本博士論文集探討了各種心血管疾病治療和預防策略在各個次族群中的有效性和經濟可行性。本研究評估了心血管疾病治療和預防措施的現狀，包括對新藥物和干預的健康技術評估，以及現行指引建議的評估。這些發現為心血管疾病領域的臨床工作者和政策制定者提供了有用的信息，更深入地了解現有和新治療和預防方法的有效性以及對不同次族群的影響。
第2章分析了不同治療和二級預防策略在具有心房顫動或冠狀動脈疾病的不同亞群中的有效性和成本效益。非維生素K抗凝劑（NOAC）常用於預防房顫患者中的中風。第2.1節建立了一個基於臨床隨機對照試驗（RCTs）的馬可夫模型，模擬使用NOAC預防中風的台灣心房顫動患者，與使用傳統的抗凝劑（如華法林）的患者進行比較。隨後，使用國民健康保險數據庫的當地醫療費用和效用數據評估非維生素K抗凝劑在心房顫動患者中的預防中風的經濟可行性。由于不同的非維生素K抗凝劑之間缺乏直接比較，本研究先進行了網絡統合分析以獲得間接有效性比較。經過30年的模型模擬，所有非維生素K抗凝劑的增量成本效益比在每個品質調整生命年介於$4115至$6415之間，遠低於願意支付的閾值（一倍台灣國內人均生產總值）。也就是說，從台灣健康保險健保的角度來看，所有非維生素K抗凝劑都是華法林在心房顫動患者中預防中風的有效替代療法。此外，對於edoxaban 60毫克，rivaroxaban 20和15毫克，apixaban 5毫克和dabigatran 150和110毫克而言，具有最佳成本效益的概率分別為27.4%，27.1%，23.6%和21.9%。第2.2節檢驗了心肌梗死患者中心導管介入治療的成本效益。本研究基於1999年至2015年台灣國民健康保險資料庫，建立了一個長期追蹤的心肌梗塞病人世代，以估計心臟介入治療和醫療治療的預期壽命、壽命損失、多得到壽命和相對的壽命醫療成本。增量成本效益比為為$3,488。此外，在調整年齡後，50-59歲接受心導管介入治療的急性心肌梗死患者被證明是節省終生醫療花費的。
第3章聚焦於心臟衰竭且射血分數減低（HFrEF）的患者。第3.1節探討了ivabradine與急性HFrEF患者不良事件之間的關聯。在1：2傾向分數匹配后，共有876名患者納入最終分析。在一年的追蹤中，ivabradine組患者與沒有使用的相比較，心率顯著較低（77.6 ± 14.7 vs. 81.1 ± 16.3每分鐘下），心臟衰竭嚴重程度也有所降低，與非ivabradine組患者相比。使用ivabradine與心血管死亡（每100人年5.8 個vs. 12.2個）、全因死亡（每100人年7.2 個vs. 14.0個）以及總心臟衰竭再住院（每100人年42.3 vs. 72.6）的風險顯著較低。章節3.2和3.3分析了鈉葡萄糖轉運蛋白-2（SGLT2）抑製劑 （dapagliflozin和empagliflozin）加入心臟衰竭標准治療的成本效益。這兩項經濟評估研究建立了馬可夫模型，以估計加入SGLT2 抑製劑和非 SGLT2 抑製劑治療的終生醫療費用和品質調整生命年。隨後，增量成本效益比被用於評估不同亞太地區國家醫療付費者角度的成本效益。第3.2節表明，在韓國、澳大利亞、台灣、日本和新加坡，與標准治療相比，使用dapagliflozin的增量成本效益比分別為每得到一個品質調整生命年需要$5,277 、$9,980、$12,305、$16,705和$23,227。所有模擬都在低於亞太地區每一個願意付出的閾值（國內生產總值人均），其顯示了成本效益的好處。第3.3節，該模型預測將輔助藥物empagliflozin 加入HFrEF標准治療后的增量成本效益比分別為每獲得一個品質調整生命年需要$20,508，$24,046，$8,846， $53,791，$21,543和$20,982在台灣、日本、南韓、新加坡、泰國、澳大利亞。研究最後指出將empagliflozin加入HFrEF治療在亞太地區是一個有效的成本選擇。
