With femoral access, bivalirudin decreases risks of major bleeding after percutaneous coronary intervention (PCI) and provides better net clinical benefit compared to unfractionated heparin (UFH) plus planned glycoprotein IIb/IIIa inhibitors. Whether this benefit exists compared to UFH monotherapy is less clear. We performed a systematic review and meta-analysis to compare outcomes in patients undergoing transfemoral PCI with UFH or bivalirudin. Randomized trials (n = 3) and observational studies (n = 13) comparing bivalirudin to UFH monotherapy were reviewed. Primary outcomes were 30-day rates of major adverse cardiovascular events (MACEs) including death, myocardial infarction (MI), urgent revascularization, as well as all-cause mortality, MI, major bleeding, and blood transfusion. We collected data from 16 studies involving 32,492 patients undergoing PCI. Most observational studies were performed in the United States, whereas all randomized trials were done in Europe. Compared to UFH monotherapy, bivalirudin was associated with similar risk of MACEs (odds ratios [OR] 0.92, 95% confidence interval [CI] 0.75 to 1.12), a substantial 45% relative decrease in major bleeding (OR 0.55, 95% CI 0.43 to 0.72), and a trend in the decrease of transfusion (OR 0.87, 95% CI 0.70 to 1.08). A decrease in mortality was seen in observational studies (OR 0.62, 95% CI 0.45 to 0.85) but remained inconclusive in randomized trials (OR 0.63, 95% CI 0.20 to 2.01). MI rate was similar with the 2 anticoagulants. In conclusion, in patients undergoing transfemoral PCI, the benefit of bivalirudin over UFH monotherapy is driven by a significant decrease in major bleeding with similar rates of MACE. As PCI practice moves toward other bleeding-avoidance strategies such as the radial approach, future studies should focus on the interaction between anticoagulant strategy and access-site choice.
A meta-analysis of 4 randomized studies performed before the widespread use of clopidogrel pretreatment (n = 11,638) showed a significant decrease in the combined event rate of death, myocardial infarction (MI), revascularization, and major bleeding with bivalirudin compared to unfractionated heparin (UFH) plus glycoprotein IIb/IIIa inhibitors (GPIs; 7.8% vs 10.8%, p <0.001). A benefit was seen for the individual end points of death (0.01% vs 0.02%, p = 0.049), revascularization (2.0% vs 2.7%, p = 0.02), and major bleeding (2.7% vs 5.8%, p <0.001). The incidence of MI at 48 hours was similar in the 2 treatment groups (4.5% vs 4.3%, p = 0.706). In contrast, an updated analysis using data from the era of potent oral dual antiplatelet therapy showed a nonsignificant decrease in death (2.5% vs 2.8%, odds ratios [OR] 0.88 95% confidence interval [CI] 0.75 to 1.03), with a trend for higher risk of periprocedural MI (6.7% vs 6.2%, OR 1.09 95% CI 0.98 to 1.21). The safety advantage of bivalirudin was maintained with a 40% decrease in major bleeding (5.8% vs 8.1%, OR 0.59 95% CI 0.63 to 0.77) compared to UFH plus GPI. Whether the net clinical benefit of bivalirudin compared to UFH in the absence of GPI is maintained is unclear. We therefore undertook a systematic review and meta-analysis of available data comparing bivalirudin to UFH monotherapy in percutaneous coronary intervention (PCI) studies to estimate the benefits of bivalirudin on ischemic and bleeding outcomes.
Methods
We carried out this review and meta-analysis with standard protocols recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group for randomized trials and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group for observational studies. We searched the PubMed database, EMBASE, and Cochrane Library using the terms “bivalirudin,” “hirulog” and “antithrombin,” “stent” and “percutaneous coronary intervention” (last update January 31, 2012). We did not restrict our selection of publication to any language. References of selected studies and all abstracts from international cardiology meeting programs were searched for relevant data. To be included, the studies needed to report clinical outcomes in bivalirudin and UFH groups. Because the goal was to assess UFH monotherapy, studies involving >20% of GPIs (bailout) were excluded. Also excluded from this analysis were case reports, abstracts not reported as peer-reviewed reports, and studies involving noncoronary interventions. Two evaluators performed literature searches and extracted data independently. Discrepancies between datasets were resolved by consensus, if necessary, after contact with authors. We classified the studies by randomized or observational design. Clinical outcomes examined were major adverse cardiac events (MACEs) including death, MI and urgent revascularization, as well as death from any cause, MI, major bleeding, and transfusions. Events were censored either during in-hospital phase or at 30 days. For bleeding, we used Thrombolysis In Myocardial Infarction (TIMI) major criteria when available or the study-defined major bleeding ( Table 1 ).
