Vorapaxar

Vorapaxar has proven to be an effective anticoagulant and is used in concert with an aspirin regimen or a drug like clopidogrel to prevent further cardiovascular events in patients who have a history of myocardial infarction, and as a treatment for patients with peripheral arterial disease.

Overview:

Vorapaxar, brand name Zontivity, is a protease activated receptor (PAR-1) that inhibits thrombin aggregation. Thrombin is an enzyme in the human body that is vital to the clotting process. As a serine protease, thrombin is encoded in the F2 gene. Thrombin is considered the most effective of the platelet activators. Vorapaxar is generally indicated for use after a patient has developed a history of myocardial infarction events or suffers from peripheral arterial disease (PAD). Because Vorapaxar works to prevent platelets from aggregating, it can prevent further clots and embolisms from developing in the veins and arteries of the patient.

Vorapaxar is derived from a substance called himbacine which exists in its natural form in the Australian magnolia. Himbacine has been synthesized and was originally thought to hold promise in researching treatment for Alzheimer's Disease. That research never fully developed successfully, but an analog was created in vorapaxar, which has proven an effective inhibitor of thrombin receptors in the blood stream, and thus is helpful in treating patients who suffer from certain types of cardiovascular disease and who are at risk of future thrombotic events.

After several years of study, vorapaxar was found to reduce risk of cardiovascular death. Those findings were published in February of 2012. While those results did find an increase in active bleeding incidence, it was recommended for FDA approval. Vorapaxar received final FDA approval in May of 2014.

Vorapaxar is prescribed as an augmentation to and in conjunction with an aspirin regimen that may also include clopidogrel. Vorapaxar has not been studied as a medication used in isolation, therefore it is not prescribed or recommended as a sole treatment for patients with PAD or a history of myocardial infarctions. In clinical trials, the addition of vorapaxar to the antiplatelet therapy proved to significantly reduce the patient's risk of another cardiac event or stroke. It does, however, add to the patient's risk of bleeding. Given its success in clinical trials, vorapaxar (Zontivity)is currently considered a valuable tool in treating patients suffering from peripheral arterial disease and in those who have already suffered one or more myocardial infarctions.

It is not recommended for treatment of anyone who has suffered from transient ischemic attack, intracerebral hemorrhage or has a history of stroke. The risk of intracerebral hemorrahge or other internal bleeding in these patients is too great. Also, vorapaxar remains in the patient's system for a significantly longer period than some other medications that reduce clotting risk, so that is an important thing to consider when adding this particular medication to a patient's treatment plan.

Conditions treated:

  • peripheral arterial disease
  • post myocardial infarction
  • prevention of blood clots

Type of Medicine:

  • Protease Activated Receptor - 1 Inhibitor
  • Thrombin inhibitor, Antiplatelet agent

Side effects:

The major side effect of voraxapar is the risk of active pathological bleeding. It has been found to increase the risk of severe or fatal bleeding by 55%. Severe bleeding is defined as intracranial bleeding, bleeding with hemodynamic compromise, gastrointestinal bleeding, fatal bleeding or any bleeding that requires emergency intervention.

There are a few other reported side effects or adverse reactions associated with use of vorapaxar. 5% of the clinical study group experienced anemia. 2.4% of patients reported symptoms of depression. 2.2% of these patients experienced rash or other skin reaction. The following adverse reactions were also reported, but in very small numbers:

  • iron deficiency
  • diplopia
  • retinopathy

Dosage:

The usual recommended dosage for vorapaxar (Zontivity) is one tablet per day at a strength of 2.08 mg. It may be taken with or without food. However, it must be taken in conjunction with either an aspirin regimen or clopidogrel. The efficacy of this medication has not been studied alone. There are no trials or studies where vorapaxar has been taken without another anticoagulating medication.

For patients with some renal or hepatic impairment, there is no recommended change to dosing levels. If kidney or liver function is severely impaired, use of vorapaxar is contraindicated. For patients with complicating conditions such as diabetes, vorapaxar may still be a part of a successful treatment plan, provided that the risk of severe bleeding can be mitigated. The dosage level would not be altered for these patients.

Neither the safety nor the efficacy of vorapaxar has been tested in children. It is not currently recommended for pediatric care at all.

Major drug interactions:

Vorapaxar interacts negatively with a class of drugs called CYP3A4 inhibitors. CYP3A4 is the common abbreviation for the enzyme Cytochrome P450 3A4. This enzyme is found mostly in the liver and intestine and functions as an oxidizer of toxins and drugs in the body. CYP3A4 inhibitors includes the following medications:

  • ketoconazole
  • irtraconazole
  • clarithromycin
  • posaconazole
  • nefazodone
  • saquinavir
  • ritonavir
  • nelfinavir
  • boceprevir
  • indinavir
  • telaprevir
  • conivaptan
  • telithromycin

This family of drugs are generally used to treat a variety of infections from fungus to HIV/AIDS.

Vorapaxar also interacts negatively with a class of medications called CYP3A4 inducers. These medications include:

  • rifampin
  • phenytoin
  • carbamazepine
  • St. John's Wort (homeopathic)

These medications treat a wide variety of conditions and diseases from depression to seizures and infections.

