3. Updated testosterone risk profile
Testosterone therapy has long been flagged with warnings about increased cardiovascular risk, including heart attacks and strokes. However, these concerns stemmed largely from early observational studies and case reports, not randomized controlled trials.
The pivotal TRAVERSE trial enrolled over 5,000 men aged 45 to 80 with existing or high risk of cardiovascular disease. It showed no increase in major adverse cardiac events among men receiving testosterone compared to placebo—7.0% versus 7.3%, respectively. Additionally, no increase in prostate cancer was observed.
As a result, the FDA removed the boxed warning about cardiovascular risk from testosterone products in early 2025, replacing it with updated labeling that includes the TRAVERSE trial results and a new warning about modest increases in blood pressure. This marks a significant change in the risk profile and supports testosterone’s continued use when clinically indicated.
Important: Patients should never stop prescribed testosterone or any hormone therapy without consulting their healthcare provider, as abrupt discontinuation can carry its own risks.
4. NSAIDs and cardiovascular risk
Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used for pain and inflammation, carry a well-documented increased risk of cardiovascular events such as heart attacks and strokes. This risk is distinct from the venous clots associated with estrogen-containing medications; NSAIDs primarily increase arterial thrombosis risk.
The risk varies across different NSAIDs:
- Diclofenac has a cardiovascular risk profile similar to rofecoxib (Vioxx), a drug withdrawn from the market due to heart risks. Diclofenac remains widely available, but its use warrants caution, especially in people with cardiovascular disease.
- Naproxen is considered the safest NSAID regarding cardiovascular risk and is often recommended for patients with heart disease requiring anti-inflammatory therapy.
- Ibuprofen has an intermediate risk that increases with higher doses and prolonged use.
Key points about NSAID cardiovascular risk include:
- Risk can develop within weeks of starting NSAIDs, not only after long-term use.
- NSAIDs may reduce the effectiveness of blood pressure medications by causing fluid retention and raising blood pressure.
- The combination of an NSAID, an ACE inhibitor, and a diuretic (the “triple whammy”) significantly increases the risk of acute kidney injury.
An effective risk reduction strategy is using topical NSAID gels, which deliver the drug locally with minimal systemic absorption and therefore a much lower cardiovascular risk. Diclofenac gel is a commonly available topical option and may be preferable for older adults with arthritis and cardiovascular risk factors.
5. Progestin types and clotting
Not all combined oral contraceptives carry the same clot risk; the type of progestin paired with estrogen influences this risk significantly.
Second-generation progestins like levonorgestrel are associated with the lowest risk of venous thromboembolism among combined pills. Newer progestins such as desogestrel, gestodene, and drospirenone carry approximately 1.5 to 2 times the clot risk compared to levonorgestrel-based pills.
The estrogen dose also matters: lower-dose estrogen formulations reduce clot risk relative to higher-dose pills.
Importantly, progestin-only contraceptives—such as the mini-pill and hormonal intrauterine devices (IUDs)—do not increase clot risk. They lack estrogen, do not stimulate liver clotting factors, and provide highly effective contraception without this risk mechanism.
Therefore, switching to a progestin-only method is a viable option for women with elevated clot risk who cannot safely use estrogen-containing contraceptives.