第4章重點關注於高血壓患者。第4.1節利用全國數據庫研究了高血壓患者的流行病學。在2005年至2010年間，65歲及以上個體高血壓的患病率和發病率有明顯差異。在2005年和2010年，最高的共病率是血脂異常。在這兩年中，最常處方的降壓藥物為1或2種。在降壓藥物中，鈣通道阻滯劑是最廣泛處方的，其次是血管張力素轉化酵素抑制劑（angiotensin converting enzyme inhibitor，ACEI）及血管張力素接受器拮抗劑（angiotensinⅡ receptor blocker，ARB）。且三年的追蹤研究表明，2010年心血管疾病和死亡的風險低於2005年。另外，在2022年台灣心血管學會和台灣高血壓學會宣佈了新的高血壓治療準則。高血壓閾值向下調整為130/80mmHg，具有高心血管疾病風險的人應將收縮壓控制在120mmHg以下。第4.2節利用經濟模型模擬了台灣的高血壓患者接受強化血壓管理的情況。新的血壓治療目標的實施將導致終生醫療成本（$31,589與$26,788相比）增加，但相對的品質調整生命年（12.54與 12.25相比）也增加。增量成本效益比則指出每獲得一個品質調整生命年需要花費$ 16,589（NT $497,670），具有99.1%和100%機率的獲得成本效益優勢。這項經濟評估能鼓勵在台灣環境下推廣強化血壓管理。此外，STEP試驗顯示，與傳統治療相比，老年高血壓患者接受強化血壓控制可顯著減少心血管不良事件。 第4.3章採用經濟學模型和多種情景分析，評估在不同情境下，即中國、美國 和英國在老年人強化血壓管理和標准血壓管理的成本效益。模型模擬了10,000名符合STEP試驗資格的患者，平均年齡為66歲，男性參出席者4,650人。每獲得一個品質調整生命年需要的花費分別為中國¥51,675（$16,362），美國$25,417，英國£4,679（$6,801）。結果表明，此血壓治療策略在中國有94.3% （一倍人均）和100% （三倍人均）的情況下是符合成本效益的。在美國則為86.9%和95.6% ( $50,000 /品質調整生命年和$100,000 /品質調整生命年)。英國在£20,000/品質調整生命年和£30,000/品質調整生命年時，符合成本效益概率分別為99.1%和100%。這項經濟評估表明，此血壓加強管理能減少心血管事件數，同時也顯示這些介入措施需要的成本低於公認的願意支付閾值。這研究也指出，在不同的臨床情境和不同國家中，對老年患者進行強化血壓管理的成本效益好處是一致的。
第5.1節，研究評估了患有後天免疫缺乏症候群的人（PLHIV）遵循抗逆轉錄病毒療法（ART）與心血管疾病之間的關聯。在這項研究中，分析了台灣2000年至2011年的國民健康保險研究資料庫，以評估18,071例在被診斷為後天免疫缺乏症候群前沒有心血管疾病的後天免疫缺乏症候群陽性患者的心血管疾病的影響。通過藥物使用率（MPR）來衡量抗逆轉錄病毒療法的遵循度。研究使用廣義估計分析來分析各種心血管疾病的成本影響。結果表明，心血管疾病的發病率從心因性休克的0.17/1000人年到缺血性心臟病的2.60/1000人年。沒有心血管疾病的基線病人的平均年醫療費用估計約為3,000美元。心血管疾病的成本影響是顯著的，腦血管疾病、心肌梗塞、心臟衰竭、心律失常和缺血性心臟病的發病率分別增加了41%、33%、30%、16%和14%的年醫療費用。在抗逆轉錄病毒療法遵循度（MPR≥0.8）高的病人，心血管疾病事件的成本影響顯著低於遵循ART （MPR<0.1）低的病人。 總之，後天免疫缺乏症病毒感染人群中發生的心血管疾病的經濟負擔是巨大的，並且抗逆轉錄病毒療法遵循度影響了醫藥花費。研究發現，更高的遵從度會減少心血管疾病的經濟影響。且根據第5.1節，後天免疫缺乏症候群人們的心血管疾病風險高於普通人群，因此在制定衛生保健計劃時，定期監測和早期檢測是至關重要的。第5.2和5.3節分別以橫斷面和縱向的世代研究方式來評估了斑點追蹤心臟超音波圖（ STE）檢測其心肌損傷的可行性和影響心肌形變量的因素。