Fixed vs weight-based heparin dosing in stable patients undergoing diagnostic coronary physiology studies

Abstract

BACKGROUND

Unfractionated heparin (UFH) is routinely used during coronary angiography, but the optimal dosing strategy for diagnostic coronary physiology procedures such as fractional flow reserve or microvascular assessment in stable patients remains unclear. While weight-based dosing is standard in percutaneous coronary intervention, a fixed-dose approach may simplify workflow.

AIM

To compare bleeding and thromboembolic outcomes between fixed-dose and weight-based UFH during diagnostic coronary physiology procedures without percutaneous coronary intervention.

METHODS

We conducted a retrospective single-center study of 128 patients undergoing fractional flow reserve or microvascular testing from January 2021 to February 2024. Patients received either fixed-dose (5000 IU) or weight-based (70-100 IU/kg) UFH. The primary outcome was a composite of thromboembolic complications: Radial artery occlusion, stroke, or periprocedural myocardial infarction. Secondary outcomes included bleeding (Bleeding Academic Research Consortium criteria), association with patient characteristics, access site, and length of stay.

RESULTS

Of 128 patients, 78 received fixed-dose and 50 received weight-based UFH. No thromboembolic events occurred in either group. Bleeding (all Bleeding Academic Research Consortium 1-2) occurred in 15% overall, with no significant difference between groups (15% vs 12%, P = 0.47). No significant association between bleeding and patient age, sex, weight, body mass index, access site, antiplatelet, or anticoagulant use. Median hospital stay was 1 day in both groups.

CONCLUSION

In this exploratory study, a fixed 5000 IU UFH regimen appeared to be a safe and practical alternative to weight-based dosing in diagnostic coronary physiology procedures. Larger prospective studies are warranted to confirm these findings.

Key Words: Unfractionated heparin; Coronary physiology; Fractional flow reserve; Microvascular function; Anticoagulation; Fixed-dose heparin; Heparin dose; Pressure-wire

Core Tip: This study explores the safety and efficacy of fixed-dose vs weight-based unfractionated heparin dosing during diagnostic coronary physiology procedures. Among 128 patients, fixed-dose 5000 IU unfractionated heparin was associated with similarly low rates of bleeding and no thrombotic events compared to weight-based dosing. These findings suggest that a fixed-dose approach may be a safe and practical alternative in low-risk, physiology-only settings. The results may inform future research and support consideration of simplified anticoagulation strategies in stable patients undergoing diagnostic coronary physiology assessments.

INTRODUCTION

Unfractionated heparin (UFH) remains the cornerstone intraprocedural anticoagulant for cardiac catheterization and interventions. In patients with acute coronary syndrome and those undergoing percutaneous coronary intervention (PCI), weight-based UFH dosing (typically 70-100 U/kg) is standard to achieve therapeutic activated clotting time (ACT) targets of 250-300 seconds[1]. However, for diagnostic coronary physiology procedures - such as fractional flow reserve (FFR) or microvascular function assessment in stable patients - the optimal heparin strategy is less clear. These procedures are generally shorter in duration and carry lower thrombotic risk than PCI, which has led some operators to adopt a fixed low-dose heparin regimen instead of full weight-adjusted doses[2].

While recent retrospective studies have shown safety and increased procedural efficiency with fixed-dose 5000 IU UFH even during elective PCI[3], current clinical guidelines offer limited recommendations for diagnostic-only procedures. Major cardiac society guidelines emphasize weight-based heparin dosing during PCI to reduce ischemic events, but they do not delineate specific recommendations for diagnostic coronary physiology procedures without intervention in stable patients[4,5]. The National Heart Foundation of Australia guidelines similarly focus on anticoagulation in acute coronary syndromes and PCI, without addressing heparin dosing for elective diagnostic procedures6. In the absence of clear guidelines, practice has become variable, underscoring the need for evidence in this setting[2].

In this exploratory single-center study, we aimed to examine whether a fixed 5000 IU (international units) heparin bolus was associated with comparable thrombotic and bleeding outcomes compared to weight-based dosing, specifically in the setting of diagnostic coronary physiology procedures. While prior larger studies have investigated heparin dosing in diagnostic angiography more broadly, evidence focusing exclusively on diagnostic coronary physiology procedures without intervention remains limited.

