Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58.

BACKGROUND: Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis. METHODS: A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer. RESULTS: Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively). CONCLUSIONS: Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.

Platelet function, coagulation and fibrinolysis in patients with previous coronary and cerebrovascular ischemic events.

OBJECTIVES: Ischemic stroke (IS) or transient ischemic attack (TIA) history is present in 4-17% of patients with coronary artery disease (CAD). This subgroup of patients is at high risk for both ischemic and bleeding events. The aim of this study was to determine the role of platelet aggregability, coagulation and endogenous fibrinolysis in patients with CAD and previous IS or TIA. METHODS: A prospective case-control study that included 140 stable CAD patients divided into two groups: the CASE group (those with a previous IS/TIA, n=70) and the CONTROL group (those without a previous IS/TIA, n=70). Platelet aggregability (VerifyNow Aspirin® and VerifyNow P2Y12®), coagulation (fibrinogen and thromboelastography by Reorox®) and endogenous fibrinolysis (D dimer and plasminogen activator inhibitor-1) were evaluated. RESULTS: Patients in the CASE group presented significantly higher systolic blood pressure levels (135.84±16.09 vs 123.68±16.11, p<0.01), significantly more previous CABG (25.71% vs 10%, p=0.015) and significantly higher calcium channel blocker usage (42.86% vs 24.29%, p=0.02) than those in the control group. In the adjusted models, low triglyceride values, low hemoglobin values and higher systolic blood pressure were significantly associated with previous IS/TIA (CASE group). Most importantly, platelet aggregability, coagulation and fibrinolysis tests were not independently associated with previous cerebrovascular ischemic events (CASE group). CONCLUSION: Platelet aggregability, coagulation and endogenous fibrinolysis showed similar results among CAD patients with and without previous IS/TIA. Therefore, it remains necessary to identify other targets to explain the higher bleeding risk presented by these patients.

Is adenosine associated with sudden death in schizophrenia? A new framework linking the adenosine pathway to risk of sudden death.

Schizophrenia is associated with an increased mortality from cardiovascular disease. Relatively few studies have assessed the putative association of schizophrenia pathophysiology with sudden death. Low adenosine levels have been associated with schizophrenia. In cardiology, increased mortality among patients with congestive heart failure has been associated with genetic polymorphisms that potentially lead to lower adenosine levels. Thus, we hypothesize that adenosine could link schizophrenia and cardiovascular mortality, with decreased adenosine levels leading to increased vulnerability to hyperexcitability following hypoxic insults, increasing the odds of fatal arrhythmias. Low adenosine levels might also lead to a small increase in overall mortality rates and a major increase in the sudden death rate. This hypothesis paves the way for further investigation of the increased cardiac mortality associated with schizophrenia. Potentially, a better characterization of adenosine-related mechanisms of sudden death in schizophrenia could lead to new evidence of factors leading to sudden death in the general population.

Platelet function, coagulation and fibrinolysis in patients with previous coronary and cerebrovascular ischemic events

OBJECTIVES: Ischemic stroke (IS) or transient ischemic attack (TIA) history is present in 4-17% of patients with coronary artery disease (CAD). This subgroup of patients is at high risk for both ischemic and bleeding events. The aim of this study was to determine the role of platelet aggregability, coagulation and endogenous fibrinolysis in patients with CAD and previous IS or TIA. METHODS: A prospective case-control study that included 140 stable CAD patients divided into two groups: the CASE group (those with a previous IS/TIA, n=70) and the CONTROL group (those without a previous IS/TIA, n=70). Platelet aggregability (VerifyNow Aspirin® and VerifyNow P2Y12®), coagulation (fibrinogen and thromboelastography by Reorox®) and endogenous fibrinolysis (D dimer and plasminogen activator inhibitor-1) were evaluated. RESULTS: Patients in the CASE group presented significantly higher systolic blood pressure levels (135.84±16.09 vs 123.68±16.11, p<0.01), significantly more previous CABG (25.71% vs 10%, p=0.015) and significantly higher calcium channel blocker usage (42.86% vs 24.29%, p=0.02) than those in the control group. In the adjusted models, low triglyceride values, low hemoglobin values and higher systolic blood pressure were significantly associated with previous IS/TIA (CASE group). Most importantly, platelet aggregability, coagulation and fibrinolysis tests were not independently associated with previous cerebrovascular ischemic events (CASE group). CONCLUSION: Platelet aggregability, coagulation and endogenous fibrinolysis showed similar results among CAD patients with and without previous IS/TIA. Therefore, it remains necessary to identify other targets to explain the higher bleeding risk presented by these patients.