A Phase 4 interventional study of Dose adjustment of statins and no dose adjustment in Dyslipidemia, Hypercholesterolemia, Hypertriglyceridemia, Stroke (CVA) or TIA and Cardio Vascular Disease, sponsored by Rehman Medical Institute - RMI. Not yet recruiting at 1 site in Pakistan. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2026-11-02.
Sponsored by Rehman Medical Institute - RMI · Phase 4, Interventional, and Treatment
To compare the efficacy of fixed-dose versus treat-to-target statin regimens in achieving the predefined LDL-C target at 12 weeks in patients with established ASCVD.
To compare the frequency of adverse effects of statin therapy between patients receiving a fixed-dose regimen and those managed with a treat-to-target approach.
Effectiveness and Tolerability of a Treat-to-Target Versus Fixed-Dose Statin Strategy in Patients with Atherosclerotic Cardiovascular Disease: A Randomized Controlled Trial
Introduction
Between 2019 to 2023, ischemic heart disease and cerebrovascular disease ranked as the first and fifth leading causes of death respectively in the United States, (1) with a similar trend in Pakistan as well, despite its developing status. (2) These diseases are atherosclerotic cardiovascular disease (ASCVD), in which atherosclerosis is driven primarily by low-density lipoprotein cholesterol (LDL-C). (3) As ASCVD development depends on cholesterol accumulation, treatment centers on reducing serum cholesterol through dietary modification, lifestyle changes, and medication.
For ASCVD, statins remain the cornerstone of preventing and treating major adverse cardiovascular or cerebrovascular events (MACCE), including acute coronary syndrome, myocardial ischemia, and stroke. Lipid-lowering therapy is initiated based on a comprehensive cardiovascular risk assessment, with intensity stratified according to the fixed-dose statin regimen. Very high-risk patients or those who have experienced a MACCE are promptly started on moderate-to-high intensity statin therapy to achieve an LDL-C target of \< 55 mg/dL and those at primary risk are advised to achieve a target level of \< 70 mg/dL. (4,5).
Unfortunately, statins cause muscle-related adverse effects, i.e. statin-associated muscle symptoms (SAMS), myalgias, myopathies with elevated creatine kinase (CK) levels, rhabdomyolysis; and hepatotoxicity (6), limiting tolerability. Literature reports a SAMS prevalence between 10% to 33%, being the major reason for therapy discontinuation. (7,8) Asian studies report higher rates, (9) with a single center study in Lahore reporting 51%. (10) Genomic studies corroborate this, showing Southeast Asians carrying the AA genotype of SLCO1B1 have increased risk of statin-induced myopathy. (11,12) In low- and middle-income countries (LMICs) such as Pakistan, where financial already hinder treatment, such adverse effects discourage patients, as shown by a national level study reporting self-discontinuation rates up to 60.6%. (13,14)
Given the above, there is a growing shift towards a treat-to-target approach, advocating for individualized statin dosing. The landmark LODESTAR trial demonstrated the non-inferiority of the treat-to-target strategy compared to standard care over a period of three years. (15,16) Statin doses were titrated based on each patient's achieved LDL-C levels to reach predefined goals, rather than relying on fixed-dose regimens. This personalized strategy could optimize both the efficacy and adherence to statin treatment by limiting side-effects. (15) Limited but promising evidence shows low-intensity statin therapy achieved target LDL-C levels reduction in small South Asian cohorts with cardiovascular disease and cerebrovascular disease. (17,18); however, high-quality comparative evidence validating a treat-to-target approach with ASCVD is notably lacking.
Given these pharmacogenetic differences in a South Asian population, a strategy based on the maximally tolerated statin dose, rather than uniform fixed-dosing therapy, may afford equivalent ischemic protection while enhancing drug tolerability and persistence. This study intends to explore the effectiveness of tailored statin therapy, with the overarching goal being to demonstrate that such dosing not only curtails side effects but also translates into superior adherence, sustained LDL-C goal attainment, and ultimately, more favorable outcomes.
Objectives
To compare the efficacy of fixed-dose versus treat-to-target statin regimens in achieving the predefined LDL-C target at 12 weeks in patients with established ASCVD.
To compare the frequency of adverse effects of statin therapy between patients receiving a fixed-dose regimen and those managed with a treat-to-target approach.