MATERIALS AND METHODS

Study design and population

We conducted a single-center retrospective observational study at Frankston Hospital, including all patients who underwent invasive pressure-wire coronary physiology studies from January 2021 to February 2024. This encompassed FFR measurements and microvascular function tests performed during elective diagnostic coronary angiography. Only diagnostic procedures were included, and patients were excluded if ad-hoc PCI was performed in the same procedure or if key procedural data were incomplete. The study was approved by our institutional Human Research Ethics Committee with approval number LNR/107040/PH-2024.

Heparin dosing strategy

Patients were categorized into two groups based on the intraprocedural UFH dosing strategy: (1) Fixed-dose group: 5000 IU intravenous bolus; and (2) Weight-based group: 70-100 IU/kg intravenous bolus. No routine ACT monitoring was performed, consistent with local protocol for diagnostic-only procedures. Additional heparin was not administered after the initial bolus since no stenting or prolonged intervention was needed or planned.

Outcome measures

Primary outcome: Incidence of thromboembolic complications, defined as a composite of documented radial artery occlusion (RAO), stroke, or periprocedural myocardial infarction (MI), comparing fixed-dose vs weight-based UFH dosing during coronary physiology studies.

Secondary outcomes: Incidence and severity of bleeding complications, classified using the Bleeding Academic Research Consortium (BARC) criteria, stratified by heparin dosing strategy. Incidence of individual thromboembolic events (RAO, stroke, periprocedural MI) stratified by dosing group. Association between thromboembolic events and patient characteristics, including weight and gender, and access site (radial vs femoral). Association between bleeding complications and patient characteristics, including weight, gender, vascular access site (radial vs femoral), and use of certain medications (antiplatelets, direct acting oral anticoagulants, warfarin).

Data collection

Data collected from electronic medical records and procedural logs included patient demographics, history of chronic kidney disease, liver disease, hemophilia, thrombocytopenia (platelet count less than 100000/L), and medication use with particular attention to antiplatelets or chronic anticoagulation with warfarin or direct acting oral anticoagulants. Procedural details noted access site (radial vs femoral) and whether FFR or a microvascular test was performed. Occurrence of any bleeding and thrombotic outcomes during the admission period were recorded.

Statistical analysis

Descriptive statistics were used to summarize baseline characteristics, procedural details, and clinical outcomes. Continuous variables were assessed for normality using the Shapiro-Wilk test and reported as mean ± SD or median with interquartile range (IQR), as appropriate. Between-group comparisons for continuous variables were performed using the Wilcoxon rank-sum test. Categorical variables were summarized as counts and percentages, with comparisons made using the χ² test or Fisher’s exact test, as appropriate.

Bleeding complications (BARC ≥ 1) were compared between the fixed-dose and weight-based UFH groups. Univariable logistic regression was performed to explore associations between bleeding and clinical variables including sex, weight, access site, antiplatelet use, anticoagulant use, body mass index (BMI), and age > 70 years. A multivariable logistic regression model was constructed including sex, access site, anticoagulant and antiplatelet use. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. Statistical significance was defined as a two-tailed P < 0.05. Analyses were conducted using R version 4.3.2.

RESULTS

Baseline characteristics

A total of 128 patients were included in the study. There was a higher proportion of patients in the fixed dose group (61%, n = 78) than the weight-based group (39%, n = 50). The overall mean age was 67 ± 11 years and was similar between the fixed-dose (68 ± 11 years) and weight-based (66 ± 11 years) groups. The overall cohort was predominantly male (68%, n = 87). A small minority of patients had a history of chronic kidney disease (2%, n = 3) and chronic liver disease (3%, n = 4). The majority of patients on both groups were categorized as being overweight or more based on their BMI (74.3% for fixed-dose group vs 84% for weight-based group). A majority of the patients are on antiplatelet agents (76%, n = 97) while a minority (12%, n = 15) were on oral anticoagulation, with roughly similar distribution between groups. Table 1 summarizes the baseline and procedural characteristics.

Table 1 Baseline characteristics, n (%).