在第5.2節中，對181名患有後天免疫缺乏症候群的人的功能進行了傳統和斑點追蹤心臟超音波圖評估。參與者分為兩組：那些有使用抗病毒藥物超過3個月以及未滿三個月的。使用回歸分析分析心肌應變與各種危險因素之間的關系。結果表明，左心室形變量在有用使用抗病毒藥物超過三個月經驗的組中較高，而高血壓和高病毒量與心肌形變量減少有關。不同的抗病毒藥物類別在這個研究並沒有被觀察到對形變量有顯著不同影響。該研究也可以看出，斑點追蹤心臟超音波在檢測後天免疫缺乏症候群早期心臟損傷方面非常有用，並強調及時使用抗病毒藥物，控制病毒量和管理高血壓在此類病人對保護心臟健康非常重要。在第5.3節中，該研究對在2年內對無心血管疾病症狀的後天免疫缺乏症候群患者進行了隨訪，收集了傳統心血管疾病危險因素和心臟超音波數據。使用基於群體的軌跡模型，研究分析了心肌形變量的變化，並進行了多項邏輯回歸，以識別不同患者群中的預測因素。總共有181名患者參加了研究並分為三種心肌應變軌跡。各組的基線左心室縱向形變量有顯著不同。與第1組（最佳形變量）相比，第2組（形變量逐漸應變差）與年齡≥ 40歲、抗病毒藥物使用持續時間≥12個月、左心室射出率<70%有關；第3組（最差形變量）則與吸煙、抗病毒藥物使用持續時間≥12 個月、左心室射出率<60%、非整合鏈轉移抑製劑組合的抗病毒藥物有關。這是第一個使用斑點追蹤心臟超音波圖監測後天免疫缺乏症候群患者臨床心肌功能障礙的縱向研究，並突顯了與心肌形變量變化相關的因素，提供了個體預防策略以及早期治療的可能。
近幾十年來，從以數量基礫向價值基礫的支付模式趨勢日益明顯。本博士研究論文評估了各種治療和預防策略在不同亞群中的有效性和成本效益。在患有心房顫動的患者中，非維生素K抗凝劑被證明是預防中風的經濟高效替代品。與醫學治療相比，心導管治療仍然是急性心肌梗死患者的經濟高效治療選擇。Ivabradine在治療心衰竭合併射出率減少患者，可以改善臨床效果。結果表明，在亞太國家，使用鈉葡萄糖轉運蛋白-2抑製劑是治療心衰竭合併射出率減少患者的經濟高效策略。後天免疫缺乏症候群患者的心血管疾病風險更高，更好的抗病毒藥物遵從率可減少經濟負擔。在後天免疫缺乏症候群患者的照護中，可以使用斑點追蹤心臟超音波監測沒症狀的心臟損傷，透過這個分析，從而制定個別差異化的預防或介入策略。以上這些發現不僅僅提供了重要的臨床發現個臨床工作者參考，也協助了醫療政策決策者在不同的次族群制定各種相異的治療或是預防策略。

This PhD thesis explores the effectiveness and financial feasibility of various treatments and prevention strategies for cardiovascular disease (CVD) in various subpopulations. The study evaluates the current state of CVD treatments and prevention measures, and also includes health technology assessment of new medications and interventions, as well as recommendations from current guidelines. The findings provide useful information for healthcare decision-makers and policymakers in the field of CVD, offering a deeper understanding of the impact of CVD on different subpopulations and the effectiveness of existing and new treatments and prevention methods.
