Episode 186: 186. ACE vs ARB, Blood Clots, and Mifepristone

Contraception 2021 Sep 20;[EPub Ahead of Print], D Grossman, S Raifman, N Morris, A Arena, L Bachrach, J Beaman, MA Biggs, C Hannum, S Ho, EB Schwarz, M Gold

STUDY DESIGN

This is an interim analysis of an ongoing prospective cohort study conducted at five sites. Clinicians assessed patients in clinic and, if they were eligible for medication abortion and ≤63 days' gestation, electronically sent prescriptions for mifepristone 200 mg orally and misoprostol 800 mcg buccally to a mail-order pharmacy, which shipped medications for next-day delivery. Participants completed surveys three and 14 days after enrollment, and we abstracted medical chart data for this interim analysis.

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  In this prospective cohort study, researchers estimated the effectiveness, feasibility, and acceptability of medication abortion with mifepristone dispensed by a mail-order pharmacy with next-day delivery after in-person clinical assessment. The researchers found that complete medication abortion occurred for 96.9% of participants; 88.4% reported being very satisfied receiving medications by mail, and 89.6% said they would use the mail-order service again if needed. Of the 4.9% who experienced adverse events, none were related to mail-order dispensing.
• This research suggests that mail-order pharmacy dispensing of mifepristone is effective and acceptable to patients, providing further evidence that the in-person dispensing requirement for this medication should be removed.

IMPLICATIONS

The in-person dispensing requirement for mifepristone, codified in the drug's Risk Evaluation and Mitigation Strategy, should be removed.

Stevens SM et al. Antithrombotic therapy for VTE disease: Second update of the CHEST Guideline and Expert Panel Report. Chest 2021 Aug 2; [e-pub]. (https://doi.org/10.1016/j.chest.2021.07.055)

The ninth edition of the CHEST Clinical Practice Guidelines for managing venous thromboembolism (VTE) — published in 2012 and updated in 2016 — now has a second update, which addresses 14 clinical questions and offers 32 guidance statements for clinicians who manage patients with VTE. The 2012 guideline (Chest 2012; 141:Suppl:e419S and the 2016 update (NEJM JW Emerg Med Feb 2016 and Chest 2016; 149:315) both are publicly available.

Key Recommendations

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  Patients with isolated subsegmental pulmonary embolism (PE): Rule out proximal deep venous thrombosis (e.g., with ultrasonography). If risk for recurrent VTE is low, surveillance is recommended over anticoagulation. If risk for recurrent VTE is high, anticoagulation is recommended. (Weak recommendation, low-certainty evidence)
• Patients with incidentally discovered asymptomatic PE (other than isolated subsegmental PE): Same initial and long-term anticoagulation that patients with symptomatic PE receive should be used. (Weak recommendation, moderate-certainty evidence)
• Patients with cancer-associated VTE: Direct-acting oral anticoagulants (DOACs; i.e., apixaban, edoxaban, or rivaroxaban) should be used for the treatment phase of therapy (strong recommendation, moderate-certainty evidence). Caveat: for patients with luminal gastrointestinal malignancies, apixaban or low-molecular-weight heparin is preferred to reduce bleeding risk.
• Patients with antiphospholipid syndrome: Warfarin (target international normalized ratio, 2.5) is recommended over DOAC therapy during the treatment phase for VTE. (Weak recommendation, low-certainty evidence)
• Catheter-assisted mechanical thrombectomy: Recommended for patients with PE and hypotension who also have high bleeding risk, failed systemic thrombolysis, or shock that is likely to lead to death before systemic thrombolysis can take effect. (Weak recommendation, low-certainty evidence)
• Initial anticoagulation setting: Outpatient treatment is recommended over hospitalization in patients with low-risk PE, if access to medications and outpatient care is available. (Strong recommendation, low-certainty evidence)
• Treatment-phase anticoagulants: DOACs are recommended over warfarin. (Strong recommendation, moderate-certainty evidence)
• Extended-phase therapy (beyond 3 months) for VTE: Extended anticoagulation should be offered to patients with unprovoked VTE — i.e., with no major or minor transient risk factors. Risk for recurrent VTE, risk for bleeding, and patients' values and preferences should be considered in decisions about extended anticoagulation therapy. (Strong recommendation, moderate-certainty evidence)
  • Low-dose apixaban or rivaroxaban is recommended over full doses of these agents. (Weak recommendation, very low-certainty evidence)
  • Aspirin is recommended for patients who are stopping anticoagulation. (Weak recommendation, low-certainty evidence)

