Dihydropyridine Calcium Antagonists Increase Fibrinolytic Activity: A Systematic Review

Abstract

Calcium antagonists have been shown to be superior over other antihypertensive drugs to prevent stroke. Because this cannot be fully attributed to blood pressure lowering effects, other mechanisms seem to play a role. Previously we found in patients with subarachnoid hemorrhage that nimodipine enhances fibrinolytic activity. The purpose of this systematic review was to investigate the fibrinolytic effect of calcium antagonists in general, especially in patients with hypertension. We systematically studied the entire PUBMED and EMBASE database with the search terms 'calcium antagonist' combined with 'fibrinolysis', '(euglobulin) clot lysis time' (ECLT), 'tissue plasminogen activator' (tPA), or 'plasminogen activator inhibitor' (PAI). Twenty-six prospective studies were identified and 22 manuscripts were included (802 investigated individuals). The results show that calcium antagonists significantly increase fibrinolysis as shown by a reduction of the ECLT standardized mean differences (SMD) À0.58 (95% confidence interval (CI) À1.05 to À0.11)) and an increase of tPA activity (SMD 0.73 (95% CI 0.25 to 1.21)). This increase of fibrinolysis is apparently caused by an increase of the tPA antigen level (SMD 0.16 (95% CI À0.05 to 0.37)) and a decrease of the plasminogen activator inhibitor-1 antigen antigen (SMD À0.36 (95% CI À0.74 to 0.02)). A sensitivity analysis showed that dihydropyridines, but not phenylalkylamines, exert a fibrinolytic effect. This fibrinolytic effect is not only seen in patients with subarachnoid hemorrhage but also in hypertensive patients. In conclusions, calcium antagonists increase fibrinolytic activity. This may add to the beneficial pharmacological effect of calcium antagonists to prevent ischemic events in patients with hypertension and subarachnoid hemorrhage.

Impaired Endogenous Thrombolysis in Acute Coronary Syndrome Patients Predicts Cardiovascular Death and Nonfatal Myocardial Infarction

“…However, at the commonly used dose of 75 or 80 mg a day, aspirin is unlikely to exert a profibrinolytic effect. It is also claimed that dihydropyridine calcium antagonists increase fibrinolytic activity independently of their antihypertensive action (41). Future studies will be required to assess whether pharmacological modulation of endogenous thrombolytic status will lead to a reduction in thrombotic events over and above that which can be achieved with dual-antiplatelet therapy.…”

A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage

“…Despite this and unlike other vasodilator drugs [24,25], it improved clinical outcome. In addition to being a potent vasodilator, even of arteries with angiographic vasospasm [12,26], it was later noted that nimodipine inhibited other delayed effects of SAH that may contribute to DCI, such as cortical spreading ischemia [27], and that it had fibrinolytic activity that could reduce microthromboemboli [23]. Other vasodilators may not have these pleiotrophic effects [28].…”

“…Importantly, this was not observed in beagles. Nimodipine has fibrinolytic activity that may contribute to its efficacy and could theoretically cause hemorrhage [7,23]. However, there is no evidence that nimodipine is associated with hemorrhage in humans with SAH, even after intracisternal or intraventricular administration [9].…”

Vasospasm: My First 25 Years—What Worked? What Didn’t? What Next?

“…Microthrombi also have been demonstrated in the brain after experimental and clinical SAH [ 48 ]. It is a reasonable hypothesis that they contribute to brain injury, and nimodipine also could abrogate this process through its fi brinolytic activity [ 59 ]. On the other hand, clinical trials of antiplatelet drugs, which should reduce microthrombosis, have not documented marked improvements in outcome [ 15 ].…”