	Total (n = 128)	Fixed dose (n = 78)	Weight-based (n = 50)
Age (mean ± SD), years	67 ± 11	68 ± 11	66 ± 11
Gender
Male	87 (68)	45 (58)	42 (84)
Female	41 (32)	33 (42)	8 (16)
BMI (mean ± SD, kg/m2)	28.97 ± 5.1	28.23 ± 5	30 ± 5
Underweight	1 (0.8)	1 (1.3)	0 (0)
Normal	28 (21.9)	19 (24.4)	9 (18)
Overweight	48 (37.5)	31 (39.7)	17 (34)
Obese	51 (39.8)	27 (34.6)	24 (48)
Weight (mean ± SD, kg)	85.1 ± 17.8	79.9 ± 15.8	93.4 ± 17.7
Medical history
Chronic kidney disease (eGFR < 60)	3 (2)	2 (3)	1 (2)
Chronic liver disease	4 (3)	3 (4)	1 (2)
Bleeding diathesis	0 (0)	0 (0)	0 (0)
Thrombocytopenia (< 100000)	0 (0)	0 (0)	0 (0)
Anticoagulation (DOAC or warfarin)	15 (12)	10 (13)	5 (10)
On anti-platelets	97 (76)	58 (74)	39 (78)
Indication
FFR	114 (89)	64 (82)	50 (100)
Microvascular	14 (11)	14 (18)	0 (0)
Access site
Radial	117 (91)	71 (91)	46 (92)
Femoral	11 (9)	7 (9)	4 (8)
Median heparin dose IU, median (IQR)		5000 (5000, 5000)	8000 (7000, 9000)
BARC bleeding score
0 (no bleeding)	110 (85)	65 (83.3)	44 (88)
1	18 (14)	12 (15.4)	6 (12)
2	1 (1)	1 (1.3)	0 (0)
3	0 (0)	0 (0)	0 (0)
4	0 (0)	0 (0)	0 (0)
5	0 (0)	0 (0)	0 (0)
Radial artery occlusion	0 (0)	0 (0)	0 (0)
Stroke	0 (0)	0 (0)	0 (0)
Post-procedure MI	0 (0)	0 (0)	0 (0)
Length of stay days, median (IQR)	1 (1, 4)	1 (1, 3)	1 (1, 4)

BMI: Body mass index; eGFR: Estimated glomerular filtration rate; DOAC: Direct acting oral anticoagulants; FFR: Fractional flow reserve; IQR: Interquartile range; BARC: Bleeding Academic Research Consortium.

Procedural characteristics

Most procedures (89%, n = 114) were performed for FFR assessment, with the remaining 11% (n = 14) undergoing microvascular function studies. While procedural times were not collected during the data collection process, in our institution, FFR adds 1-2 minutes while microvascular studies add roughly 10 minutes to the overall procedure time. All procedures used 6 Fr sized guides and 5 Fr sized diagnostic catheters. Transradial access was used in 91% (n = 117) of all cases, with similar distribution between groups. All patients received a heparin bolus during the procedures once the catheter is in the ascending aorta. The fixed dose group received 5000 IU of UFH, whereas the weight-based group received a median of 8000 IU (IQR 7000, 9000). For transradial access, a Terumo radial band was used to achieve and maintain hemostasis and removed as per local protocol; this involved gradual deflation starting at 60-120 minutes depending on procedural anticoagulation, with staged air removal every 15 minutes while monitoring for bleeding, with patient instructed to limit use of the affected hand for 48 hours. For femoral access, the sheath was removed by an accredited nurse or medical officer using firm digital pressure just proximal to the puncture site until hemostasis was achieved, typically over 5-15 minutes depending on sheath size and ACT. A compression dressing was applied, and patients were maintained on bedrest (typically 3-4 hours post-hemostasis) with vascular observations and gradual head-of-bed elevation as per protocol. High-risk patients (e.g., hypertensive, elderly, or those with coagulopathy) were monitored closely and may have required extended compression time.

Thromboembolic events

There were no documented thromboembolic complications in the entire cohort. Specifically, no cases of RAO, stroke, or periprocedural MI occurred in either group.

Bleeding complications

Bleeding events of any severity (BARC ≥ 1) occurred in 15% of patients (n = 19), with all the patients classified as BARC 1 except for only one patient in the fixed-dose group classified as BARC 2. There was no statistically significant difference in bleeding rates between dosing strategies: 15% (n = 12) in the fixed-dose group and 12% (n = 7) in the weight-based group (P = 0.469).