Primary Outcomes
Achievement of LDL-C Target Levels. The proportion of patients with elevated LDL-C who achieve the treatment goal of LDL-C levels \< 55 mg/dL (high risk) and \< 70 mg/dL (low risk) at 4 and 12 weeks of therapy. (4,19)
Secondary Outcomes
Treatment Tolerability and Adverse Effects. At each follow-up assessment, there will be an evaluation SAMS for frequency and severity, per the SRM classification, as well as hepatic function, as indicated by ALT levels at the 4 and 12 week follow up. A rise in ALT times above the upper limit of normal is considered significant for statin-induced liver injury. (20-22)
Materials and Methods
The study will be started after receiving approval from the Institutional Review Board, conducted at Rehman Medical Institute, Peshawar. It will be a randomized, parallel-group, open label, controlled trial designed to compare the efficacy and adverse effects experienced by patients in a fixed-dose regimen versus a treat-to-target approach in managing dyslipidemia.
Patients will be enrolled from the Medicine and Allied clinics who meet specific inclusion criteria: i) adults aged between 18 to 80 years requiring primary prevention or those with history of at least 1 episode of ASCVD, ii) who are either statin-naïve or already on statins but not at target LDL-C levels and are eligible for dose adjustment. Patients will be excluded if they i) have already achieved target LDL-C levels on a high-dose statin and tolerate it well, ii) have contraindications to statin therapy such as active liver disease or severe renal impairment (eGFR \< 30 mL/min/1.73m²), iii) have known hypersensitivity or a prior life-threatening reaction to any statin, iv) are pregnant or lactating, or v) are using other lipid-lowering agents like ezetimibe, PCSK9 inhibitors, fibrates, or bile acid sequestrants.
A structured, proforma will be used to collect demographic data, medical history, concurrent medications, and baseline lipid profile results. Potential participants will be identified from the outpatient Medicine and Allied clinics, as well as from inpatient wards upon discharge. For the interventional phase, eligible patients will be randomized 1:1 to receive a statin using either a targeted strategy of titrated-intensity statin therapy (treat-to-target) or a strategy of high-intensity statin therapy. Computerized permuted block randomization will be used to allocate patients. Patients will be stratified by whether they require primary or secondary prevention and then by baseline LDL-C levels of 100 mg/dL. In addition, each group of patients will be secondarily randomized 1:1 to receive 1 of 2 statins, rosuvastatin or atorvastatin (once daily).
The intensity of statin treatment was divided into high or moderate intensity according to the 2026 American College of Cardiology/American Heart Association guideline for the treatment of blood cholesterol. Patients will be treated with rosuvastatin 10 mg or atorvastatin 20 mg for moderate-intensity statin therapy and rosuvastatin 20 mg or atorvastatin 40 mg for high-intensity statin therapy. In the treat-to-target group, the target LDL-C level chosen was the lowest recommended LDL-C level for our population in the latest guidelines at the time of trial design (March 2026), which was below 70 mg/dL, and statin intensity was titrated as follows. For statin-naive patients, moderate-intensity statin therapy will be initiated. For those already taking a statin, an equivalent intensity will be maintained when the LDL-C level at randomization was below 70 mg/dL, and the intensity will be uptitrated when the LDL-C level was 70 mg/dL or greater. During follow-up in the treat-to-target group, uptitration for those with an LDL-C level of 70 mg/dL or greater, maintenance of the same intensity for those with an LDL-C level of 50 mg/dL or greater to less than 70 mg/dL, and downtitration for those with an LDL-C level less than 50 mg/dL will be performed. In the high-intensity statin group, maintenance of high-intensity statin therapy was recommended without adjustment regardless of follow-up LDL-C levels during the study period. However, given adherence, tolerance, and clinical situations of individual patients, up- or downtitration of statin intensity not following the study protocol may have been exceptionally allowed in both groups at the physician's discretion, but those changes will require a detailed report of reasons. Nonstatin add-on therapy, such as ezetimibe, will not be strongly recommended in the treat-to-target group, even when the target was not achieved with high-intensity statin therapy, to focus on the strategy for choosing statin intensity and avoid confounding by any imbalance in their use. For other medical treatments, guideline-directed medical therapy was strongly recommended, and it was also allowed to be changed by a personal physician, except for the change in statin intensity. Risk factor modification, including blood pressure or glucose control, dietary changes, weight reduction, exercise, and smoking cessation, will be encouraged.