In Chapter 2, the effectiveness and cost-effectiveness of different treatment and secondary prevention strategies in different subpopulation with atrial fibrillation (AF) or coronary artery diseases (CAD) were analysed. Non-vitamin K oral anticoagulants (NOAC) are commonly used in the prevention of stroke in patients with atrial fibrillation (SPAF). Chapter 2.1 constructed a Markov model based on the clinical randomized controlled trial (RCTs) to simulated Taiwanese AF patients using NOAC to prevent stroke, comparing to those using traditional oral anticoagulants, e.g., warfarin. Subsequently, the local medical cost and utility data from the national health insurance database were employed to evaluate the economic feasibility of NOAC in SPAF. Due to the lack of head-to-head comparison between the NOACs, this study performed a network meta-analysis to obtain the indirect efficacy comparison in advance. After 30-year simulation, the model projected that the incremental cost-effectiveness ratios (ICERs) of all NOACs are between $4,115 and $6,415 per quality-adjusted life year (QALY), much lower than the willingness-to-pay (WTP) thresholds, i.e., one-time Taiwanese national gross domestic product (GDP). Namely, all NOACs are cost-effective substitute therapy to warfarin in SPAF from Taiwanese national payer’s perspective. Besides, the probability of having the best cost-effectiveness was projected to be 27.4%, 27.1%, 23.6% and 21.9% for edoxaban 60 mg, rivaroxaban 20 and 15 mg, apixaban 5 mg and dabigatran 150 and 110 mg, respectively. Chapter 2.2 examined the cost-effectiveness of the existing procedure, i.e., percutaneous coronary intervention (PCI), in patients with myocardial infarction. This study constructed a longitudinal AMI cohort to estimate life expectancy (LE), loss-of-LE, life-years saved, and lifetime medical costs in PCI and medical therapy, based on the claim database of Taiwan’s National Health Insurance during 1999 and 2015. The ICER was $3,488 per life-year saved. Also, after adjusting age, the patients with acute myocardial infarction aged 50–59 years receiving PCI was shown to be cost-saving.
In Chapter 3, the studies focused on the patients with heart failure and reduced ejection fraction (HFrEF). Chapter 3.1 is a retrospective study examining the association between ivabradine and adverse events in patients with acute decompensation HFrEF between two multicentered cohorts. After 1:2 propensity score matching, a total of 876 patients were included in the final analysis. At the one-year follow-up, the patients who were part of the ivabradine group showed a significantly lower heart rate (77.6 ± 14.7 vs. 81.1 ± 16.3 bpm) and reduced symptoms of heart failure severity, compared to those in the non-ivabradine group. The use of ivabradine was also associated with a significantly lower risk of cardiovascular mortality (5.8 vs. 12.2 per 100-person year), all-cause mortality (7.2 vs. 14.0 per 100-person year), and total heart failure rehospitalization (42.3 vs. 72.6 per 100-person year) compared to non-ivabradine users. Chapters 3.2 and 3.3 examined the cost-effectiveness of sodium-glucose cotransporter-2 (SGLT2) Inhibitors (dapagliflozin and empagliflozin) adding to standard therapy in HFrEF patients. These two economic evaluation studies constructed the Markov model to estimate the lifetime medical costs and QALYs in add-on SGLT2 inhibitor and non-SGLT2 inhibitor therapy. Subsequently, the ICERs were used to assess the cost-effectiveness from the perspective of the national payer in different Asia-Pacific countries. Chapter 3.2 showed that in Korea, Australia, Taiwan, Japan, and Singapore, the ICER was $5,277, $9,980, $12,305, $16,705, and $23,227 per QALY gained respectively, when comparing add-on dapagliflozin to standard care alone. All simulations showed cost-effectiveness at a willingness-to-pay threshold of one gross domestic product per capita in the relevant Asia-Pacific country. In Chapter 3.3, the model projected that the ICER of add-on empagliflozin to standard therapy alone in HFrEF was $20,508, $24,046, $8,846, $53,791, $21,543, and $20,982 per QALY gained in Taiwan, Japan, South Korea, Singapore, Thailand, and Australia,, respectively. The addition of empagliflozin to HFrEF treatment is predicted to be a cost-effective option across the Asia-Pacific region. The cost-effectiveness is impacted by the WTP thresholds of the individual countries.