Vorapaxar should NOT be used in conjunction with other anticoagulant medications such as warfarin as it can lead to serious bleeding issues.

Vorapaxar can also increase bleeding when used concomitantly with fibrinolytics (another family of anticoagulant medications). It is also contraindicated for use with SNRIs (serotonin-norepinephrine reuptake inhibitors - i.e. Effexor, Cymbalta, Pristiq), SSRIs (selective serotonin reuptake inhibitors - i.e. sertraline, fluoxetine, paroxetine, citalopram) and chronic NSAIDS (celecoxib, rofecoxib, naproxen) due to increased risk of bleeding.

Warnings:

Vorapaxar has been clinically demonstrated to increase the risk of serious internal bleeding.

This can take the form of gastrointestinal bleeding (peptic ulcer), intracranial bleeding, or other potentially fatal bleeding situations. Patients who have experience a stroke, transient ischemic attack or intracranial hemorrhage should discontinue use of vorapaxar immediately. Before vorapaxar is prescribed, certain indicators should be considered. These indicators might include low body weight, history of ulcer, compromised kidney function, age of the patient, reduced liver function, any sort of bleeding disorder or other history of issues with an inability to clot. Vorapaxar is not recommended for pregnant or nursing mothers.

It should also be noted that vorapaxar remains in the body for up to 8 days from the last dose. For patients who may need a regular medical treatment, or some other risk factor that may be impacted by the half life of this medication must be taken into consideration before it is prescribed.

Storage:

Vorapaxar is sold under the brand name Zontivity. It is packaged in three different ways. Patients can get it in bottles of 30 tablets, bottle of 90 tablets or in blister packs of 100 tablets (10 cards of 10 tablets). Zontivity tablets are yellow ovals, coated with film. Each tablet has a strength of 2.08 mg.

When the patient is prescribed the tablets in bottles, bottles should be stored at room temperature, between 68-77 degrees Fahrenheit or 20-25 degrees Celsius. Tablets should never be exposed to temperatures approaching freezing. Tablets should remain in the original bottle until taken. It is best to leave the desiccant pack in the bottle to prevent moisture from affecting the tablets' structural integrity and efficacy.

If tablets are supplied in blister packages, the same guidelines would apply. They should be stored at room temperature and kept out of direct light. Tablets should remain in the blister packaging until they are taken.

As with all medications, vorapaxar should be stored safely and securely, out of the reach of children. It should also be disposed of properly according to local health department guidelines or with the help of a healthcare professional. If the seals or packaging is damaged or broken in any way, the patient should not take it.

Summary:

In the fight against heart disease, vorapaxar and the family of protease inhibitor medications have proven to be valuable tools. Vorapaxar is generally not used as an initial preventative medication. It is prescribed to patients who have already suffered some sort of myocardial infarction or other serious cardiac event. It is also indicated for patients that suffer with peripheral arterial disease. It is used in conjunction with an aspirin protocol that works to prevent future thrombotic events. Since its FDA approval in 2014, vorapaxar (Zontivity) has become one of the standard choices for doctors in treating patients that meet these criteria. Vorapaxar has not be studied, nor should it be prescribed, as a stand alone treatment for patients that suffer from myocardial infarction risk or peripheral arterial disease. Its efficacy at preventing subsequent cardiac events and preventing endpoint cardiovascular death has been proven, and where it can be used, it is an effective choice for treatment.

It is not recommended for patients that have experienced specific kinds of stroke (e.g. transient ischemic attack or intracranial hemorrhage)because it does significantly increase the patient's risk for severe bleeding. For this reason, it is not indicated with patients who are at risk for some sort of severe bleeding condition. It does negatively interact with other medications that can also lead to serious bleeding outcomes.

Other than the risk of bleeding, vorapaxar actually has very few side effects, and none are really dangerous. Risk of anemia, depression and rash are relatively low and would not be so significant that the patient would need to discontinue use of the medication.

It interacts poorly with a couple of families of drugs that function in the body at the enzyme level. These include a cluster of medications that inhibit production of the CYP3A4. Counter-intuitively, it also negatively interferes with the group of medicines that induce production of CYP3A4. Patients who have conditions that require medications from these two groups need to select a different form of anticoagulant medication to address their cardiovascular conditions.

Further study would be indicated to determine if vorapaxar has a role in prevention of the development of peripheral arterial disease or in preventing an initial cardiac event. It would also be helpful to study its use alone, without other anticoagulant medications. If the medication could be used by itself, the risk of bleeding may be reduced, but it is not known at this time if vorapaxar would prove effective if prescribed as a sole treatment. Another area of research in the use of vorapaxar would be as a standard of care in pediatric patients who suffer from cardiovascular disease and conditions that require the use of antiplatelet agents. Also, further study of the medication with other antiplatelet therapies, lengths of treatment and dosing levels could help determine if vorapaxar could be useful in treating other cardiovascular conditions.

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Last Reviewed:
December 23, 2017
Last Updated:
December 22, 2017
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