Introduction
Valsartan belongs to the group of angiotensin receptor antagonists (ARBs), which are one of the first-line medications for the treatment of hypertension (HT). (1,2) In Europe, valsartan was first approved in 1996 for the treatment of HT in adults. Since then, indications for valsartan have been extended to also include heart failure (HF) and post-myocardial infarction (MI) in order to reduce cardiovascular mortality. Valsartan’s efficacy in lowering blood pressure (BP) and good tolerability across broad patient populations have been demonstrated in numerous clinical studies that included over 100,000 patients. Moreover, valsartan has also been shown to possess effects beyond BP control that positively influence cardiovascular, cerebrovascular, renal, and metabolic outcomes. (1)
Krka’s valsartan story began more than 15 years ago when we offered Slovenian physicians a monoform version of the medication. Since then, Krka’s valsartan portfolio has grown and now includes five medications: monoform (Valsacor®) and four single-pill combinations (SPCs) with a diuretic and/or a calcium channel blocker and a statin (Valsacombi® – valsartan/hydrochlorothiazide (HCTZ), Wamlox® – amlodipine/valsartan; Valtricom® – amlodipine/valsartan/HCTZ; and Valarox® – rosuvastatin/valsartan); these medications are available in 19 different strengths and can be used in all grades of HT and in patients with different needs. (3-5) Krka’s valsartan medications are recognized for their high quality, award-winning innovations, and extensive international clinical evidence, which all contribute to the trust of millions of patients with HT, making Krka the current leading producer of valsartan-based products in Europe (Central, Eastern, and South-Eastern Europe). (4)
High quality ensuring continuous availability for patients
Krka’s vertically integrated production model allows the company to have complete oversight of the whole production process from the active ingredient to the finished product, resulting in high-quality products. In 2011, Krka’s valsartan obtained the Certificate of Suitability issued by the European Directorate for the Quality of Medicines (EDQM), which is the highest quality standard in Europe, confirming that its active substance meets European pharmaceutical standards. (6,7)
In recent years, several producers of sartan products (containing valsartan, losartan, and irbesartan) in Europe had to withdraw their products from the markets due to nitrosamine impurities. Following a review by the European Medicines Agency (EMA), EMA set limits on maximum nitrosamine impurity levels in sartan-containing products with a goal of achieving no quantifiable impurities. (8) In 2021, new information about potentially mutagenic azido impurities in certain sartan-containing products emerged. Consequently, EDQM ordered producers to take appropriate actions to ensure that the level of azido impurities is below threshold levels. (9,10)
Krka’s valsartan products were not affected by these recalls, since we scientifically evaluated the synthesis routes for all active sartan substances. The results have shown that there are no conditions for the formation of any nitrosamine impurities. We have implemented all necessary measures and conducted rigorous testing to prove no quantifiable levels of nitrosamine or azido impurities are to be found in its valsartan products. As a result, our valsartans have been continuously available for many years and have remained in the markets without restriction. (6,11)
Award-winning innovations demonstrate high quality
Krka’s valsartan products received two awards for innovation from the Slovenian Chamber of Commerce and Industry. In 2020, they received an award in the category of best innovation.
The gold award was received for a substitute medicine with a triple combination that contains three active substances in one tablet (amlodipine, valsartan, and hydrochlorothiazide). This triple combination enables a more convenient form of therapy for patients, thereby improving BP treatment control; this patent-independent active substance also allows us to have the highest quality standards.
The improved production process of valsartan’s active ingredient received a silver award. The process of synthesis of the active substance has been optimized at different technological stages, especially through an innovative approach at the laboratory stage. This enabled not only increased production capacity but also improved quality of the active substance, relatively higher process yield, and reduction of hazardous solvent waste.