Bleeding rates did not differ significantly between groups when stratified by age (P = 0.42), age > 70 years (P = 0.31), body weight (P = 0.33), BMI (P = 0.51), vascular access site (P = 0.21), antiplatelet therapy (P = 0.16), or concurrent anticoagulant use (P = 1.00). In a multivariate logistic regression model, access site and antiplatelet use was not independently associated with bleeding (Table 2). Femoral access was associated with an adjusted OR of 2.09 (95%CI: 0.42-8.22, P = 0.32), and antiplatelet use with an adjusted OR of 2.90 (95%CI: 0.76-19.1, P = 0.17).

Table 2 Logistic regression analysis for bleeding predictors.

Predictor	Unadjusted OR (95%CI)	P value	Adjusted OR (95%CI)	P value
Sex	0.60 (0.20-1.89)	0.424
Access site	2.35 (0.36-11.19)	0.210	2.09 (0.42-8.22)	0.318
Antiplatelet use	3.06 (0.66-28.95)	0.158	2.90 (0.76-19.1)	0.713
Anticoagulant use	0.87 (0.09-4.41)	1

OR: Odds ratio; CI: Confidence interval.

Length of stay

There was no significant difference in length of stay between groups [median 1 day (IQR 1, 3) in fixed-dose vs 1 day (IQR 1, 4) in weight-based, P = 0.31].

DISCUSSION

The findings of this retrospective study suggest that a fixed-dose heparin strategy (5000 IU intravenous bolus) is a safe and practical alternative to weight-based dosing for diagnostic coronary physiology procedures. While there is variability in contemporary heparin dosing, in our experience, a fixed dose of 5000 units is commonly used in Australia and is the most common dosage used worldwide according to an international survey[2]. Similarly, 5000 units is also the recommended minimum dose for functional coronary angiography[6]. In our cohort of stable patients undergoing FFR or microvascular assessment, no thrombotic events were observed, and bleeding complications were infrequent and minor, with no significant difference between the dosing strategies.

International guidelines largely focus on PCI, recommending weight-based UFH dosing to achieve a target ACT. However, they do not specifically comment on anticoagulation for diagnostic coronary physiology procedures without intervention in stable patients[1,4,7]. Interestingly, contemporary data have questioned the utility of routine ACT measurement even for PCI in the era of modern antiplatelet therapy as ACT levels correlate poorly with outcomes, and the variability in ACT measurement with different company analyzers[8,9].

Expert consensus suggests routine heparinization during FFR procedures to mitigate thrombotic risk. However, specific dosing strategies are not standardized and there remains variability in real-world practice[10]. A key consideration for adopting any anticoagulation strategy is bleeding risk. Patient factors and procedural factors may influence both bleeding and thrombotic complications. In our cohort, we observed no major bleeding and only a 15% rate of minor bleeding (most small hematomas), with no statistically significant difference between fixed and weight-based groups. Femoral access showed numerically higher bleeding risk, though this did not reach statistical significance (adjusted OR = 2.09, 95%CI: 0.42-8.22, P = 0.318). This may be due to the vast majority of our cases were done through the transradial approach. The concurrent use of antiplatelet agents did increase the risk of bleeding outcomes, however this did not show statistical significance. Equally important, these minor bleeding complications did not increase hospital length of stay in either group [1 (1, 3) days vs 1 (1, 4) days, P = 0.31].

Crucially, there were no thrombotic complications of RAO, stroke, or periprocedural MI in either our fixed-dose and weight-based heparin groups. RAO is a known potential complication following transradial access during coronary angiography and traditionally high-dose UFH is recommended to reduce the risk of RAO[11]. A study comparing 100 IU/kg in two divided doses against 50 IU/kg of UFH showed superiority in the high dose arm for decreasing the incidence of RAO (3% vs 8%, OR = 0.35 95%CI: 0.22-0.55, P = < 0.001)[12]. However, the median total dose of heparin in the low-dose arm would have been much lower than the 5000 IU in our fixed-dose arm in our study. A study on the “standard” fixed dose of 5000 IU UFH showed marked improvement in RAO outcomes compared to a 2500 IU fixed low dose UFH (1.2% vs 5.5%, P = 0.010)[13]. A systematic review by Bossard et al[14] also highlighted that 5000 IU UFH was associated with lower rates of RAO compared to lower dose regimen, albeit with a non-significant trend toward increased bleeding events. It should be noted that no systematic doppler ultrasound was performed in our patient population and that the median hospital stay was just around 1 day, so the chances of subclinical or delayed RAO cannot be ruled out.