| Study | Indications | Site | Year | GPI | C | H (U/kg) | Women | Age (years) | DM | CKD | Major Bleeding Definitions | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| B | H | B | H | B | H | |||||||||
| Observational studies | ||||||||||||||
| Wolfram et al | 82% ACS | 1 | 2003 | 0% | 0% | 91% | 40 | 37% | 37% | 76 | 74 | 36% | 2.6% | intracranial or overt bleeding with Ht decrease >15% |
| Gurm et al | any | 1 | 2005 | 0% | 0% | — | — | 30% | 27% | 66 | 66 | 34% | 5.9% | — |
| Rha et al | 100% SVG | 1 | 2005 | 0% | 0% | 93% | 40 | 28% | 23% | 72 | 69 | 40% | — | intracranial or overt bleeding with Hb decrease ≥5 g/dl or Ht decrease ≥15% |
| Chu et al | 100% ACS | 1 | 2006 | 15% | 20% | 100% | 40 | 41% | 37% | 66 | 65 | 35% | 18% | Ht decrease ≥15% |
| Gurm et al | 100% elective | 18 | 2007 | 7.6% | 0% | — | — | 36% | 36% | 66 | 65 | 34% | 12% | — |
| Bonello et al | 100% ACS | 1 | 2009 | 0% | 0% | 97% | 50 | 32% | 38% | 63 | 62 | 30% | 16% | intracranial or overt bleeding with Ht decrease >15% |
| Lemesle et al | 82% ACS | 1 | 2009 | 1.3% | 17% | 100% | — | 49% | 53% | 93 | 92 | 28% | 26% | intracranial or Ht decrease ≥15% or Hb decrease ≥5 g/dl or transfusion |
| Lemesle et al | 61% ACS | 1 | 2009 | 2% | 16% | 100% | — | 49% | 52% | 84 | 84 | 28% | 22% | intracranial or overt bleeding with Ht decrease ≥15% |
| Delhaye et al | 79% ACS | 1 | 2010 | 0% | 0% | 100% | 50–70 | 43% | 54% | 66 | 65 | 68% | 100% | intracranial or overt bleeding with Hb decrease ≥5 g/dl or Ht decrease ≥15% |
| Lindsey et al | any | 4 | 2010 | 2% | 20% | 100% | 70 | 39% | 32% | 65 | 64 | 36% | 5.4% | resulting in transfusion, prolonged hospital stay, and/or Hb decrease >3.0 g/dl |
| ACTION | 100% ACS | 217 | 2010 | 0% | 0% | 76% | — | 37% | 39% | 66 | 66 | 34% | 2.5% | intracranial, retroperitoneal, Ht decrease ≥12%, transfusion when baseline Ht ≥28%, or transfusion when baseline Ht <28% with witnessed bleed |
| ISAR-REACT 3A | 100% elective | 3 | 2010 | 0.2% | 0% | 100% | 100 | 24% | 22% | 68 | 68 | 29% | — | intracranial or overt bleeding with Hb decrease ≥5 g/dl or Ht decrease ≥15% |
| EVENT | 34% ACS | 50 | 2011 | 0% | 0% | 48% | — | 35% | 33% | 65 | 66 | 34% | — | intracranial or overt bleeding with Hb decrease ≥5 or ≥3 g/dl or Ht decrease ≥15% or transfusion, important access site bleeding |
| Randomized trials | ||||||||||||||
| ISAR-REACT 3 | 100% elective | 7 | 2008 | 0.2% | 0.2% | 100% | 140 | 24% | 23% | 67 | 67 | 27% | — | intracranial or overt bleeding with Hb decrease ≥5 g/dl or Ht decrease ≥15% |
| ARNO | 100% elective | 1 | 2010 | 0% | 0% | 100% | 100 | 23% | 25% | 69 | 69 | 22% | — | intracranial, intraocular, or retroperitoneal hemorrhage, or clinically overt bleeding resulting in Hb decrease >3 g/dl, Hb decrease >4 g/dl, or transfusion ≥2 U |
| ARMYDA-BIVALVE | 100% elective | — | 2011 | 12% | 14% | 100% | 75 | 29% | 27% | 70 | 70 | 63% | 21% | intracranial or overt bleeding with Hb decrease ≥5 g/dl or Ht decrease ≥15% |
Information on study design, sample size, population demographics and coronary angiographic characteristics, procedural adjuvant pharmacotherapy, ischemic and bleeding outcomes, and follow-up data were entered into a datasheet. The absolute number of events for each outcome in every study was entered into Review Manager 5.1.6 (Cochrane Collaboration, Copenhagen, Denmark). Differences in study characteristics may introduce a level of heterogeneity in the estimated treatment effect among studies. Hence, we used a random-effects model to better account for differences among studies. Outcomes are reported as ORs and 95% CIs for randomized and observational studies. We examined heterogeneity across studies with the Cochrane Q statistic and I 2 test. I 2 values <25% were considered to indicate low heterogeneity, 25% to 50% moderate heterogeneity, and >50% substantial heterogeneity. The weight of each trial on the overall results of meta-analysis outcome was calculated as the percentage of the number of patients in that given trial over the total number of patients included in each outcome analysis. Separate ORs and 95% CIs were calculated for randomized trials and observational studies to compare effect sizes, and a third analysis combined all information from all studies regardless of design.
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