Chapter 4 focused on patients with hypertension. Chapter 4.1 used nationwide database to investigate the epidemiology of patients with hypertension. Between 2005 and 2010, there was a marked contrast in the trend of hypertension prevalence and incidence among individuals aged 65 and above. The highest rate of co-morbidity observed in both 2005 and 2010 was dyslipidemia. In both years, the most frequently prescribed categories of anti-hypertensive agents were 1 or 2. Among the anti-hypertensive agents, Calcium channel blockers emerged as the most widely prescribed, followed by angiotensin converting enzyme inhibitors/angiotensin receptor blockers. A three-year follow-up study in Taiwan revealed that in 2010, the risks of CVD and death were lower compared to 2005. In 2022, Taiwan Society of Cardiology and Taiwan Society of Hypertension announced the new recommendations of hypertension managements. The hypertension threshold became 130/80mmHg, and those with high CVD risks should control the systolic blood pressure below 120mmHg. Chapter 4.2 used the economic model to simulate the hypertensive Taiwanese receiving intensive blood-pressure managements. The implementation of a new blood-pressure treatment target resulted in increased lifetime medical costs ($31,589 compared to $26,788) and increased QALYs (12.54 compared to 12.25). The ICER was determined to be $16,589 (NT$497,670) per QALY gained, with a 99.1% and 100% probability of the treatment strategy being very cost-effective and cost-effective, respectively. This economic evaluation may encourage the promotion of intensive blood-pressure managements in Taiwan setting. Moreover, the STEP trial showed a significant reduction of cardiovascular adverse events for older hypertensive patients receiving intensive blood-pressure control, compared to those with traditional treatments. Chapter 4.3 employed the economic model and multiple scenario analyses to evaluate the cost-effectiveness of intensive versus standard blood-pressure managements in different setting, i.e., China, the U.S., and the U.K. A simulation of 10,000 patients eligible for STEP trial was performed, with a mean age of 66 years and 4,650 male participants. The ICER values per QALY gained were estimated to be ¥51,675 ($16,362) in China, $25,417 in the U.S., and£4,679 ($6,801) in the U.K. The results indicated that intensive management in China was cost-effective in 94.3% and 100% of cases when compared to the willing-to-pay thresholds of one-time and three-time GDP per capita. The probabilities of cost-effectiveness in the U.S. were 86.9% and 95.6% at $50,000/QALY and $100,000/QALY, respectively. Meanwhile, the U.K. had a cost-effectiveness probability of 99.1% and 100% at £20,000/QALY and £30,000/QALY, respectively. This economic evaluation showed that such intervention resulted in a reduction in the number of cardiovascular events, while also demonstrating acceptable costs per QALY gained. These costs were well below the commonly accepted willing-to-pay thresholds. The cost-effectiveness of intensive blood pressure management in older patients was found to be consistent across various clinical scenarios and different countries.
In Chapter 5.1, the study assessed the association between CVD and adherence to antiretroviral therapy (ART) among people living with HIV (PLHIV). In this study, the National Health Insurance Research Database of Taiwan from the years 2000 to 2011 was analyzed to evaluate the impact of CVDs in 18,071 HIV-positive patients who were free of CVDs prior to their diagnosis with HIV. The level of ART adherence was measured through the use of the medication possession ratio (MPR). A generalized estimating equations analysis was performed to estimate the cost impact of various CVDs. The results indicated that the incidence of CVDs ranged from 0.17/1000 person-years for cardiogenic shock to 2.60/1000 person-years for ischemic heart diseases. The average annual medical cost for a base-case patient without CVDs was estimated to be $3000. The cost impact of CVDs was significant, with the incidence of cerebrovascular diseases, myocardial infarction, heart failure, arrhythmia, and ischemic heart diseases increasing annual costs by 41%, 33%, 30%, 16%, and 14%, respectively. The cost impact of incident CVDs in years with high adherence to ART (MPR ≥ 0.8) was found to be significantly lower compared to years with low adherence (MPR < 0.1). Conclusively, the economic burden of incident CVDs in the HIV-infected population was substantial and varied based on the extent of ART use. The study found that a greater adherence to ART led to a reduced economic impact of CVDs. Based on Chapter 5.1, PLHIV’s CVD risks are higher than general population and regular monitor and early detection becomes crucial when making the healthcare plans. Chapters 5.2 and 5.3 cross-sectionally and longitudinally evaluated the feasibility of speckle-tracking echocardiogragm (STE) in detecting subclinical myocardial damage and the factors influencing the myoicardial stain among PLHIV. In Chapter 5.2, 181 people living with HIV (PLHIV) were