Both awards have an environmentally friendly component, as they also evaluated reduction of the negative impact on the environment due to the optimization of organic solvent regeneration. (12,13)
Extensive international clinical evidence
The effectiveness and safety of Krka’s valsartan products have been clinically demonstrated, both in strict, controlled environments, which are characteristic of clinical trials, and in real-clinical practice (more than 15 years of clinical experience). They were assessed in two main clinical trials – VICTORY and VICTORY II. These two trials included almost 500 patients and demonstrated that valsartan therapies were effective and safe in patients with all grades of HT. After 16 weeks of treatment, 9 out of 10 patients achieved target BP (<140/90 mmHg). At the same time, therapy was well-tolerated by more than 90% of patients. Valsartan products were also shown to have beneficial effects beyond BP control as they improved vessel function, erectile function, quality of life, and kidney function while being metabolically neutral. (14-17) The results of the VICTORY clinical trial were presented at the 26th Meeting of the European Society of Hypertension (ESH 2016). (18)
The VICTORY trial was performed to assess the efficacy and safety of valsartan monoform (Valsacor®) and SPC of valsartan and HCTZ (Valsacombi®) in patients with mild to moderate HT. A total of 365 patients were enrolled in this 16-week, international, multicenter, open-label, prospective trial. The patients started treatment with 80 mg valsartan daily, which could be up-titrated to 320 mg daily or combined with HCTZ as an SPC to achieve target BP. The results showed that valsartan and the SPC of valsartan and HCTZ effectively reduced BP and had a very good tolerability profile. During the trial, the mean systolic BP (SBP) and diastolic BP (DBP) steadily decreased. The mean absolute decreases of SBP and DBP were 26.60 ± 10.41 mmHg and 14.84 ± 7.57 mmHg, respectively, while the mean relative decreases of SBP and DBP were 16.8 ± 6.1% and 15.2 ± 7.3%. The decrease in mean SBP and DBP between two consecutive visits was statistically significant in every case (p<0.0001) (Figure 1). A very good therapeutic effect (BP below 140/90 mmHg or below 140/85 mmHg for high-risk and diabetic patients) was observed in 91% of the patients. (14,15)
Furthermore, based on a statistically significant decrease of pulse wave velocity (PWV) (Figure 2), both medications helped improve and reduce aortic stiffness. The trial results also showed that patients with HT treated with valsartan and SPC of valsartan/HCTZ had improved quality of life, including erectile function in men. (14,16)
The VICTORY II trial was performed to assess the efficacy and safety of SPCs of amlodipine/valsartan and amlodipine/valsartan/HCTZ in achieving target BP in newly-diagnosed or uncontrolled patients with grade 2 or 3 hypertension. A total of 100 patients were enrolled in this 16-week multicenter, open-label, prospective trial. Patients with grade 2 hypertension started treatment with an SPC of amlodipine/valsartan 5 mg/80 mg, and patients with grade 3 hypertension started with an SPC of amlodipine/valsartan 5 mg/160 mg; both could be up-titrated step-by-step to the SPC of amlodipine/valsartan/HCTZ 10 mg/160 mg/12.5 mg to achieve target BP. After 16 weeks of therapy, target office BP was achieved in 90% of the patients (Figure 3), with good tolerability. Additionally, both treatments also decreased albuminuria (in 58.8% of patients) and central aortic pressure (at least a 5% reduction in 73% of patients), improved vessel elasticity (speed of PWV was improved in 66.7% of patients), and showed a positive effect on the vascular endothelial function, erectile function in men, and quality of life. (17,19-21)
Additionally, further studies demonstrated the benefits of Valsacor® in patients with HF and in patients with HT hospitalized for acute MI, and the benefits of Valsacor® and Valsacombi® in hypertensive patients with an impaired left ventricular diastolic function. (22)
Conclusion
Today, Krka’s valsartans are highly trusted among physicians, pharmacists, and patients with HT, but trust in our valsartans was not built overnight. It is the result of a more than 15 year long process of ensuring high quality and continuous presence in the markets, providing clinical evidence through both highly-controlled clinical trials for the entire valsartan family and real-clinical practice, and receiving awards for innovations. As a result, Krka’s valsartans are now registered in more than 50 markets worldwide, with four million patients being treated every day. In addition, two out of three European patients who take valsartan receive Krka´s valsartan. (4,23)