Clinical and laboratory findings were assessed at baseline, and all patients were scheduled for follow-up visits at 4 weeks and 12 weeks. General health status, use of drugs, and the occurrence of clinical end points or adverse events will be assessed at baseline and each follow-up visit. Serial follow-up of lipid profiles, including total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglyceride levels, was performed at 4 and 12 weeks. When the dose or type of study medication was changed during follow-up, patients were recommended to present for a laboratory test within 4 to 6 weeks in both groups. Secondary outcomes will be to record the presence, severity, and duration of any SAMS and hepatotoxicity. To monitor adverse effects related to statin therapy, alanine aminotransferase and creatine kinase levels will be assessed at 4 and 12 weeks. Medication adherence will be tracked via pill counts and self-reporting. To maximize retention and minimize loss to follow-up, participants who miss a visit will receive a reminder phone call within 72 hours to reschedule.
Data collection will occur at baseline (enrollment) and at scheduled follow-up visits at 4 and 12 weeks. (4,23)
All adverse events will be documented and reported to the principal investigator and the ERB within 24 hours if serious, and managed according to standard clinical protocols, including dose reduction or discontinuation if clinically indicated.
The sample size was estimated based on a similar Iranian study that compared the outcomes of different fixed-dose statins (25) using the following parameters: an expected mean difference of 10.9% between 2 regimens, a pooled standard deviation of approximately 24.48 (derived from moderate and high SDs of 23.5 and 25.5, respectively), a two-sided alpha of 0.05, and 80% power with a 1:1 allocation ratio. Applying the standard formula for two independent groups yielded 79 participants per arm. To account for an anticipated 10% attrition rate, this was adjusted to 89 per group. Thus, the final recommended sample size is 178 total participants, with 89 participants per treatment arm. The sample size estimation was performed based on the primary objective of comparing the treat-to-target strategy with the high-intensity strategy, not for comparing different statin types.
Data will be analyzed using SPSS version 27. Frequencies and percentages will be calculated for categorical variables, while mean±SD will be calculated for continuous variables. The primary analysis will follow the intention-to-treat principle. The proportion achieving the LDL-C target at 12 weeks will be compared between two groups. P value and 95% CI will be calculated. P \< 0.05 will be taken statistically significant. The between-group difference in percentage LDL-C reduction will be assessed using an appropriate regression model adjusted for baseline LDL-C. Adverse effects, adherence and treatment discontinuation will be compared using appropriate categorical or continuous-data tests. A per-protocol analysis will be performed as a sensitivity analysis. Missing outcome data will be handled according to a predefined missing-data strategy.
Ethical considerations
Prior to any study procedures, detailed verbal and written explanation of the study in Pashto and Urdu will be provided to all eligible patients. Written informed consent will be obtained from each participant voluntarily, with explicit assurance of their right to withdraw at any time without affecting their standard medical care. Data will be collected and dealt with as per RMI ERB guidelines.
REFERENCES
1,106 studies on the registry are indexed under Dyslipidemias; 166 are open to participants now.
This study's planned enrollment of 178 is above the median of 100 across 865 interventional studies indexed under Dyslipidemias.
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Exclusion Criteria:
rosuvastatin 10 mg or atorvastatin 20 mg ( to be adjusted as per response of patinet)
Drug: Dose adjustment of statins
fixed dose atorvastatin or rosuvastatin
Drug: no dose adjustment
dose will be titrated as per patient's LDL on follow-up. It is not routinely done
no drug dose adjustment will be done in this group
Achievement of LDL-C Target Levels.
The proportion of patients with elevated LDL-C who achieve the treatment goal of LDL-C levels \< 55 mg/dL (high risk) and \< 70 mg/dL (low risk) at 4 and 12 weeks of therapy.
Time frame: 12 weeks
Treatment Tolerability and Adverse Effects
At each follow-up assessment, there will be an evaluation SAMS for frequency and severity, per the SRM classification, as well as hepatic function, as indicated by ALT levels at the 4 and 12 week follow up. A rise in ALT times above the upper limit of normal is considered significant for statin-induced liver injury.
Time frame: 12 weeks
Plan to share: Undecided
Start is estimated for Nov 2026; primary completion for Jun 2027, 7 months later.
Of 40 phase 4 interventional studies under Dyslipidemias, half reached primary completion within 27 months of starting (the median), counting those still running; a quarter within 19 and three quarters within 35. This study's planned 7 months is below that.
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Rehman Medical Institute - RMI