evaluated for heart function using conventional and strain echocardiogram methods. The participants were divided into two groups: those who were experienced with ART and those who were not. Regression analysis was used to analyze the relationship between myocardial strain and various risk factors. The results showed that left ventricular strain was higher in the ART-experienced group, while hypertension and high viral loads were associated with reduced myocardial strain. ART classes were not found to impact strain changes. The study concluded that STE is useful in detecting early heart impairment in PLHIV, and emphasized the importance of timely ART, virus control, and hypertension management in preserving heart health. In Chapter 5.3, this study followed up asymptomatic PLHIV without CVDs for 2 years, collecting data on traditional CVD risk factors and echocardiographic parameters. Using a group-based trajectory model, the study analyzed myocardial strain changes and performed multinomial logistic regression to identify predictors in different patient groups. A total of 181 patients were recruited and categorized into three myocardial strain trajectories. The baseline LVGLS of the groups differed significantly. Comparing to the Group 1 (the best strain), the gradual strain decline (Group 2) was associated with age ≥ 40, ART duration ≥ 12 months, and LVEF < 70%, and the worst strain (Group 3) was linked to smoking, ART duration ≥ 12 months, LVEF < 60%, and ART regimens with non-integrase strand transfer inhibitors. This is the first longitudinal study to use STE to monitor subclinical myocardial dysfunction in PLHIV, and highlights key factors associated with myocardial strain changes, enabling individualized preventative strategies and early interventions.
In conclusion, there has been a growing trend in recent decades towards a shift in the payment model from quantity-based to value-based. This PhD thesis evaluates the effectiveness and cost-effectiveness of various treatment and prevention strategies in different subpopulations. NOACs were found to be a cost-effective alternative to warfarin in patients with SPAF. PCI remained a cost-effective treatment option for patients with acute myocardial infarction when compared to medical therapy. Ivabradine was associated with improved clinical outcomes for patients with HFrEF. The use of add-on SGLT2 inhibitors was determined to be a cost-effective strategy for treating HFrEF across Asia-Pacific countries. PLHIV have a higher risk of CVD, and better adherence to ART leads to a lower economic burden. STE can be utilized to monitor subclinical heart injury in the management of PLHIV, allowing for the development of individualized prevention or intervention strategies. These findings provide important clinical and economic outcomes that can be used by healthcare providers and policymakers in various situations and subpopulations.

Chapter 1 Introduction
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Chapter 2.2 Cost-effectiveness of percutaneous coronary intervention versus medical therapy in patients with acute myocardial infarction: real-world and lifetime-horizon data from Taiwan
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Chapter 3.1 The association between ivabradine and adverse cardiovascular events in acute decompensated HFrEF patients
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Chapter 3.2 Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region
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Chapter 3.3 Cost-effectiveness evaluation of add-on empagliflozin in patients with heart failure and a reduced ejection fraction from the healthcare system's perspective in the Asia-Pacific region
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Chapter 4.1 Higher hypertension prevalence, lower incidence, and aggressive treatment with decreasing mortality, cardiovascular and cerebrovascular incidence in Taiwan from 2005 to 2010: a two population-based cohorts study
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Chapter 4.2 Economic evaluation of new blood pressure target for hypertensive patients in Taiwan. according to the 2022 hypertension clinical practice guidelines of the Taiwan society of cardiology: a simulation modeling study
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Chapter 4.3 Cost-effectiveness of intensive vs standard blood pressure control among patients with hypertension
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Chapter 5.1 Association of adherence to antiretroviral therapy with economic burden of cardiovascular disease in HIV-infected population
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Chapter 5.2 Assessment of subclinical cardiac dysfunction by speckle tracking echocardiography among people living with HIV
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Chapter 5.3 Group-based trajectory modelling to identify patterns of myocardial strain and its predictors in people living with HIV: two-years longitudinal follow-up with speckle tracking echocardiogram
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