Our findings should also be interpreted in the context of recent larger studies. A larger prospective multicenter subgroup analysis of 1494 patients undergoing diagnostic transradial coronary angiography found no incremental benefit of weight-adjusted dosing above a fixed 5000 IU heparin bolus[15]. Our findings complement these findings however we focused specifically on coronary physiology procedures, a subgroup underrepresented in prior literature.

From a practical standpoint, using a fixed-dose confers simplicity. It avoids the need for dose calculation according to weight, which can be prone to error or delay. A uniform 5000 IU dose is quick to prepare and administer and its consistency may help our nurses and techs become accustomed to drawing up the same dose for all diagnostic cases, reducing variability and potential errors. They may also contribute to reduced cost in the long run with slightly lower heparin usage on average and fewer ACT cartridges used.

Limitations

Several limitations of this study should be acknowledged. It has a retrospective observational design that is subject to potential biases and unmeasured confounders, with a modest sample size of only 128 patients. The choice of heparin dosing was at the operator’s discretion rather than randomized or standardized, and it is possible the operators selected the strategy based on clinical judgement. This operator-driven dosing strategy could have introduced subtle selection bias despite baseline similarities between groups. We attempted to mitigate this by confirming baseline characteristics were largely similar between groups, but subtle biases cannot be excluded. While operator experience is a confounder, the interventionalists in our institution have largely similar experience having more than 10 years post-fellowship. The sample size (n = 128) provides reasonable insights but is still modest, and total procedure time and the number of coronary arteries interrogated were not routinely recorded as part of this retrospective dataset although nearly all pressure wire studies in our institution involve only a single vessel assessment. Bleeding complications are inherently infrequent during diagnostic-only procedures, as reflected in large registries where the incidence of major bleeding is typically around 1%[16]. Given the low expected event rate, our retrospective study was not powered to detect small differences in bleeding between fixed and weight-based dosing, and any such analysis should be considered exploratory and hypothesis-generating. Our patient population also did not undergo routine radial artery doppler ultrasound and no systematic follow-up was done to assess for RAO; therefore, subclinical RAO could not be excluded limiting the robustness of our thrombotic outcome assessment. Certain populations at elevated risk for thrombotic or bleeding complications, such as patients with inherited thrombophilias, chronic liver disease, or coagulation factor deficiencies were not represented in our cohort. Similarly, our findings may not be generalizable to patients at the extremes of body weight, particularly those who are markedly underweight or obese and receive a fixed-dose regimen. Nevertheless, our study reflects real-world practice, with approximately three-quarters of patients in both groups classified as overweight or obese.

Multiple hypothesis tests were performed without adjustment for multiplicity due to the exploratory nature and limited sample size. Accordingly, P values should be interpreted with caution and considered hypothesis-generating. Detailed data on antiplatelet type, procedure duration, contrast volume, and specific adenosine dosing were not available in this retrospective dataset, which we acknowledge as a limitation. Nonetheless, it is reassuring to find the absolute absence of any thrombotic events in both groups, and the bleeding rates were so low. Our conclusions apply to stable cases that remain diagnostic throughout. In a scenario where an intervention is performed, standard practice would be to administer additional heparin to reach therapeutic ACT for PCI. We did not address such scenarios in this study. Lastly, the single-center nature may limit generalizability - practices and patient characteristics elsewhere could differ.

Future directions

Despite these limitations, our findings suggest that a standardized fixed-dose of 5000 IU UFH is a viable strategy for coronary physiology procedures in stable patients. Given the lack of dedicated guidelines, our findings could be hypothesis-generating for developing prospective randomized control trials in a multicenter setting to confirm our findings.

CONCLUSION

For stable patients undergoing diagnostic coronary physiology assessments without PCI, our exploratory study suggests that a fixed 5000 IU heparin regimen may be a safe and practical approach. Its simplicity and ease of administration may streamline workflow without compromising patient safety in this low-risk setting. As current guidelines have yet to specifically address this specific setting, our findings call for the need for prospective studies and could inform future consensus on standardizing anticoagulation in uncomplicated diagnostic procedures.