Ingason AB et al. Rivaroxaban is associated with higher rates of gastrointestinal bleeding than other direct oral anticoagulants: A nationwide propensity score–weighted study. Ann Intern Med 2021 Oct 12; [e-pub]. (https://doi.org/10.7326/M21-1474)

The study used icelands National databank to compare GI bleeding among almost 6000 patients receiving apixaban, dabigatran, and rivaroxaban for the first time. Patients were followed for 1-1/2 years and GI bleeding was verified by review of the medical records. Once there was a propensity score analysis it was deemed that rivaroxaban had significantly high rates of minor and major gastrointestinal bleeding compared to apixaban with a number needed to treat of around 40 or 50. However there was no difference between rivaroxaban and dabigatran. I think this goes to what we have all seen and that the bleeding risk among most anticoagulate medications is not equal but unfortunately which medication the insurance companies will pay for it is also not equal. However if your patient is at large risk for GI bleed likely should consider not using rivaroxaban

Chen R et al. Comparative first-line effectiveness and safety of ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers: A multinational cohort study. Hypertension 2021 Sep; 78:591. (https://doi.org/10.1161/HYPERTENSIONAHA.120.16667)

In this retrospective study of patients who initiated monotherapy for hypertension, researchers used eight large observational databases to compare outcomes for 2.3 million new users of ACE inhibitors and nearly 700,000 new users of ARBs.

Myocardial infarction, stroke, and heart failure occurred with similar frequency in the two groups, after extensive adjustment for demographic and clinical variables. However, cough, angioedema, pancreatitis, and gastrointestinal bleeding occurred significantly more often in ACE-inhibitor users than in ARB users.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism: A Systematic Review and Meta-analysis: Annals of Internal Medicine: Vol 174, No 10 (acpjournals.org)

What happens if you extend anticoagulation past the 3 to 6 months for an individual who has a first unprovoked venous thromboembolism. Often this is a debate in the clinical practice of while you seem low risk so maybe we should discontinue this anticoagulation or well you had his lab value is off to me we should continue anticoagulation. The scary thing is you do not want to discontinue the anticoagulation and the may have a massive saddle embolism and die! It is easy to start a medication but it is always so hard to stop the medication. this study looked at that exact question --it looked at 14 randomized control trials and 13 cohort studies with just over 17,000 patients taking either vitamin K antagonist or DOACs. The patient had to have received a minimum of at least 9 months of anticoagulation in order to be enrolled in the final analysis and they looked at patients who had had extended anticoagulation up to 5 years.

In the end the incidence of major bleeding with warfarin was 1.7 events per year per 100 patients and much lower with the DOACs at 1.12 events per year per 100 people. While that does not sound like a lot with the newer agents he has remember that is only after 1 year if he looked at the 5-year cumulative incidence of major bleeding for those individuals on either warfarin or a DOAC it was 6.3% which is certainly at significant risk of bleeding especially when you consider that the case fatality rate was 8.3% expiration

That was a whole bunch of numbers but basically I guess with this meta-analysis is really saying is that the current recommendations for anticoagulation after a unprovoked venous thromboembolism are 3 to 6 months and if you are going to extend that out to 9 months or a year or even up to 5 years he better have a darn good reason given that the eventual rates of bleeding are so high and the mortality rate from those bleeds are also so high.