAD with concomitant diabetes, the goals of diabetes with placebo, aspirin had no effect on the composite endpoint of fatal
care include control of hyperglycemia and attention to diabetic foot or nonfatal MI, stroke, or revascularization.
care. Not only is diabetes associated with adverse limb outcomes When clopidogrel was compared with aspirin in the CAPRIE trial,
(increased risk of ischemic ulceration and amputation in patients with clopidogrel was associated with an 8% reduction in cardiovascular
PAD), but it also is associated with increased mortality. Aggressive events. The CHARISMA study showed no benefit of dual antiplatelet
glycemic control reduces both macrovascular events (MI, stroke, and therapy with aspirin plus clopidogrel in a population of patients with
death) and microvascular events (nephropathy, neuropathy, and established CAD, cerebrovascular disease, or PAD or in those with risk
retinopathy) in patients with type I diabetes. Although aggressive factors for these disorders. In a post-hoc analysis that focused on
glycemic control reduces microvascular events in individuals with patients with symptomatic or asymptomatic PAD, there also was no
type II diabetes, reductions in macrovascular events have not been benefit of dual antiplatelet therapy for the primary endpoint. However,
shown. Several recent studies, such as the ADVANCE (Action in the risk of MI and repeat hospitalization for ischemic events was lower
Diabetes and Vascular Disease: Preterax and Diamicron Modified with dual antiplatelet therapy (HR, 0.63; 95% CI, 0.42–0.96 and
Release Controlled Evaluation), Action to Control Cardiovascular HR, 0.81; 95% CI, 0.68–0.95, respectively).
Risk in Diabetes and Veterans Affairs Diabetes trials, have failed to Newer antiplatelet agents have also been evaluated in patients with
show a reduction in cardiovascular events with aggressive treatments PAD. The TRA2P-TIMI 50 study found that the addition of vora-
aimed at lowering the hemoglobin A1c to 6%. Likewise in patients paxar, a protease-activated receptor-1 antagonist, significantly reduced
with type II diabetes who were at risk for cardiovascular events, the the composite endpoint of cardiovascular death, MI, or stroke by
PROactive study (Prospective Pioglitazone Clinical Trial in Macro- 13% in patients with established atherosclerosis manifesting as a prior
vascular Events) failed to show a reduction in the primary composite MI, ischemic stroke, or established PAD. Among the subset of
endpoint of cardiovascular or limb outcomes (lower rates of extremity patients with PAD, vorapaxar did not significantly affect the com-
revascularization or amputation) with pioglitazone. However, the posite endpoint, but did reduce the risk of hospitalization for acute
study did show a significant 16% reduction in the secondary end- limb ischemia by 42% (p = .006) and peripheral artery revasculariza-
point, a composite of total mortality, nonfatal MI, or stroke, with tion by 16% (p = .017), albeit with an increased risk of bleeding (HR